Neuroprotection by the soy isoflavone, genistein, via inhibition of mitochondria-dependent apoptosis pathways and reactive oxygen induced-NF-?B activation in a cerebral ischemia mouse model

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Yisong Qian, Teng Guan, Menghao Huang, Liangxun Cao, Yunman Li, Hao Cheng, Hangxia Jin, Deyue Yu

Recently, the treatment of stroke has focused on antioxidant therapies, where oxidative stress is implicated. The preventive and therapeutic potential of plant compounds on ischemic stroke has been intensively studied because many of them contain antioxidant properties. Genistein, one of the active ingredients in soybean, possesses many bioactivities. In this study, we investigated the potential neuroprotective effects of genistein and its possible mechanism of action in a cerebral ischemia mouse model. Mice were pretreated with genistein (2.5, 5, and 10mg/kg) or vehicle orally once daily for 14 consecutive days before transient middle cerebral artery occlusion was performed. Genistein at doses of 2.5–10mg/kg significantly reduced the infarct volume, improved the neurological deficit and prevented cell apoptosis after ischemia. In addition, genistein pretreatment was shown to inhibit the ischemia-induced reactive oxygen species (ROS) production, enhance the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), and decrease levels of malondialdehyde (MDA) in stroke mice. Moreover, genistein reversed the mitochondria dysfunction after ischemia, as evidenced by decreasing mitochondria ROS levels, preventing cytochrome C release to the cytoplasm and inhibiting caspase-3 activation. Western blotting showed ischemia activated the ROS-dependent nuclear factor-?B (NF-?B) signaling pathway, and genistein suppressed phosphorylation and activation of the NF-?B p65 subunit, as well as the phosphorylation and degradation of the inhibitor protein of ?B? (I?B?). Our findings suggested that genistein has a neuroprotective effect in transient focal ischemia, which may involve regulation of mitochondria-dependent apoptosis pathways and suppression of ROS-induced NF-?B activation.

Highlights

Posted on 28 May 2012 | 1:02 pm

Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: Role of glutamine redefined

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 7

Paul Desjardins, Ting Du, Wenlei Jiang, Liang Peng, Roger F. Butterworth

Acute liver failure (ALF) is characterized neuropathologically by cytotoxic brain edema and biochemically by increased brain ammonia and its detoxification product, glutamine. The osmotic actions of increased glutamine synthesis in astrocytes are considered to be causally related to brain edema and its complications (intracranial hypertension, brain herniation) in ALF. However studies using multinuclear ¹H- and ¹³C-NMR spectroscopy demonstrate that neither brain glutamine concentrations per se nor brain glutamine synthesis rates correlate with encephalopathy grade or the presence of brain edema in ALF. An alternative mechanism is now proposed whereby the newly synthesized glutamine is trapped within the astrocyte as a consequence of down-regulation of its high affinity glutamine transporter SNAT5 in ALF. Restricted transfer out of the cell rather than increased synthesis within the cell could potentially explain the cell swelling/brain edema in ALF. Moreover, the restricted transfer of glutamine from the astrocyte to the adjacent glutamatergic nerve terminal (where glutamine serves as immediate precursor for the releasable/transmitter pool of glutamate) could result in decreased excitatory transmission and excessive neuroinhibition that is characteristic of encephalopathy in ALF. Paradoxically, in spite of renewed interest in arterial ammonia as a predictor of raised intracranial pressure and brain herniation in ALF, ammonia-lowering agents aimed at reduction of ammonia production in the gut have so far been shown to be of limited value in the prevention of these cerebral consequences. Mild hypothermia, shown to prevent brain edema and intracranial hypertension in both experimental and human ALF, does so independent of effects on brain glutamine synthesis; whether or not hypothermia restores expression levels of SNAT5 in ALF awaits further studies. While inhibitors of brain glutamine synthesis such as methionine sulfoximine, have been proposed for the prevention of brain edema in ALF, potential adverse effects have so far limited their applicability.

Highlights

Posted on 28 May 2012 | 1:02 pm

Eriodictyol protects against H2O2-induced neuron-like PC12 cell death through activation of Nrf2/ARE signaling pathway

Publication year: 2012
Source:Neurochemistry International

Haiyan Lou, Xu Jing, Dongmei Ren, Xinbing Wei, Xiumei Zhang

Eriodictyol, a flavonoid isolated from the Chinese herb Dracocephalum rupestre has long been established as an antioxidant. The present study was designed to explore the protective effects of eriodictyol against hydrogen peroxide (H2O2)-induced neurotoxicity with cultured rat pheochromocytoma cells (PC12 cells) and the possible mechanisms involved. For this purpose, differentiated PC12 cells were cultured and exposed to 200?M H2O2 in the absence or presence of eriodictyol (20, 40 and 80?M). In addition, the potential contribution of the Nrf2/ARE neuroprotective pathway in eriodictyol-mediated protection against H2O2-induced neurotoxicity was also investigated. The results showed that H2O2-induced cell death can be inhibited in the presence of eriodictyol as measured by assays for MTT and apoptosis. Further study revealed that eriodictyol induced the nuclear translocation of Nrf2, enhanced the expression of heme oxygenase (HO-1) and ?-glutamylcysteine synthetase (?-GCS), and increased the levels of intracellular glutathione. Treatment of PC12 cells with Nrf2 small interference RNA abolished eriodictyol-induced HO-1 and ?-GCS expression and its protective effects. In conclusion, these results suggest that eriodictyol upregulates HO-1 and ?-GCS expression through the activation of Nrf2/ARE pathway and protects PC12 cells against H2O2-induced oxidative stress.

Highlights

Posted on 28 May 2012 | 1:02 pm

Blood–brain barrier in acute liver failure

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 7

Justin H. Nguyen

Brain edema remains a challenging obstacle in the management of acute liver failure (ALF). Cytotoxic mechanisms associated with brain edema have been well recognized, but evidence for vasogenic mechanisms in the pathogenesis of brain edema in ALF has been lacking. Recent reports have not only shown a role of matrix metalloproteinase-9 in the pathogenesis of brain edema in experimental ALF but have also found significant alterations in the tight junction elements including occludin and claudin-5, suggesting a vasogenic injury in the blood–brain barrier (BBB) integrity. This article reviews and explores the role of the paracellular tight junction proteins in the increased selective BBB permeability that leads to brain edema in ALF.

Highlights

Posted on 28 May 2012 | 1:02 pm

Effect of Angeli’s salt on the glutamate/glutamine cycle activity and on glutamate excitotoxicity in the hamster retina

Publication year: 2012
Source:Neurochemistry International, Volume 61, Issue 1

María Elena Knott, Damián Dorfman, Mónica S. Chianelli, Daniel A. Sáenz

Glutamate is the main excitatory neurotransmitter in the retina, but it is toxic when present in excessive amounts. It is well known that NO is involved in glutamate excitotoxicity, but information regarding the possibility that NO-related species could reciprocally affect glutamate synaptic levels was not previously provided. The dependence of glutamatergic neurons upon glia via the glutamate/glutamine cycle to provide the precursor for neurotransmitter glutamate is well established. The aim of the present work was to comparatively analyze the effect of nitroxyl and NO on the retinal glutamate/glutamine cycle in vitro activity. For this purpose, Angeli’s salt (AS) and diethylamine NONOate (DEA/NO) were used as nitroxyl and NO donor, respectively. AS and DEA/NO significantly decreased retinal l-glutamate uptake and glutamine synthetase activity, but only AS decreased l-glutamine influx. Dithiothreitol prevented all the effects of AS and DEA/NO. The intravitreal injection of DEA/NO (but not AS) or a supraphysiological concentration of glutamate induced retinal histological alterations. Although AS could increase glutamate synaptic concentration in vitro, the histological alterations induced by glutamate were abrogated by AS. These results suggest that nitroxyl could regulate the hamster retinal glutamatergic pathway by acting through differential mechanisms at pre- and postsynaptic level.

Highlights

Posted on 28 May 2012 | 1:02 pm

Alterations in NADPH oxidase expression and blood–brain barrier in bile duct ligation-treated young rats: Effects of melatonin

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Yu-Chieh Chen, Jiunn-Ming Sheen, You-Lin Tain, Chih-Cheng Chen, Miao-Meng Tiao, Ying-Hsien Huang, Chih-Sung Hsieh, Li-Tung Huang

Bile duct ligation (BDL)-treated rats exhibit cholestasis and increased systemic and brain oxidative stress. Activation of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase and disruption of the blood–brain barrier (BBB) are implicated as the pathogenetic mechanisms of brain dysfunction in BDL-treated adult rats. Young rats underwent sham ligation or BDL at day 17 for 2 or 4weeks. Treatment group rats were administered melatonin between day 17 and 45. We found a progressive increase in prefrontal cortex NADPH-dependent superoxide anion (${\text{O}}_2^{-}$) production and increased expression of NADPH oxidase subunits in either the prefrontal cortex or the hippocampus in BDL-treated young rats. In addition, expression of intercellular adhesion molecule-1 (ICAM) and tissue plasminogen activator (t-PA) genes were increased in either the prefrontal cortex or the hippocampus. Prefrontal cortex capillary junctional complex proteins expressions including occludin, claudin-5, platelet endothelial cell adhesion molecule-1 and vascular endothelial cadherin were not altered. Melatonin lowered the prefrontal cortex NADPH-dependent ${\text{O}}_2^{-}$ production and t-PA gene expression. We conclude that alterations in NADPH oxidase expression and BBB are involved in brain dysfunction in BDL-treated young rats. In addition, melatonin regulates NADPH oxidase activity and t-PA gene expression.

Highlights

Posted on 28 May 2012 | 1:02 pm

The Role of amino acid transporters in gsh synthesis in the blood-brain barrier and central nervous system

Publication year: 2012
Source:Neurochemistry International

Cesar Valdovinos-Flores, María E. Gonsebatt

Glutathione (GSH) plays a critical role in protecting cells from oxidative stress and xenobiotics, as well as maintaining the thiol redox state, most notably in the central nervous system (CNS). GSH concentration and synthesis are highly regulated within the CNS and are limited by availability of the sulfhydryl amino acid (AA) L-cys, which is mainly transported from the blood, through the blood-brain barrier (BBB), and into neurons. Several antiporter transport systems (e.g., xc ^-, x^- AG, and L) with clearly different luminal and abluminal distribution, Na⁺, and pH dependency have been described in brain endothelial cells (BEC) of the BBB, as well as in neurons, astrocytes, microglia and oligodendrocytes from different brain structures. The purpose of this review is to summarize information regarding the different AA transport systems for L-cys and its oxidized form L-cys2 in the CNS, such as expression and activity in blood-brain barrier endothelial cells, astrocytes and neurons and environmental factors that modulate transport kinetics.

Highlights

Posted on 28 May 2012 | 1:02 pm

Neuropathology of acute liver failure

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 7

Kiran K. Thumburu, Sunil Taneja, Rakesh K. Vasishta, Radha K. Dhiman

Cerebral edema has been identified in all forms of liver disease and is closely related to the development of hepatic encephalopathy. Cerebral edema is most readily recognized in acute liver failure (ALF), while the main cause of death in patients with ALF is multi-organ failure; brain herniation as a result of intracranial hypertension does remain a major cause of mortality. The mechanisms responsible for cerebral edema in ALF suggest both cytotoxic and vasogenic injury. This article reviews the gross and ultrastructural changes associated with cerebral edema in ALF. The primary cause of cerebral edema is associated with astrocyte swelling, mainly perivascular edema and ammonia still remains the primary neurotoxin involved in its pathogenesis. The astrocytic changes were confined to the gray matter. The other organelles involved in the pathogenesis of ALF include mitochondria, basement membrane, pericytes, microglial cells, blood–brain barrier (BBB) etc. Discrete neuronal changes have recently been reported. Recent studies in animal and humans have demonstrated the microglial changes which have the potential to cause neuronal dysfunction in ALF. The alterations in BBB still remain unclear though few studies have showed disruption of tight junction proteins indicating the involvement of BBB in cellular swelling.

Highlights

Posted on 28 May 2012 | 1:02 pm

Hydrogen sulfide prevents formaldehyde-induced neurotoxicity to PC12 cells by attenuation of mitochondrial dysfunction and pro-apoptotic potential

Publication year: 2012
Source:Neurochemistry International, Volume 61, Issue 1

Xiao-Qing Tang, Yan-Kai Ren, Cheng-Fang Zhou, Chun-Tao Yang, Hong-Feng Gu, Jian-Qin He, Rong-Qian Chen, Yuan-Yuan Zhuang, Heng-Rong Fang, Chun-Yan Wang

Hydrogen sulfide (H2S) has been shown to act as a neuroprotectant and antioxidant. Numerous studies have demonstrated that exposure to formaldehyde (FA) causes neuronal damage and that oxidative stress is one of the most critical effects of FA exposure. Accumulation of FA is involved in the pathogenesis of Alzheimer’s disease (AD). The aim of present study is to explore the inhibitory effects of H2S on FA-induced cytotoxicity and apoptosis and the molecular mechanisms underlying in PC12 cells. We show that sodium hydrosulfide (NaHS), a H2S donor, protects PC12 cells against FA-mediated cytotoxicity and apoptosis and that NaHS preserves the function of mitochondria by preventing FA-induced loss of mitochondrial membrane potential and release of cytochrome c in PC12 cells. Furthermore, NaHS blocks FA-exerted accumulation of intracellular reactive oxygen species (ROS), down-regulation of Bcl-2 expression, and up-regulation of Bax expression. These results indicate that H2S protects neuronal cells against neurotoxicity of FA by preserving mitochondrial function through attenuation of ROS accumulation, up-regulation of Bcl-2 level, and down-regulation of Bax expression. Our study suggests a promising future of H2S-based preventions and therapies for neuronal damage after FA exposure.

Highlights

Posted on 28 May 2012 | 1:02 pm

Tributyltin induces oxidative stress and neuronal injury by inhibiting glutathione S-transferase in rat organotypic hippocampal slice cultures

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Yasuhiro Ishihara, Tomohito Kawami, Atsuhiko Ishida, Takeshi Yamazaki

Tributyltin (TBT) has been used as a heat stabilizer, agricultural pesticide and antifouling agents on ships, boats and fish-farming nets; however, the neurotoxicity of TBT has recently become a concern. TBT is suggested to stimulate the generation of reactive oxygen species (ROS) inside cells. The aim of this study was to determine the mechanism of neuronal oxidative injury induced by TBT using rat organotypic hippocampal slice cultures. The treatment of rat hippocampal slices with TBT induced ROS production, lipid peroxidation and cell death. Pretreatment with antioxidants such as superoxide dismutase, catalase or trolox, suppressed the above phenomena induced by TBT, indicating that TBT elicits oxidative stress in hippocampal slices, which causes neuronal cell death. TBT dose-dependently inhibited glutathione S-transferase (GST), but not glutathione peroxidase or glutathione reductase in the cytosol of rat hippocampus. The treatment of hippocampal slices with TBT decreased the GST activity. Pretreatment with reduced glutathione attenuated the reduction of GST activity and cell death induced by TBT, indicating that the decrease in GST activity by TBT is involved in hippocampal cell death. When hippocampal slices were treated with sulforaphane, the expression and activity of GST were increased. Notably, TBT-induced oxidative stress and cell death were significantly suppressed by pretreatment with sulforaphane. These results indicate that GST inhibition could contribute, at least in part, to the neuronal cell death induced by TBT in hippocampal slices. This study is the first report to show the link between neuronal oxidative injury and the GST inhibition elicited by TBT.

Highlights

Posted on 28 May 2012 | 1:02 pm

Brain energy metabolism and mitochondrial dysfunction in acute and chronic hepatic encephalopathy

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 7

Kakulavarapu V. Rama Rao, Michael D. Norenberg

One proposed mechanism for acute and chronic hepatic encephalopathy (HE) is a disturbance in cerebral energy metabolism. It also reviews the current status of this mechanism in both acute and chronic HE, as well as in other hyperammonemic disorders. It also reviews abnormalities in glycolysis, lactate metabolism, citric acid cycle, and oxidative phosphorylation as well as associated energy impairment. Additionally, the role of mitochondrial permeability transition (mPT), a recently established factor in the pathogenesis of HE and hyperammonemia, is emphasized. Energy failure appears to be an important pathogenetic component of both acute and chronic HE and a potential target for therapy.

Highlights

Posted on 28 May 2012 | 1:02 pm

Alteration of serotonin system by polychlorinated biphenyls exposure

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Jordi Boix, Omar Cauli

Although commercial production of polychlorinated biphenyls (PCBs) was banned in 1979, PCBs continue to be an environmental and health concern due to their high bioaccumulation and slow degradation rates. In fact, PCBs are still present in our food supply (fish, meat, and dairy products). In laboratory animals, exposure to single PCB congener or to mixtures of different congeners induces a variety of physiological alterations. PCBs cross the placenta and even exposure at low level is harmful for the foetus by leading to neurodevelopment alterations. Serotonin system which regulates many physiological functions from platelet activation to high cerebral processes and neurodevelopment is one of the targets of PCBs toxicity. The effects of PCBs exposure on serotonin system have been investigated although to a lesser extent compared to its effect in other neurotransmitter systems. This review provides a summary of the results concerning the impact of PCBs exposure (in vitro and in vivo) on serotonin system. Further research is needed to correlate specific deficits with PCB-induced changes in the serotonin system.

Highlights

Posted on 28 May 2012 | 1:02 pm

Effect of glutamate and riluzole on manganese-induced apoptotic cell signaling in neuronally differentiated mouse P19 Cells

Publication year: 2012
Source:Neurochemistry International, Volume 61, Issue 1

Jerome A. Roth, Swetha Sridhar, Steven T. Singleton

Excess exposure to Mn causes a neurological disorder known as manganism which is similar to dystonic movements associated with Parkinson’s disease. Manganism is largely restricted to occupations in which high atmospheric levels are prevalent which include Mn miners, welders and those employed in the ferroalloy processing or related industrial settings. T1 weighted MRI images reveal that Mn is deposited to the greatest extent in the globus pallidus, an area of the brain that is presumed to be responsible for the major CNS associated symptoms. Neurons within the globus pallidus receive glutamatergic input from the subthalamic nuclei which has been suggested to be involved in the toxic actions of Mn. The neurotoxic actions of Mn and glutamate are similar in that they both affect calcium accumulation in the mitochondria leading to apoptotic cell death. In this paper, we demonstrate that the combination of Mn and glutamate potentiates toxicity of neuronally differentiated P19 cells over that observed with either agent alone. Apoptotic signals ROS, caspase 3 and JNK were increased in an additive fashion when the two neurotoxins were combined. The anti-glutamatergic drug, riluzole, was shown to attenuate these apoptotic signals and prevent P19 cell death. Results of this study confirm, for the first time, that Mn toxicity is potentiated in the presence of glutamate and that riluzole is an effective antioxidant which protects against both Mn and glutamate toxicity.

Highlights

Posted on 28 May 2012 | 1:02 pm

Brain edema and encephalopathy in acute liver failure: a primary neurogliopathy?

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 7

Roger F. Butterworth

Posted on 28 May 2012 | 1:02 pm

Tianma modulates proteins with various neuro-regenerative modalities in differentiated human neuronal SH-SY5Y cells

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Umamaheswari Ramachandran, Arulmani Manavalan, Husvinee Sundaramurthi, Siu Kwan Sze, Zhi Wei Feng, Jiang-Miao Hu, Klaus Heese

Tianma (Rhizoma gastrodiae) is the dried rhizome of the plant Gastrodia elata Blume (Orchidaceae family). As a medicinal herb in traditional Chinese medicine (TCM) its functions are to control convulsions, pain, headache, dizziness, vertigo, seizure, epilepsy and others. In addition, tianma is frequently used for the treatment of neurodegenerative disorders though the mechanism of action is widely unknown. Accordingly, this study was designed to examine the effects of tianma on the proteome metabolism in differentiated human neuronal SH-SY5Y cells to explore its specific effects on neuronal signaling pathways. Using an iTRAQ (isobaric tags for relative and absolute quantitation)-based proteomics research approach, we identified 2390 modulated proteins, out of which 406 were found to be altered by tianma in differentiated human neuronal SH-SY5Y cells. Based on the observed data, we hypothesize that tianma promotes neuro-regenerative signaling cascades by controlling chaperone/proteasomal degradation pathways (e.g. CALR, FKBP3/4, HSP70/90) and mobilizing neuro-protective genes (such as AIP5) as well as modulating other proteins (RTN1/4, NCAM, PACSIN2, and PDLIM1/5) with various regenerative modalities and capacities related to neuro-synaptic plasticity.

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Posted on 28 May 2012 | 1:02 pm

The neurological manifestations of acute liver failure

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 7

Debbie L. Shawcross, Julia A. Wendon

Acute liver failure is a disorder which impacts on multiple organ systems and results from hepatocellular necrosis in a patient with no previous history of chronic liver disease. It typically culminates in the development of liver dysfunction, coagulopathy and encephalopathy, and is associated with high mortality in poor prognostic groups. In acute liver failure, some patients may develop cerebral edema and increased intracranial pressure although recent data suggest that intracranial hypertension is less frequent than previously described, complicating 29% of acute cases who have proceeded to grade 3/4 coma. Neurological manifestations are primarily underpinned by the development of brain edema. The onset of encephalopathy can be rapid and dramatic with the development of asterixis, delirium, hyperreflexia, clonus, seizures, extensor posturing and coma. Ammonia plays a definitive role in the development of cytotoxic brain edema. Patients with acute liver failure have a marked propensity to develop renal insufficiency and hence impaired ammonia excretion. The incidence of both bacterial and fungal infection occurs in approximately one third of patients. The relationship between inflammation, as opposed to infection, and progression of encephalopathy is similar to that observed in chronic liver disease. Intracranial pressure monitoring is valuable in identifying surges in intracranial hypertension requiring intervention. Insertion of an intracranial bolt should be considered only in the subgroup of patients who have progressed to grade 4 coma. Risk factors for developing intracranial hypertension are those with hyperacute and acute etiologies, progression to grade 3/4 hepatic encephalopathy, those who develop pupillary abnormalities (dilated pupils, sluggishly responsive to light) or seizures, have systemic inflammation, an arterial ammonia >150?mol/L, hyponatremia, and those in receipt of vasopressor support. Strategies employed in patients with established encephalopathy (grade 3/4) aim to maintain freedom from infection/inflammatory milieu, provide adequate sedation, and correct hypo-osmolality.

Highlights

Posted on 28 May 2012 | 1:02 pm

Bcl-2 increases stroke-induced striatal neurogenesis in adult brains by inhibiting BMP-4 function via activation of ?-catenin signaling

Publication year: 2012
Source:Neurochemistry International, Volume 61, Issue 1

Zhi-Nian Lei, Fang Liu, Lin-Mei Zhang, Ya-Lin Huang, Feng-Yan Sun

Our previous experiments suggest that treatment with Bcl-2 increases proliferation and differentiation of neuronal progenitors induced by ischemic injury and ameliorates neurological functional deficits after stroke. However, in addition to its traditional anti-apoptotic effect, little is known about the concrete molecular modulation mechanism. In this study, Bcl-2-expressing plasmids were injected into the lateral ventricle of rat brains immediately following a 30-min occlusion of the middle cerebral artery to determine the role of Bcl-2 in adult neurogenesis. Bcl-2 overexpression reduced ischemic infarct and astrogenesis, and enhanced ischemia-induced striatal neurogenesis. We further found that Bcl-2 increased ?-catenin, a key mediator of canonical Wnt/?-catenin signaling pathway, and reduced bone morphogenetic proteins-4 (BMP-4) expression in the ipsilateral striatum following ischemia. Treatment of stroke with ?-catenin siRNA (i.c.v.) showed that ?-catenin siRNA antagonized Bcl-2 neuroprotection against ischemic brain injury. More interestingly, ?-catenin siRNA simultaneously abolished Bcl-2-mediated reduction of BMP-4 expression and enhancement of neurogenesis in the ipsilateral striatum. This effect is independent of Noggin, the known BMP antagonist. These findings highlight a new regulatory mechanism that Bcl-2 elevates ischemia-induced striatal neurogenesis by down-regulating expression of BMP-4 via activation of the Wnt/?-catenin signaling pathway in adult rat brains.

Highlights

Posted on 28 May 2012 | 1:02 pm

Calmidazolium selectively inhibits exocytotic glutamate release evoked by P2X7 receptor activation

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Chiara Cervetto, Maria Chiara Mazzotta, Daniela Frattaroli, Susanna Alloisio, Mario Nobile, Guido Maura, Manuela Marcoli

We previously observed that activation of presynaptic P2X7 receptors located on rat cerebrocortical nerve terminals induced the release of glutamate through different modes: the channel conformation allowing Ca²⁺ entry triggered exocytotic release, while the receptor itself functioned as a permeation pathway for the non-exocytotic glutamate release. Considering that exocytotic and non-exocytotic glutamate release evoked by the activation of P2X7 receptors might play a role in the control of glutamatergic synapses, we investigated whether calmidazolium (which has been found to inhibit small cation currents through recombinant P2X7 receptors, but not organic molecule permeation) could distinguish between P2X7-related exocytotic and non-exocytotic modes of glutamate release. We found that calmidazolium inhibited the intrasynaptosomal Ca²⁺ response to P2X7 receptor activation and the Ca²⁺-dependent exocytotic glutamate release from rat cerebrocortical nerve terminals, but was ineffective against the Ca²⁺-independent glutamate release. The P2X7 competitive antagonist A-438079 eliminated both exocytotic and non-exocytotic P2X7 receptor-evoked glutamate release. Selective inhibition of exocytotic glutamate release indicates that calmidazolium inhibits events dependent on the function of native rat P2X7 receptors as Ca²⁺ channels, and suggests that it can be used as a tool to dissociate P2X7-evoked exocytotic from non-exocytotic glutamate release.

Posted on 28 May 2012 | 1:02 pm

Electroacupuncture inhibits CB1 upregulation induced by ethanol withdrawal in mice

Publication year: 2012
Source:Neurochemistry International

João Carlos Escosteguy-Neto, Paula Fallopa, Patrícia Varela, Renato Filev, Angela Tabosa, Jair Guilherme Santos-Junior

CB1R play a role in alcohol withdrawal and in some effects of acupuncture. Interestingly, acupuncture has been used to alleviate alcohol withdrawal. Here, we investigated electroacupuncture (EA) effects during ethanol withdrawal on CB1R immunoreactivity. Male Swiss mice were daily injected with ethanol (2g/kg, i.p) (EtOH group), for 21days. EA was performed daily during 4days of ethanol withdrawal. The stimuli of 2 or 100Hz were provided in two acupoints combination: Ea1 [(ST-36/Zusanli) and (PC-6/Neiguan)] or Ea2 [(DU-14/Dazhui) and (DU-20/Baihui)]. The specificity of the acupoints were assessed by the inclusion of three additional groups, Ea3 [(ST 25/Tianshu – acupoints used to other non-related disorders)], Sham1 and Sham2 (transdermic stimulation nearly to the respective acupoints). EtOH group were only handled during withdrawal and Saline group was chronically treated with Saline and handled similarly to EtOH group. One day after withdrawal the animals were perfused and their brains processed for immunohistochemistry. There was an increase of CB1R in the prefrontal cortex, striatum, hippocampus, amygdala and ventral tegmental area. The procedures used in the 2HzEa1 and 100HzEa2 groups were the most effective and specific to inhibit this CB1R upregulation. Therefore, EA inhibits CB1R upregulation seen in ethanol withdrawn mice. The specificity of acupoints stimulation depends of the encephalic nuclei, acupoints association and frequency of stimulation.

Highlights

Posted on 28 May 2012 | 1:02 pm

Fluazinam targets mitochondrial complex I to induce reactive oxygen species-dependent cytotoxicity in SH-SY5Y cells

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Jeong Eun Lee, Jin Sun Kang, Yeo-Woon Ki, Jae Hyeon Park, In Chul Shin, Hyun Chul Koh

Although the underlying cause of Parkinson’s disease (PD) is not well characterized, epidemiological studies suggest that exposure to agricultural chemicals is a risk factor for PD. Fluazinam (FZN) is a new active ingredient for the control of grey mould, belonging to the novel broad spectrum phenylpyridinamine fungicides. We used human neuroblastoma SH-SY5Y cells to investigate mechanisms of dopaminergic cell death in response to FZN. FZN treatment produced dose-dependent cytotoxicity, and decreased the tyrosine hydroxylase (TH) expression in SH-SY5Y cells. We provided evidence for the occurrence of oxidative stress and oxidative damage during FZN exposure on dopaminergic cells through the measurement of reactive oxygen species (ROS) in cells with DCFH-DA. The cytotoxic effects of FZN appear to involve an increase in ROS generation since pretreatment with N-acetyl cysteine (NAC), an anti-oxidant, reduced cell death. After FZN treatment, dopamine (DA) levels decreased in both cell and culture media, and oxidative effects of FZN were blocked by NAC pretreatment. We show that cell death in response to FZN was due to apoptosis since FZN exposure results in an increased in cytochrome c release into the cytosol and activated caspase-3 through p38 and JNK signaling. Furthermore, the blocking of p38 or JNK signaling inhibits FZN-induced cell death. Phosphorylation of mitogen-activated protein kinases precedes cytochrome c release and caspase-3 activation. This cellular response is characteristic of mitochondrial dysfunction. Therefore, we also investigated the effect of FZN on mitochondrial complex I activity in FZN-treated cell. Interestingly, we show that FZN inhibited the complex I activity. Thus in this study, we report a new mode of action by which the fungicide FZN could triggers apoptosis.

Highlights

Posted on 28 May 2012 | 1:02 pm

The expression of NR2B subunit of NMDA receptor in the suprachiasmatic nucleus of Wistar rats and its role in glutamate-induced CREB and ERK1/2 phosphorylation

Publication year: 2012
Source:Neurochemistry International, Volume 61, Issue 1

Zde?ka Bendová, Martin Sládek, Irena Svobodová

Most behavioral and physiological processes in living organisms exhibit periodic circadian rhythmicity. In mammals, these rhythms are coordinated by the circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. In order to precisely synchronize free-running circadian oscillations to the 24h solar cycle, signals from the external environment, primarily the light/dark cycle, must reach the circadian clock within the SCN. A light pulse elevates intracellular Ca²⁺ levels, and activates signaling cascades, leading to transcriptional activation of the clock genes mPer1 and mPer2 via phosphorylation of extracellular-signal-regulated kinases 1/2 (ERK1/2) and cyclic AMP-responsive element binding protein (CREB). Glutamate is the primary excitatory transmitter in retinal terminals in the SCN, and NMDA receptors (NMDAR) are the principal glutamate receptors that mediate the effect of light on resetting the circadian clock. Here we show the circadian rhythm in mRNA expression and protein level of the NMDAR 2B subunit (NR2B) in the SCN, with a peak at night. Also, we demonstrate ifenprodil inhibition of glutamate-induced phosphorylation of CREB (pCREB) and ERK1/2 (pERK1/2), and support thus the evidence for NR2B role in activation of signaling cascade involved in photic resetting of the circadian clock.

Posted on 28 May 2012 | 1:02 pm

Reprint of: Neuroimaging in acute liver failure

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 7

Laia Chavarria, Juli Alonso, Alex Rovira, Juan Córdoba

Acute liver failure (ALF) is frequently complicated by the development of brain edema that can lead to intracranial hypertension and severe brain injury. Neuroimaging techniques allow a none-invasive assessment of brain tissue and cerebral hemodynamics by means of transcranial Doppler ultrasonography, magnetic resonance and nuclear imaging with radioligands. These methods have been very helpful to unravel the pathogenesis of this process and have been applied to patients and experimental models. They allow monitoring the outcome of patients with ALF and neurological manifestations. The increase in brain water can be detected by observing changes in brain volume and disturbances in diffusion weighted imaging. Neurometabolic changes are detected by magnetic resonance spectroscopy, which provides a pattern of abnormalities characterized by an increase in glutamine and a decrease in myo-inositol. Disturbances in cerebral blood flow are depicted by SPECT or PET and can be monitored and the bedside by assessing the characteristics of the waveform provided by transcranial Doppler ultrasonography. Neuroimaging methods, which are rapidly evolving, will undoubtedly lead to future diagnostic and therapeutic progress that could be very helpful for patients with ALF.

Highlights

Posted on 28 May 2012 | 1:02 pm

Exenatide prevents high-glucose-induced damage of retinal ganglion cells through a mitochondrial mechanism

Publication year: 2012
Source:Neurochemistry International, Volume 61, Issue 1

Ming Hao, Hong-Yu Kuang, Zheng Fu, Xin-Yuan Gao, Yu Liu, Wei Deng

Exenatide (exendin-4 analogue) is widely used in clinics and shows a neuroprotective effect. The main objectives of the present study were to prove that retinal ganglion cells (RGC-5) express GLP-1R, to ascertain whether exenatide prevents a high-glucose-induced RGC-5 impairment, to determine the appropriate concentration of exenatide to protect RGC-5 cells, and to explore the neuroprotective mechanisms of exenatide. Immunofluorescence and Western blot analyses demonstrated that RGC-5 cells express GLP-1R. We incubated RGC-5 cells with 25mM glucose prior to incubation with either 25mM glucose, 55mM glucose (high), high glucose plus exenatide or high glucose plus a GLP-1R antagonist. The survival rates of the cells were measured by CCK-8, and cellular injury was detected by electron microscopy. There were statistical differences between the high-glucose group and the control group (P <0.05). Exenatide improved the survival rate of the cells and suppressed changes in the mitochondrial morphology. The optimum concentration of exenatide to protect the RGC-5 cells from high-glucose-induced RGC injury was 0.5?g/ml, and this protective effect could be inhibited by exendin (9–39). To further study the mechanism underlying the beneficial effects of exenatide, the expression levels of cytochrome c, Bcl-2, Bax and caspase-3 were analysed by Western blot. The present study showed that treatment with exenatide significantly inhibited cytochrome c release and decreased the intracellular expression levels of Bax and caspase-3, whereas Bcl-2 was increased (P <0.05). These results suggested that GLP-1R activation can inhibit the cellular damage that is induced by high glucose. A mitochondrial mechanism might play a key role in the protective effect of exenatide on the RGC-5 cells, and exenatide might be beneficial for patients with diabetic retinopathy.

Highlights

Posted on 28 May 2012 | 1:02 pm

Effects of amphetamine on dopamine release in the rat nucleus accumbens shell region depend on cannabinoid CB1 receptor activation

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

J. Kleijn, J. Wiskerke, T.I.F.H. Cremers, A.N.M. Schoffelmeer, B.H.C. Westerink, T. Pattij

The psychostimulant drug amphetamine is often prescribed to treat Attention-Deficit/Hyperactivity Disorder. The behavioral effects of the psychostimulant drug amphetamine depend on its ability to increase monoamine neurotransmission in brain regions such as the nucleus accumbens (NAC) and medial prefrontal cortex (mPFC). Recent behavioral data suggest that the endocannabinoid system also plays a role in this respect. Here we investigated the role of cannabinoid CB1 receptor activity in amphetamine-induced monoamine release in the NAC and/or mPFC of rats using in vivo microdialysis. Results show that systemic administration of a low, clinically relevant dose of amphetamine (0.5mg/kg) robustly increased dopamine and norepinephrine release (to ?175–350% of baseline values) in the NAC shell and core subregions as well as the ventral and dorsal parts of the mPFC, while moderately enhancing extracellular serotonin levels (to ?135% of baseline value) in the NAC core only. Although systemic administration of the CB1 receptor antagonist SR141716A (0–3mg/kg) alone did not affect monoamine release, it dose-dependently abolished amphetamine-induced dopamine release specifically in the NAC shell. SR141716A did not affect amphetamine-induced norepinephrine or serotonin release in any of the brain regions investigated. Thus, the effects of acute CB1 receptor blockade on amphetamine-induced monoamine transmission were restricted to dopamine, and more specifically to mesolimbic dopamine projections into the NAC shell. This brain region- and monoamine-selective role of CB1 receptors is suggested to subserve the behavioral effects of amphetamine.

Highlights

Posted on 28 May 2012 | 1:02 pm

Reduced brain levels of DHEAS in hepatic coma patients: Significance for increased GABAergic tone in hepatic encephalopathy

Publication year: 2012
Source:Neurochemistry International, Volume 61, Issue 1

Samir Ahboucha, Giuseppe Talani, Tomas Fanutza, Enrico Sanna, Giovanni Biggio, Halima Gamrani, Roger F. Butterworth

Increased neurosteroids with allosteric modulatory activity on GABAA receptors such as 3?–5? tertrahydroprogesterone; allopregnanolone (ALLO), are candidates to explain the phenomenon of “increased GABAergic tone” in hepatic encephalopathy (HE). However, it is not known how changes of other GABAA receptor modulators such as dehydroepiandrosterone sulfate (DHEAS) contribute to altered GABAergic tone in HE. Concentrations of DHEAS were measured by radioimmunoassay in frontal cortex samples obtained at autopsy from 11 cirrhotic patients who died in hepatic coma and from an equal number of controls matched for age, gender, and autopsy delay intervals free from hepatic or neurological diseases. To assess whether reduced brain DHEAS contributes to increased GABAergic tone, in vitro patch clamp recordings in rat prefrontal cortex neurons were performed. A significant reduction of DHEAS (5.81±0.88ng/g tissue) compared to control values (9.70±0.79ng/g, p <0.01) was found. Brain levels of DHEAS in patients with liver disease who died without HE (11.43±1.74ng/g tissue), and in a patient who died in uremic coma (12.56ng/g tissue) were within the control range. Increasing ALLO enhances GABAergic tonic currents concentration-dependently, but increasing DHEAS reduces these currents. High concentrations of DHEAS (50?M) reduce GABAergic tonic currents in the presence of ALLO, whereas reduced concentrations of DHEAS (1?M) further stimulate these currents. These findings demonstrate that decreased concentrations of DHEAS together with increased brain concentrations of ALLO increase GABAergic tonic currents synergistically; suggesting that reduced brain DHEAS could further increase GABAergic tone in human HE.

Highlights

Posted on 28 May 2012 | 1:02 pm

Neuroprotective and anticonvulsant effects of organic and conventional purple grape juices on seizures in Wistar rats induced by pentylenetetrazole

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Adriana Dalpicolli Rodrigues, Thamiris Becker Scheffel, Gustavo Scola, Maitê Telles dos Santos, Bruna Fank, Suzana Cesa Vieira de Freitas, Caroline Dani, Regina Vanderlinde, João Antonio Pegas Henriques, Adriana Simon Coitinho, Mirian Salvador

Epilepsy is the most common neurological disorder worldwide. Studies have shown that recurrent seizures may increase the concentration of reactive oxygen species, which can lead to oxidative stress and neuronal damage. These seizures result in substantial deleterious effects on an individual’s health. Organic and conventional grape juices are rich in polyphenols, compounds with important antioxidant activity. However, these juices could have differences in their polyphenol content. The aim of this study was to investigate the neuroprotective and anticonvulsant effects of organic and conventional grape juice treatments in Wistar rats against pentylenetetrazole (a convulsant drug)-induced damage. In addition, we evaluated potential behavioral changes in rats treated with the juices and the polyphenolic profile of those samples. Animals (n =16 in each group) received treatment with saline, organic or conventional grape juice for 17days. On the eighteenth day, behavioral changes were evaluated by an open field test. Afterwards, half of the rats from each group received pentylenetetrazole and were observed for 30min to evaluate possible seizure characteristics. The animals were subsequently killed by decapitation and their hippocampus, cerebellum and cerebral cortex tissues were isolated. The results of this study showed that neither organic nor conventional grape juice altered the behavior parameters, and no statistical differences were observed in the seizure characteristics of the groups. Nevertheless, both juice types were able to protect from lipid and protein oxidative damage, decrease nitric oxide content and increase enzymatic (superoxide dismutase and catalase) and non-enzymatic (sulfhydryl protein) antioxidant defenses in brain tissues following pentylenetetrazole-induced seizures. In general, organic juice showed superior results in each test, probably due to its higher polyphenol content relative to conventional juice. These results indicate that grape juices can provide further insight into natural neuroprotective compounds and may lead to the development of new therapeutic strategies for epileptic patients.

Highlights

Posted on 28 May 2012 | 1:02 pm

GABAergic neurosteroids: The “endogenous benzodiazepines” of acute liver failure

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 7

Samir Ahboucha, Halima Gamrani, Glen Baker

Acute liver failure (ALF) or fulminant hepatic failure represents a serious life-threatening condition. ALF is characterized by a significant liver injury that leads to a rapid onset of hepatic encephalopathy (HE). In ALF, patients manifest rapid deterioration in consciousness leading to hepatic coma together with an onset of brain edema which induces high intracranial pressure that frequently leads to herniation and death. It is well accepted that hyperammonemia is a cardinal, but not the sole, mediator in the pathophysiology of ALF. There is increasing evidence that neurosteroids, including the parent neurosteroid pregnenolone, and the progesterone metabolites tetrahydroprogesterone (allopregnanolone) and tetrahydrodeoxycorticosterone (THDOC) accumulate in brain in experimental models of ALF. Neurosteroids in ALF represent good candidates to explain the phenomenon of “increased GABAergic tone” in chronic and ALF, and the beneficial effects of benzodiazepine drugs. The mechanisms that trigger brain neurosteroid changes in ALF are not yet well known, but could involve partially de novo neurosteroidogenesis following activation of the translocator protein (TSPO). The factors that contribute to TSPO changes in ALF may include ammonia and cytokines. It is possible that increases in brain levels of neurosteroids in ALF may result in auto-regulatory mechanisms where hypothermia may play a significant role. Possible mechanisms that may involve neurosteroids in the pathophysiology of HE, and more speculatively in brain edema, and inflammatory processes in ALF are suggested.

Highlights

Posted on 28 May 2012 | 1:02 pm

Dimebon attenuates methamphetamine, but not MPTP, striatal dopamine depletion

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Werner J. Geldenhuys, Altaf S. Darvesh, Dean E. Dluzen

Dimebon is an anti-histamine with central nervous system activity. In this report the effects of dimebon as a neuroprotectant in animal models of Parkinson’s disease were tested as assessed in methamphetamine- and MPTP-induced striatal dopaminergic toxicity. Dimebon (1mg/kg) administered at 30min prior to methamphetamine (40mg/kg) significantly reduced the amount of striatal dopamine depletion in mice, without altering the initial methamphetamine-induced increase in body temperature. In contrast, dimebon at either 1 or 25mg/kg administered at 30min prior to MPTP (35mg/kg) was unable to prevent MPTP-induced striatal dopamine loss as determined at 7days post-methamphetamine/MPTP. These data suggest that dimebon may be exerting a neurotoxin specific neuroprotective effect upon the striatal dopaminergic system and may serve as an important tool for discriminating the mechanistic basis of these two dopaminergic neurotoxins.

Posted on 28 May 2012 | 1:02 pm

The levels of renin–angiotensin related components are modified in the hippocampus of rats submitted to pilocarpine model of epilepsy

Publication year: 2012
Source:Neurochemistry International, Volume 61, Issue 1

Telma Luciana Furtado Gouveia, Maria Isabel Berzaghi Frangiotti, Joíse Marques Vieira de Brito, Eduardo Ferreira de Castro Neto, Maisa Mayume Sakata, Andreia Cristina Febba, Dulce Elena Casarini, Débora Amado, Esper Abrão Cavalheiro, Sandro Soares Almeida, Martha Trindade Manchini, Ronaldo Carvalho Araújo, José Antonio Silva, Maria da Graça Naffah-Mazzacoratti

We previously showed that patients with temporal lobe epilepsy (TLE) present an increased expression of angiotensin II (AngII) AT1 and AT2 receptors in the hippocampus, supporting the idea of an upregulation of renin–angiotensin system (RAS) in this disease. This study aimed to verify the relationship between the RAS and TLE during epileptogenesis. Levels of the peptides angiotensin I (AngI), angiotensin II (AngII) and angiotensin 1–7 (Ang 1–7), were detected by HPLC assay. Angiotensin AT1 and AT2 receptors, Mas mRNA receptors and angiotensin converting enzyme (ACE), tonin and neutral endopeptidase (NEP) mRNA were also quantified at the hippocampus of Wistar rats by real time PCR, during acute (n =10), silent (n =10) and chronic (n =10) phases of pilocarpine-induced epilepsy. We observed an increased peptide level of Ang1–7 into acute and silent phases, decreasing importantly (p ?0.05) in the chronic phase, suggesting that AngI may be converted into Ang 1–7 by NEP, which is present in high levels in these periods. Our results also showed increased peptide level of AngII in the chronic phase of this model. In contraposition, the ACE expression is reduced in all periods. These data suggest that angiotensinogen or AngI may be cleaved to AngII by tonin, which showed increased expression in all phases. We found changes in AT1, AT2 and Mas mRNA receptors levels suggesting that Ang1–7 could act at Mas receptor during the silent period. Herein, we demonstrated for the first time, changes in angiotensin-related peptides, their receptors as well as the releasing enzymes in the hippocampus of rats during pilocarpine-induced epilepsy.

Graphical abstract

Graphical abstract Highlights

Posted on 28 May 2012 | 1:02 pm

Reprint of: Neuroinflammation in acute liver failure: Mechanisms and novel therapeutic targets

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 7

Roger F. Butterworth

It is increasingly evident that neuroinflammatory mechanisms are implicated in the pathogenesis of the central nervous system (CNS) complications (intracranial hypertension, brain herniation) of acute liver failure (ALF). Neuroinflammation in ALF is characterized by microglial activation and arterio-venous difference studies as well as studies of gene expression confirm local brain production and release of proinflammatory cytokines including TNF-? and the interleukins IL-1? and IL-6. Although the precise nature of the glial cell responsible for brain cytokine synthesis is not yet established, evidence to date supports a role for both astrocytes and microglia. The neuroinflammatory response in ALF progresses in parallel with the progression of hepatic encephalopathy (HE) and with the severity of brain edema (astrocyte swelling). Mechanisms responsible for the relaying of signals from the failing liver to the brain include transduction of systemic proinflammatory signals as well as the effects of increased brain lactate leading to increased release of cytokines from both astrocytes and microglia. There is evidence in support of a synergistic effect of proinflammatory cytokines and ammonia in the pathogenesis of HE and brain edema in ALF. Therapeutic implications of the findings of a neuroinflammatory response in ALF are multiple. Removal of both ammonia and proinflammatory cytokines is possible using antibiotics or albumen dialysis. Mild hypothermia reduces brain ammonia transfer, brain lactate production, microglial activation and proinflammatory cytokine production resulting in reduced brain edema and intracranial pressure in ALF. N-Acetylcysteine acts as both an antioxidant and anti-inflammatory agent at both peripheral and central sites of action independently resulting in slowing of HE progression and prevention of brain edema. Novel treatments that directly target the neuroinflammatory response in ALF include the use of etanercept, a TNF-? neutralizing molecule and minocycline, an agent with potent inhibitory actions on microglial activation that are independent of its antimicrobial properties; both agents have been shown to be effective in reducing neuroinflammation and in preventing the CNS complications of ALF. Translation of these findings to the clinic has the potential to provide rational targeted approaches to the prevention and treatment of these complications in the near future.

Highlights

Posted on 28 May 2012 | 1:02 pm

Therapeutic hypothermia in the management of acute liver failure

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 7

Javier Vaquero

A large body of experimental data and preliminary clinical studies point to the induction of mild hypothermia (32–35°C) as a valuable approach to control the development of brain edema and intracranial hypertension in acute liver failure (ALF). The ability of hypothermia to affect multiple processes probably explains its efficacy to prevent these cerebral complications. Remarkably, mild hypothermia has been shown to prevent or attenuate most of the major alterations involved in the pathogenesis of the cerebral complications of ALF, including the accumulation of ammonia in the brain and the circulation, the alterations of brain glucose metabolism, the brain osmotic disturbances, the accumulation of glutamate and lactate in brain extracellular space, the development of inflammation and oxidative/nitrosative stress, and others. Limited information suggests that the systemic effects of hypothermia may also be beneficial for some peripheral complications of ALF. Translation of the beneficial effects of therapeutic hypothermia into standard clinical practice, however, needs to be confirmed in adequately designed clinical trials. Such trials will be important to determine the safety of therapeutic hypothermia, to identify which patients might benefit from it, and to provide the optimal guidelines for its use in patients with ALF.

Highlights

Posted on 28 May 2012 | 1:02 pm

Spinal astrocytes contribute to the circadian oscillation of glutamine synthase, cyclooxygenase-1 and clock genes in the lumbar spinal cord of mice

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Norimitsu Morioka, Tatsuhiko Sugimoto, Masato Tokuhara, Yoki Nakamura, Hiromi Abe, Kazue Hisaoka, Toshihiro Dohi, Yoshihiro Nakata

Spinal astrocytes have key roles in the regulation of pain transmission. However, the relationship between astrocytes and the circadian system in the spinal cord remains poorly defined. In the current study, the circadian variations in the expression of several clock genes in the lumbar spinal cord of mice were examined by using real-time PCR. The expression of Period1, Period2 and Cryptochrome1 showed significant circadian oscillations, each gene peaking in the early evening. The expression of Bmal1 mRNA also exhibited a circadian pattern, peaking from around midnight to early morning. The mRNA levels of Cryptochrome2 were slightly, but not significantly altered. Molecules related to pain transmission were also investigated. The mRNA expression of glutamine synthase (GS), and cyclooxygenases (COXs), known to be involved in various spinal sensory functions, showed rhythmicity with a peak in the early evening, although the expression of the neurokinin-1 receptor, subunits of the N-methyl-d-aspartate receptor, and glutamate transporters did not change. In addition, we found that protein levels of GS and COX-1 were also high at midnight compared with midday. Furthermore, we examined the effect of intrathecal fluorocitrate (100pmol), an inhibitor of astrocytic metabolism, on the expression of oscillating genes in lumbar spinal cord. Fluorocitrate significantly suppressed astrocyte function. Furthermore, the circadian oscillation of clock gene expression and GS and COX-1 expression were suppressed. Together, these results suggest that a significant circadian rhythmicity of the expression of clock genes is present in the spinal cord and that the components of the circadian clock timed by astrocytes might contribute to spinal functions, including nociceptive processes.

Highlights

Posted on 28 May 2012 | 1:02 pm

Differential effects of chronic hyperammonemia on modulation of the glutamate–nitric oxide–cGMP pathway by metabotropic glutamate receptor 5 and low and high affinity AMPA receptors in cerebellum in vivo

Publication year: 2012
Source:Neurochemistry International, Volume 61, Issue 1

Andrea Cabrera-Pastor, Marta Llansola, Vitaliy Reznikov, Jordi Boix, Vicente Felipo

Previous studies show that chronic hyperammonemia impairs learning ability of rats by impairing the glutamate–nitric oxide (NO)–cyclic guanosine mono-phosphate (cGMP) pathway in cerebellum. Three types of glutamate receptors cooperate in modulating the NO–cGMP pathway: metabotropic glutamate receptor 5 (mGluR5), (RS)-?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptors. The aim of this work was to assess whether hyperammonemia alters the modulation of this pathway by mGluR5 and AMPA receptors in cerebellum in vivo. The results support that in control rats: (1) low AMPA concentrations (0.1mM) activate nearly completely Ca²⁺-permeable (glutamate receptor subunit 2 (GluR2)-lacking) AMPA receptors and the NO–cGMP pathway; (2) higher AMPA concentrations (0.3mM) also activate Ca²⁺-impermeable (GluR2-containing) AMPA receptors, leading to activation of NMDA receptors and of NO–cGMP pathway. Moreover, the data support that chronic hyperammonemia: (1) reduces glutamate release and activation of the glutamate–NO–cGMP pathway by activation of mGluR5; (2) strongly reduces the direct activation by AMPA receptors of the NO–cGMP pathway, likely due to reduced entry of Ca²⁺ through GluR2-lacking, high affinity AMPA receptors; (3) strongly increases the indirect activation of the NO–cGMP pathway by high affinity AMPA receptors, likely due to increased entry of Na⁺ through GluR2-lacking AMPA receptors and NMDA receptors activation; (4) reduces the indirect activation of the NO–cGMP pathway by low affinity AMPA receptors, likely due to reduced activation of NMDA receptors.

Highlights

Posted on 28 May 2012 | 1:02 pm

Neurological complications of acute liver failure: Pathophysiological basis of current management and emerging therapies

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 7

Liliane Mpabanzi, Rajiv Jalan

One of the major causes of mortality in patients with acute liver failure (ALF) is the development of hepatic encephalopathy (HE) which is associated with increased intracranial pressure (ICP). High ammonia levels, increased cerebral blood flow and increased inflammatory response have been identified as major contributors to the development of HE and the related brain swelling. The general principles of the management of patients with ALF are straightforward. They include identifying the insult causing hepatic injury, providing organ systems support to optimize the patient’s physical condition, anticipation and prevention of development of complications. Increasing insights into the pathophysiological mechanisms of ALF are contributing to better therapies. For instance, the evident role of cerebral hyperemia in the pathogenesis of increased ICP has led to a re-evaluation of established therapies such as hyperventilation, N-acetylcysteine, thiopentone sodium and propofol. The role of systemic inflammatory response in the pathogenesis of increased ICP has also gained importance supporting the concept that antibiotics given prophylactically reduce the risk of developing sepsis during the course of illness. Moderate hypothermia has also been established as a therapy able to reduce ICP in patients with uncontrolled intracranial hypertension and to prevent increases in ICP during orthopic liver transplantation. Ornithine phenylacetate, a new drug in the treatment of liver failure, and liver replacement therapies are still being investigated both experimentally and clinically. Despite many advances in the understanding of the pathophysiological basis and the management of intracranial hypertension in ALF, more clinical trials should be conducted to determine the best therapeutic management for this difficult clinical event.

Highlights

Posted on 28 May 2012 | 1:02 pm

Polycation-mediated enhancement of retroviral transduction efficiency depends on target cell types and pseudotyped Env proteins: Implication for gene transfer into neural stem cells

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Jiwon Jang, Junsup Lee, Seong-Tae Kim, Ki-Young Lee, Jae Youl Cho, Dae-Hyuk Kweon, Suk-Tae Kwon, Young Ho Koh, Sunyoung Kim, Keejung Yoon

Polycations such as polybrene (PB) are routinely used for most retroviral vector-mediated gene transfer studies because they can increase the infectivity of retroviruses. However, it was not systematically determined if addition of the polycation is an essential prerequisite for all retroviral transductions. To test this, we measured the effects of the polycation on transduction efficiency using various combinations of target cells and pseudotyped viral envelope (Env) proteins. Here, we show polycations do not always increase retroviral transduction efficiency and that their enhancing effect depends on both the type of target cells and Env proteins. The findings presented here also suggest that high transduction rates can be achieved in primary neural stem cells in vitro and in vivo by choosing an appropriate Env protein for pseudotyping without using polycations which are potentially toxic to primary cells and may change the intrinsic characteristics of cells.

Posted on 28 May 2012 | 1:02 pm

d-Serine diffusion through the blood–brain barrier: Effect on d-serine compartmentalization and storage

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Pierre Pernot, Caroline Maucler, Yannick Tholance, Natalia Vasylieva, Gabriel Debilly, Loredano Pollegioni, Raymond Cespuglio, Stéphane Marinesco

d-Serine is a co-agonist of N-methyl-d-aspartate (NMDA) receptors. It has been implicated in the etiology of schizophrenia and has shown efficacy as an adjuvant to reduce positive and negative symptoms of schizophrenia. In addition, d-serine can modulate cognition in animals when administered alone. However, the neurochemical effects of exogenous d-serine on extra- and intra-cellular d-serine brain levels are poorly understood. In this study, we used both high performance liquid chromatography (HPLC) and enzyme-based microelectrode biosensors to quantify d-serine in the rat brain. We demonstrated levels of 2.3–2.8?M in the extracellular medium, 4?M in plasma and 188pmol/mg in brain tissue samples. An intraperitoneal (i.p.) d-serine injection (1g/kg) produced a slow increase in extracellular d-serine concentration in the cortex despite a surge in d-serine up to 13mM in the plasma, indicating poor diffusion through the blood–brain barrier. Using the respective volume fractions of blood, extracellular and intracellular spaces published in the literature, we estimated that d-serine intracellular stores represented more than 99% of total d-serine. These intracellular stores almost doubled 3h after d-serine administration. Overall, our data indicate that d-serine administration increases brain extra- and intra-cellular concentrations despite weak diffusion through the blood–brain barrier. These results pave the way for a better understanding of the neurochemical mechanisms by which d-serine administration modulates cognition.

Highlights

Posted on 28 May 2012 | 1:02 pm

Kinin-mediated inflammation in neurodegenerative disorders

Publication year: 2012
Source:Neurochemistry International, Volume 61, Issue 1

Ibeth Guevara-Lora

The mediatory role of kinins in both acute and chronic inflammation within nervous tissues has been widely described. Bradykinin, the major representative of these bioactive peptides, is one of a few mediators of inflammation that directly stimulates afferent nerves due to the broad expression of specific kinin receptors in cell types in these tissues. Moreover, kinins may be delivered to a site of injury not only after their production at the endothelium surface but also following their local production through the enzymatic degradation of kininogens at the surface of nerve cells. A strong correlation between inflammatory processes and neurodegeneration has been established. The activation of nerve cells, particularly microglia, in response to injury, trauma or infection initiates a number of reactions in the neuronal neighborhood that can lead to cell death after the prolonged action of inflammatory substances. In recent years, there has been a growing interest in the effects of kinins on neuronal destruction. In these studies, the overexpression of proteins involved in kinin generation or of kinin receptors has been observed in several neurologic disorders including neurodegenerative diseases such Alzheimer’s disease and multiple sclerosis as well as disorders associated with a deficiency in cell communication such as epilepsy. This review is focused on recent findings that provide reliable evidence of the mediatory role of kinins in the inflammatory responses associated with different neurological disorders. A deeper understanding of the role of kinins in neurodegenerative diseases is likely to promote the future development of new therapeutic strategies for the control of these disorders. An example of this could be the prospective use of kinin receptor antagonists.

Highlights

Posted on 28 May 2012 | 1:02 pm

Pro-domain in precursor nerve growth factor mediates cell death

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Arunmozhiarasi Armugam, Dawn C.I. Koh, Chai Siaw Ching, Karthikeyan Chandrasekaran, Prameet Kaur, Kandiah Jeyaseelan

Nerve growth factor (NGF) is synthesized as a precursor, proNGF that undergoes post-translational processing to generate the biologically active mature NGF. While the neurotrophic function of NGF is well established, the activity of the proNGF precursor is still unclear. In this study, we have cloned the pro-domain of the precursor NGF molecule and have elucidated its function. We have used both mature and the furin resistant pro^(R/G)NGF as controls in our experiments. Both pro^(R/G)NGF and mature NGF (NGF) exhibited neurotrophic activity on PC12 cells while the pro-domain itself promoted cell death. The pro-domain, has been found to mediate apoptosis possibly by promoting the formation of a signaling complex comprising of endogenous p75^NTR receptor, Bim/Bcl2 group of proteins and JNK and MEK1/2 signaling pathways.

Highlights

Posted on 28 May 2012 | 1:02 pm

Decreased oxidative stress during glycolytic inhibition enables maintenance of ATP production and astrocytic survival

Publication year: 2012
Source:Neurochemistry International

Christina Nodin, Changlian Zhu, Klas Blomgren, Michael Nilsson, Fredrik Blomstrand

Depressed energy metabolism and oxidative stress are common features in many pathological situations in the brain, including stroke. In order to investigate astrocytic responses to such stress, we induced metabolic depression in cultured rat astrocytes. Iodoacetate (IA), an inhibitor of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used and resulted in a rapid inhibition of GAPDH activity. After 1h of GAPDH inhibition the ATP levels started to decrease and were completely abolished at 4h. In parallel, the activity of reactive oxygen species (ROS) was significantly increased, followed by extensive cell death involving flipping of phosphatidylserine and translocation of apoptosis-inducing factor, but not caspase-3 activation. When IA was combined with azide, a respiratory chain complex IV inhibitor, the ATP levels decreased immediately. Interestingly, with azide present, the ROS activity remained low and the astrocytes remained viable even at very low ATP levels. Addition of exogenous ROS-scavengers prevented the IA-induced ROS activity, the ATP levels were maintained and cell death was prevented. Similar protection could be obtained when astrocytes, prior to addition of IA, were incubated with substances known to activate the nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated endogenous antioxidant system. When IA was washed out, after a relatively moderate ATP depression, massive cell death occurred. This was efficiently prevented by addition of azide or ROS scavengers during the IA treatment or by pre-activation of the Nrf2 system. Our results demonstrate that astrocytes in culture can endure and recover from glycolytic inhibition if the ROS activity remained at a low level and suggest that oxidative stress can be an important component for astrocytic cell death following metabolic stress.

Highlights

Posted on 28 May 2012 | 1:02 pm

Ebselen inhibits iron-induced tau phosphorylation by attenuating DMT1 up-regulation and cellular iron uptake

Publication year: 2012
Source:Neurochemistry International

Ling Xie, Wei Zheng, Na Xin, Jing-Wei Xie, Tao Wang, Zhan-You Wang

Dysregulation of iron homeostasis is involved in the pathological process of Alzheimer’s disease (AD). We have recently reported that divalent metal transporter 1 (DMT1) is upregulated in an AD transgenic mouse brain, and that silencing of DMT1, which reduces cellular iron influx, results in inhibition of amyloidogenesis in vitro, suggesting a potential target of DMT1 for AD therapy. In the present study, we tested the hypothesis that inhibition of DMT1 with ebselen, a DMT1 transport inhibitor, could affect tau phosphorylation. Human neuroblastoma SH-SY5Y cells were pre-treated with ebselen and then treated with ferrous sulfate (dissolved in ascorbic acid), and the effects of ebselen on tau phosphorylation and the relative signaling pathways were examined. Our results showed that ebselen decreased iron influx, reduced iron-induced ROS production, inhibited the activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3?, and ultimately attenuated the levels of tau phosphorylation at the sites of Thr205, Ser396 and Thr231. The present study indicates that the neuroprotective effect of ebselen on AD is not only related to its antioxidant activity as reported previously, but is also associated with a reduction in tau phosphorylation by inhibition of DMT1.

Highlights

Posted on 28 May 2012 | 1:02 pm

Differences in NGFI-B, Nurr1, and NOR-1 expression and nucleocytoplasmic translocation in glutamate-treated neurons

Publication year: 2012
Source:Neurochemistry International, Volume 61, Issue 1

Karen A. Boldingh Debernard, Gro H. Mathisen, Ragnhild E. Paulsen

NGFI-B (NR4A1, Nur77 or TR3) together with Nurr1 (NR4A2) and NOR-1 (NR4A3) constitute the NR4A subgroup of orphan nuclear receptors. They play critical roles in proliferation, differentiation, survival and apoptosis in different cell types, including neurons, immature T-cells, and different cancer cells. As ligand-independent and constitutively active receptors, the diverse biological activities of NGFI-B, Nurr1 and NOR-1 depend on their levels of expression, post-translational modifications and subcellular localization. Nuclear localization of the NR4A proteins leads to transcriptional activity, whereas NGFI-B and recently also NOR-1 have been shown to induce apoptosis by a more direct mechanism when localized at mitochondria. In the present study we investigated mRNA expression and subcellular translocation of the NR4A proteins during glutamate excitotoxicity in rat cerebellar granule neurons. NGFI-B and Nurr1 mRNA, but not NOR-1 mRNA, were induced by treatments associated with calcium influx, although their regulation seemed to be different. NR4Agfp fusion proteins showed a predominant nuclear localization in untreated cells. After glutamate treatment NGFI-Bgfp translocated to cytosol and mitochondria within a few hours, whereas Nurr1gfp translocation was delayed, and NOR-1gfp mainly stayed in the nucleus. Subcellular targeting of NGFI-B seems to be tightly regulated, as a single mutation of threonine 142 altered NGFI-Bgfp localization. Differences in expression and subcellular translocation of NGFI-B, Nurr1, and NOR-1 may reflect different functions in neurons in glutamate excitotoxicity.

Highlights

Posted on 28 May 2012 | 1:02 pm

Proteomic analysis of the brain tissues from a transgenic mouse model of amyloid ? oligomers

Publication year: 2012
Source:Neurochemistry International

Masaoki Takano, Kouji Maekura, Mieko Otani, Keiji Sano, Tooru Nakamura-Hirota, Shogo Tokuyama, Kyong Son Min, Takami Tomiyama, Hiroshi Mori, Shogo Matsuyama

Amyloid ? (A?) oligomers are presumed to be one of the causes of Alzheimer’s disease (AD). Previously, we identified the E693? mutation in amyloid precursor protein (APP) in patients with AD who displayed almost no signals of amyloid plaques in amyloid imaging. We generated APP-transgenic mice expressing the E693? mutation and found that they possessed abundant A? oligomers from 8months of age but no amyloid plaques even at 24months of age, indicating that these mice are a good model to study pathological effects of A? oligomers. To elucidate whether A? oligomers affect proteome levels in the brain, we examined the proteins and phosphoproteins for which levels were altered in 12-month-old APPE693?-transgenic mice compared with age-matched non-transgenic littermates. By two-dimensional gel electrophoresis (2DE) followed by staining with SYPRO Ruby and Pro-Q Diamond and subsequent mass spectrometry techniques, we identified 17 proteins and 3 phosphoproteins to be significantly changed in the hippocampus and cerebral cortex of APPE693?-transgenic mice. Coactosin like-protein, SH3 domain-bind glutamic acid-rich-like protein 3 and astrocytic phosphoprotein PEA-15 isoform 2 were decreased to levels less than 0.6 times those of non-transgenic littermates, whereas dynamin, profilin-2, vacuolar adenosine triphosphatase and creatine kinase B were increased to levels more than 1.5 times those of non-transgenic littermates. Furthermore, 2DE Western Blotting validated the changed levels of dynamin, dihydropyrimidinase-related protein 2 (Dpysl2), and coactosin in APPE693?-transgenic mice. Glyoxalase and isocitrate dehydrogenase were increased to levels more than 1.5 times those of non-transgenic littermates. The identified proteins could be classified into several groups that are involved in regulation of different cellular functions, such as cytoskeletal and their interacting proteins, energy metabolism, synaptic component, and vesicle transport and recycling. These findings indicate that A? oligomers altered the levels of some proteins and phosphoproteins in the hippocampus and cerebral cortex, which could illuminate novel therapeutic avenues for the treatment of AD.

Highlights

Posted on 28 May 2012 | 1:02 pm

Inhibition of forebrain ?-opioid receptor signaling by low concentrations of rimonabant does not require cannabinoid receptors and directly involves ?-opioid receptors

Publication year: 2012
Source:Neurochemistry International

Ferenc Zádor, Ferenc Ötvös, Sándor Benyhe, Andreas Zimmer, Eszter Páldy

Increasing number of publications shows that cannabinoid receptor 1 (CB1) specific compounds might act in a CB1 independent manner, including rimonabant, a potent CB1 receptor antagonist. Opioids, cannabinoids and their receptors are well known for their overlapping pharmacological properties. We have previously reported a prominent decrease in ?-opioid receptor (MOR) activity when animals were acutely treated with the putative endocannabinoid noladin ether (NE). In this study, we clarified whether the decreased MOR activation caused by NE could be reversed by rimonabant in CB1 receptor deficient mice. In functional [³⁵S]GTP?S binding assays, we have elucidated that 0.1mg/kg of intraperitoneal (i.p.) rimonabant treatment prior to that of NE treatment caused further attenuation on the maximal stimulation of Tyr-d-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO), which is a highly specific MOR agonist. Similar inhibitory effects were observed when rimonabant was injected i.p. alone and when it was directly applied to forebrain membranes. These findings are cannabinoid receptor independent as rimonabant caused inhibition in both CB1 single knockout and CB1/CB2 double knockout mice. In radioligand competition binding assays we highlighted that rimonabant fails to displace effectively [³H]DAMGO from MOR in low concentrations and is highly unspecific on the receptor at high concentrations in CB1 knockout forebrain and in their wild-type controls. Surprisingly, docking computational studies showed a favorable binding position of rimonabant to the inactive conformational state of MOR, indicating that rimonabant might behave as an antagonist at MOR. These findings were confirmed by radioligand competition binding assays in Chinese hamster ovary cells stably transfected with MOR, where a higher affinity binding site was measured in the displacement of the tritiated opioid receptor antagonist naloxone. However, based on our in vivo data we suggest that other, yet unidentified mechanisms are additionally involved in the observed effects.

Graphical abstract

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Posted on 28 May 2012 | 1:02 pm

Attenuation of NF-?? mediated apoptotic signaling by tocotrienol ameliorates cognitive deficits in rats postnatally exposed to ethanol

Publication year: 2012
Source:Neurochemistry International

Vinod Tiwari, Vipin Arora, Kanwaljit Chopra

Ethanol-induced damage in the developing brain may result in cognitive impairment including deficits on neuropsychological tests of learning, memory and executive function, yet the underlying mechanisms remain elusive. In the present study we investigated the protective effect of tocotrienol against cognitive deficit, neuroinflammation and neuronal apoptosis in rat pups postnatally exposed to ethanol. Pups were administered ethanol (5g/kg, 12% v/v) by intragastric intubation on postnatal days 7, 8 and 9. Ethanol-exposed pups showed significant memory impairment in Morris water maze task as evident from increase in escape latency and total distance travelled to reach the hidden platform. Time spent in target quadrant, % total distance traversed in target quadrant and frequency of appearance in target quadrant was also significantly decreased in ethanol exposed pups in probe trial. Poor memory retention was exhibited by ethanol-exposed pups in elevated plus maze test also. Impaired cognition was associated with significantly enhanced acetylcholinesterase activity, increased neuroinflammation (oxidative-nitrosative stress, TNF-?, IL-1? and TGF-?1) and neuronal apoptosis (NF-?? and Caspase-3) in different brain regions of ethanol-exposed pups. Co-administration with tocotrienol significantly ameliorated all the behavioral, biochemical and molecular alterations in the different brain regions of ethanol exposed pups. The current study thus demonstrates the possible involvement of NF-?? mediated apoptotic signaling in cognitive deficits associated with postnatal ethanol exposure in rats and points to the potential of tocotrienol in the prevention of cognitive deficits in children with fetal alcohol spectrum disorders (FASDs).

Highlights

Posted on 28 May 2012 | 1:02 pm

Editorial board and Publication Information

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 7

Posted on 28 May 2012 | 1:02 pm

Linkage of N-cadherin to multiple cytoskeletal elements revealed by a proteomic approach in hippocampal neurons

Publication year: 2012
Source:Neurochemistry International

Hidekazu Tanaka, Kazuaki Takafuji, Akihiko Taguchi, Pattama Wiriyasermkul, Ryuichi Ohgaki, Shushi Nagamori, Pann-Ghill Suh, Yoshikatsu Kanai

The CNS synapse is an adhesive junction differentiated for chemical neurotransmission and is equipped with presynaptic vesicles and postsynaptic neurotransmitter receptors. Cell adhesion molecule cadherins not only maintain connections between pre- and postsynaptic membranes but also modulate the efficacy of synaptic transmission. Although the components of the cadherin-mediated adhesive apparatus have been studied extensively in various cell systems, the complete picture of these components, particularly at the synaptic junction, remains elusive. Here, we describe the proteomic assortment of the N-cadherin-mediated synaptic adhesion apparatus in cultured hippocampal neurons. N-cadherin immunoprecipitated from Triton X-100-solubilized neuronal extract contained equal amounts of ?- and ?-catenins, as well as F-actin-related membrane anchor proteins such as integrins bridged with ?-actinin-4, and Na⁺/K⁺-ATPase bridged with spectrins. A close relative of ?-catenin, plakoglobin, and its binding partner, desmoplakin, were also found, suggesting that a subset of the N-cadherin-mediated adhesive apparatus also anchors intermediate filaments. Moreover, dynein heavy chain and LEK1/CENPF/mitosin were found. This suggests that internalized pools of N-cadherin in trafficking vesicles are conveyed by dynein motors on microtubules. In addition, ARVCF and NPRAP/neurojungin/?2-catenin, but not p120ctn/?1-catenin or plakophilins-1, -2, -3, -4 (p0071), were found, suggesting other possible bridges to microtubules. Finally, synaptic stimulation by membrane depolarization resulted in an increased 93-kDa band, which corresponded to proteolytically truncated ?-catenin. The integration of three different classes of cytoskeletal systems found in the synaptic N-cadherin complex may imply a dynamic switching of adhesive scaffolds in response to synaptic activity.

Highlights

Posted on 28 May 2012 | 1:02 pm

Rosiglitazone treatment reduces hippocampal neuronal damage possibly through alleviating oxidative stress in chronic cerebral hypoperfusion

Publication year: 2012
Source:Neurochemistry International

Hale Sayan-Ozacmak, Veysel Haktan Ozacmak, Figen Barut, Ewa Jakubowska-Dogru

Oxygen free radicals and lipid peroxidation may play significant roles in the progress of injury induced by chronic cerebral hypoperfusion of the central nervous system. Rosiglitazone, a well known activator of PPAR?, has neuroprotective properties in various animal models of acute central nervous system damage. In the present study, we evaluate the possible impact of rosiglitazone on chronic cerebral hypoperfused-rats in regard to the levels of oxidative stress, reduced glutathione, and hippocampal neuronal damage. Chronic cerebral hypoperfusion was generated by permanent ligation of both common carotid arteries of Wistar rats for one month. Animals in treatment group were given rosiglitazone orally at doses of 1.5, 3, or 6mg/kg per day of the 1month duration. The treatment significantly lowered the levels of both malondialdehyde and neuronal damage, while elevated the reduced glutathione level markedly. These findings suggest that the beneficial effect of rosiglitazone on hypoperfusion-induced hippocampal neuronal damage might be the result of inhibition of oxidative insult.

Posted on 28 May 2012 | 1:02 pm

Renin inhibitor aliskiren exerts neuroprotection against amyloid beta-peptide toxicity in rat cortical neurons

Publication year: 2012
Source:Neurochemistry International

Shang-Der Chen, Chia-Lin Wu, Tsu-Kung Lin, Yao-Chung Chuang, Ding-I. Yang

Accumulation of amyloid ?-peptide (A?) in senile plaques, a pathological hallmark of Alzheimer’s disease (AD), has been implicated in neuronal degeneration. Renin–angiotensin system (RAS) blockers, including the renin inhibitor aliskiren, are a group of clinically relevant anti-hypertensive agents. The present study was initiated to investigate whether aliskiren may modulate A? neurotoxicity as an additional function aside from its established property of lowering blood pressure. We found aliskiren conferred neuronal resistance to A? toxicity in primary rat cortical cultures. Moreover, both A?25-35 and A?1-42 induced renin expression in cortical neurons; in parallel, a heightened expression of renin was detected in the cerebral cortices of 9-month-old AD transgenic mice. Notably, aliskiren blocked A?-mediated neuronal induction of renin. We therefore concluded that aliskiren may carry neuroprotective action against A? toxicity. Furthermore, the aliskiren effects may involve downregulation of renin expression induced by A?.

Highlights

Posted on 28 May 2012 | 1:02 pm

MicroRNA expression profiling of NGF-treated PC12 cells revealed a critical role for miR-221 in neuronal differentiation

Publication year: 2012
Source:Neurochemistry International, Volume 60, Issue 8

Nanako Hamada, Yasunori Fujita, Toshio Kojima, Aya Kitamoto, Yukihiro Akao, Yoshinori Nozawa, Masafumi Ito

MicroRNAs (miRNAs) are small non-coding RNAs that control protein expression through translational inhibition or mRNA degradation. MiRNAs have been implicated in diverse biological processes such as development, proliferation, apoptosis and differentiation. Upon treatment with nerve growth factor (NGF), rat pheochromocytoma PC12 cells elicit neurite outgrowth and differentiate into neuron-like cells. NGF plays a critical role not only in neuronal differentiation but also in protection against apoptosis. In an attempt to identify NGF-regulated miRNAs in PC12 cells, we performed miRNA microarray analysis using total RNA harvested from cells treated with NGF. In response to NGF treatment, expression of 8 and 12 miRNAs were up- and down-regulated, respectively. Quantitative RT-PCR analysis of 11 out of 20 miRNAs verified increased expression of miR-181a^?, miR-221 and miR-326, and decreased expression of miR-106b^?, miR-126, miR-139-3p, miR-143, miR-210 and miR-532-3p after NGF treatment, among which miR-221 was drastically up-regulated. Functional annotation analysis of potential target genes of 7 out of 9 miRNAs excluding the passenger strands (*) revealed that NGF may regulate expression of various genes by controlling miRNA expression, including those whose functions and processes are known to be related to NGF. Overexpression of miR-221 induced neuronal differentiation of PC12 cells in the absence of NGF treatment, and also enhanced neuronal differentiation caused by low-dose NGF. Furthermore, miR-221 potentiated formation of neurite network, which was associated with increased expression of synapsin I, a marker for synapse formation. More importantly, knockdown of miR-221 expression by antagomir attenuated NGF-mediated neuronal differentiation. Finally, miR-221 decreased expression of Foxo3a and Apaf-1, both of which are known to be involved in apoptosis in PC12 cells. Our results suggest that miR-221 plays a critical role in neuronal differentiation as well as protection against apoptosis in PC12 cells.

Highlights

Posted on 28 May 2012 | 1:02 pm

Presynaptic CB1 cannabinoid receptors control frontocortical serotonin and glutamate release – Species differences

Publication year: 2012
Source:Neurochemistry International

Samira G. Ferreira, Filipe M. Teixeira, Pedro Garção, Paula Agostinho, Catherine Ledent, Luísa Cortes, Ken Mackie, Attila Köfalvi

Both the serotonergic and endocannabinoid systems modulate frontocortical glutamate release; thus they are well positioned to participate in the pathogenesis of psychiatric disorders. With the help of fluorescent and confocal microscopy, we localized the CB1 cannabinoid receptor (CB1R) in VGLUT1- and 2- (i.e. glutamatergic) and serotonin transporter- (i.e. serotonergic) -positive fibers and nerve terminals in the mouse and rat frontal cortex. CB1R activation by the synthetic agonists, WIN55212-2 (1?M) and R-methanandamide (1?M) inhibited the simultaneously measured evoked Ca²⁺-dependent release of [¹⁴C]glutamate and [³H]serotonin from frontocortical nerve terminals of Wistar rats, in a fashion sensitive to the CB1R antagonists, O-2050 (500nM) and LY320135 (5?M). CB1R agonists also inhibited the evoked release of [¹⁴C]glutamate in C57BL/6J mice in a reversible fashion upon washout. Interestingly, the evoked release of [¹⁴C]glutamate and [³H]serotonin was significantly greater in the CB1R knockout CD-1 mice. Furthermore, CB1R binding revealed similar frontocortical CB1R density in the rat and the CD-1 mouse. Still, the evoked release of [³H]serotonin was modulated by neither CB1R agonists nor antagonists in wild-type CD-1 or C57BL/6J mice. Altogether, this is the first study to demonstrate functional presynaptic CB1Rs in frontocortical glutamatergic and serotonergic terminals, revealing species differences.

Highlights

Posted on 28 May 2012 | 1:02 pm