GPR18 drives FAAH inhibition-induced neuroprotection against HIV-1 Tat-induced neurodegeneration.

Human immunodeficiency virus type 1 (HIV-1) is known to provoke microglial immune responses which likely play a paramount role in the development of chronic neuroinflammatory conditions and neuronal damage related to HIV-1 associated neurocognitive disorders (HAND). In particular, HIV-1 Tat protein is a proinflammatory neurotoxin which predisposes neurons to synaptodendritic injury. Drugs targeting the degradative enzymes of endogenous cannabinoids have shown promise in reducing inflammation with minimal side effects in rodent models. Considering that markers of neuroinflammation can predict the extent of neuronal injury in HAND patients, we evaluated the neurotoxic effect of HIV-1 Tat-exposed microglia following blockade of fatty acid amid hydrolyze (FAAH), a catabolic enzyme responsible for degradation of endocannabinoids, e.g. anandamide (AEA). In the present study, cultured murine microglia were incubated with Tat and/or a FAAH inhibitor (PF3845). After 24 h, cells were imaged for morphological analysis and microglial conditioned media (MCM) was collected. Frontal cortex neuron cultures (DIV 7-11) were then exposed to MCM, and neurotoxicity was assessed via live cell calcium imaging and staining of actin positive dendritic structures. Results demonstrate a strong attenuation of microglial responses to Tat by PF3845 pretreatment, which is indicated by 1) microglial changes in morphology to a less proinflammatory phenotype using fractal analysis, 2) a decrease in release of neurotoxic cytokines/chemokines (MCP-1/CCL2) and matrix metalloproteinases (MMPs; MMP-9) using ELISA/multiplex assays, and 3) enhanced production of endocannabinoids (AEA) using LC/MS/MS. Additionally, PF3845's effects on Tat-induced microglial-mediated neurotoxicity, decreased dysregulation of neuronal intracellular calcium and prevented the loss of actin-positive staining and punctate structure in frontal cortex neuron cultures. Interestingly, these observed neuroprotective effects appeared to be independent of cannabinoid receptor activity (CB1R & CB2R). We found that a purported GPR18 antagonist, CID-85469571, blocked the neuroprotective effects of PF3845 in all experiments. Collectively, these experiments increase understanding of the role of FAAH inhibition and Tat in mediating microglial neurotoxicity in the HAND condition.

Neuroprotective effects of novel nitrones: In vitro and in silico studies.

Neurodegenerative diseases affect millions of people around the world. Several studies point out caspase-3 as a key player in the development and progression of neurological disorders including amyotrophic lateral sclerosis, Alzheimer's, Parkinson's and Huntington's diseases. Furthermore, oxidative stress and mitochondrial dysfunction plays an important role in neurodegenerative pathologies leading to neuronal damage and cell death. Pharmacological properties of nitrones such as free radical trapping and neuroprotection has been previously described. In the present work, we have assessed ten non-cytotoxic nitrones for their ability to inhibit apoptosis plus their potential to reduce active caspase-3 and oxidative stress in the hippocampal neuronal cell line HT22. Our results highlight the faculty of nitrones to inhibit apoptosis by a mechanism that involves active caspase-3 reduction and decrease of reactive oxygen species. Moreover, docking and molecular dynamics approaches lead to a detailed analysis at the atomic level of the nitrones binding mode to caspase-3 suggesting that compounds bind in a region close to the catalytic site. All these data place these molecules as excellent hits for further efforts to redesign novel compounds in the search of a new therapy against neurodegenerative disorders.

Role of c-Jun N-Terminal Kinases (JNKs) in Epilepsy and Metabolic Cognitive Impairment.

Previous studies have reported that the regulatory function of the different c-Jun N-terminal kinases isoforms (JNK1, JNK2, and JNK3) play an essential role in neurological disorders, such as epilepsy and metabolic-cognitive alterations. Accordingly, JNKs have emerged as suitable therapeutic strategies. In fact, it has been demonstrated that some unspecific JNK inhibitors exert antidiabetic and neuroprotective effects, albeit they usually show high toxicity or lack therapeutic value. In this sense, natural specific JNK inhibitors, such as Licochalcone A, are promising candidates. Nonetheless, research on the understanding of the role of each of the JNKs remains mandatory in order to progress on the identification of new selective JNK isoform inhibitors. In the present review, a summary on the current gathered data on the role of JNKs in pathology is presented, as well as a discussion on their potential role in pathologies like epilepsy and metabolic-cognitive injury. Moreover, data on the effects of synthetic small molecule inhibitors that modulate JNK-dependent pathways in the brain and peripheral tissues is reviewed.

Inhibition of mitochondrial permeability transition pore opening contributes to cannabinoid type 1 receptor agonist ACEA-induced neuroprotection.

Cannabinoid type 1 (CB1) receptor agonist arachidonyl-2-chloroethylamide (ACEA) induces neuroprotection against brain ischemia, and the mechanism, however, is still elusive. In this study, we used bilateral common carotid artery occlusion (BCCAO) in mice and oxygen-glucose deprivation (OGD) in primary cultured neurons to mimic brain ischemic injury, and hypothesized that cannabinoid CB1 receptor agonist ACEA protects ischemic neurons via inhibiting the opening of mitochondrial permeability transition pore (MPTP). In vivo, we found that BCCAO treatment reduced the neurological functions, increased the number of apoptotic neuronal cells and deteriorated the mitochondrial morphology in the ischemic brain tissue. And in vitro, we observed that OGD injury reduced cell viability, mitochondrial function and anti-oxidant SOD2 expression, increased lactate dehydrogenase (LDH), mitochondrial cytochrome C (Cyto C) and apoptosis-inducing factor (AIF) releases, elevated the cell apoptosis and mitochondrial superoxide level. And the CB1 receptor agonist ACEA significantly abolished the BCCAO and OGD-induced neuronal injury above. However, the MPTP opener atractyloside (Atr) markedly reversed the ACEA-induced neuroprotective effects, inhibited the mitochondrial Cyto C and AIF releases and relieved the mitochondrial swelling, but the MPTP inhibitor cyclosporin A (CsA) did not cause significant effects on the ACEA-induced neuroprotection above. These findings indicated that inhibition of MPTP opening may be involved in the cannabinoid CB1 receptor agonist ACEA-induced neuroprotection.

Increased autophagic degradation contributes to the neuroprotection of hydrogen sulfide against cerebral ischemia/reperfusion injury.

Hydrogen sulfide (H2S), an endogenous gaseous signal molecule, exhibits protective effect against ischemic injury. However, its underlying mechanism is not fully understood. We have recently reported that exogenous H2S decreases the accumulation of autophagic vacuoles in mouse brain with ischemia/reperfusion (I/R) injury. To further investigate whether this H2S-induced reduction of autophagic vacuoles is caused by the decreased autophagosome synthesis and/or the increased autophagic degradation inautophagic flux, we performed in vitro and in vivo studies using SH-SY5Y cells for the oxygen and glucose deprivation/reoxygenation (OGD/R) and mice for the cerebral I/R, respectively. NaHS (a donor of H2S) treatment significantly increased cell viability and reduced cerebral infarct volume. NaHS treatment reduced the OGD/R-induced elevation in LC3-II (an autophagic marker), which was completely reversed by co-treatment with an autophagic flux inhibitor bafilomycin A1 (BafA1). However, H2S did not affect the OGD/R-induced increase of the ULK1 self-association and decrease of the ATG13 phosphorylation, which are the critical steps for the initiation of autophagosome formation. Cerebral I/R injury caused an increase in LC3-II, a decrease in p62 and the accumulation of autophagosomes in the cortex and the hippocampus, which were inhibited by NaHS treatment. This H2S-induced decline of LC3-II in ischemic brain was reversed by BafA1. Moreover, BafA1 treatment abolished the protection of H2S on the cerebral infarction. Collectively, the neuroprotection of exogenous H2S against ischemia/hypoxia and reperfusion/reoxygenation injury is mediated by the enhancement of autophagic degradation.

Dopamine D3 receptor-modulated neuroprotective effects of lisuride.

Dopamine (DA) contributes to the regulation of voluntary movement, and a deficiency in DAergic neurons leads to movement disorders. The objective of this study was to examine the neuroprotective effect of DA D2-like receptor agonist, lisuride, and the role of DA receptors in this protection. Treatment with lisuride alleviated loss of tyrosine hydroxylase (TH) both direct and intraperitoneal injection in 6-hydroxydopamine (6-OHDA) mouse model. Similar results were obtained in primary neuronal cultures treated with lisuride. Lisuride protected TH expression against 6-OHDA-induced cytotoxicity in a concentration-dependent manner. Then, we evaluated the role of DA D2 and D3 receptor in neuroprotective effect of lisuride. Treatment of neuronal cultures with L-741,626, a DA D2 receptor-selective antagonist, did not alter neuroprotective effect of lisuride. However, protective effect of lisuride on TH expression was abolished when cells were treated with GR103691, a D3 receptor selective antagonist. Furthermore, whether lisuride can alleviate mitochondrial damage of DAergic neurons induced by 6-OHDA, we investigated the expression of the mitochondrial regulatory protein, paraplegin, and changes in mitochondria morphology. Treatment with lisuride countered a 6-OHDA-induced reduction in paraplegin and TH expression, and co-treatment with GR103691 blocked this effect of lisuride. Transmission electron microscopy confirmed the lisuride mitigation of 6-OHDA-induced damage to the mitochondrial membrane and cristae. These results suggest that the DA D3 receptor mediates the neuroprotective effects of lisuride by preventing mitochondrial damage.

SIRT1 plays a neuroprotective role in traumatic brain injury in rats via inhibiting the p38 MAPK pathway.

Traumatic brain injury (TBI) is a major cause of disability and death in patients who experience a traumatic injury. Mitochondrial dysfunction is one of the main factors contributing to secondary injury in TBI-associated brain damage. Evidence of compromised mitochondrial function after TBI has been, but the molecular mechanisms underlying the pathogenesis of TBI are not well understood. Silent information regulator family protein 1 (SIRT1), a member of the NAD+-dependent protein deacetylases, has been shown to exhibit neuroprotective activities in animal models of various pathologies, including ischemic brain injury, subarachnoid hemorrhage and several neurodegenerative diseases. In this study, we investigated whether SIRT1 also exert neuroprotective effect post-TBI, and further explored the possible regulatory mechanisms involved in TBI pathogenesis. A lateral fluid-percussion (LFP) brain injury model was established in rats to mimic the insults of TBI. The expression levels of SIRT1, p-p38, cleaved caspase-9 and cleaved caspase-3 were all markedly increased and reached a maximum at 12 h post-TBI. In addition, mitochondrial function was impaired, evidenced by the presence of swollen and irregularly shaped mitochondria with disrupted and poorly defined cristae, a relative increase of the percentage of neurons with low ΔΨm, the opening of mPTP, and a decrease in neuronal ATP content, especially at 12 h post-TBI. Pretreatment with the SIRT1 inhibitor sirtinol (10 mg/kg, ip) induced p-p38 activation, exacerbated mitochondrial damage, and promoted the activation of the mitochondrial apoptosis pathway. In contrast, pretreatment with the p38 inhibitor SB203580 (200 µg/kg, ip) significantly attenuated post-TBI-induced expression of both cleaved caspase-9 and cleaved caspase-3 and mitochondrial damage, whereas it had no effects on SIRT1 expression. Together, these results reveal that the 12 h after TBI may be a crucial time at which secondary damage occurs; the activation of SIRT1 expression and inhibition of the p38 MAPK pathway may play a neuroprotective role in preventing secondary damage post-TBI. For this reason, both SIRT1 and p38 are likely to be important targets to prevent secondary damage post-TBI.

[PECULIARITIES OF THE CEREBROVASCULAR EFFECTS OF GLUTAMIC ACID].

Experiments on nonlinear rats subjected to global transient cerebral ischemia revealed the ability of glutamic acid to improve cerebral circulation. Consequently, the excitatory amino acid can produce adverse (neurotoxic) and positive (anti-ischemic) effects in cerebral ischemia. The cerebrovascular effect of glutamic acid in cerebral ischemia is attenuated on the background action of the MNDA receptor blocker MK-801 (0.5 mg/kg intravenously) and eliminated by bicuculline. When glutamic acid is combined with the non-competitive MNDA receptor antagonist MK-801, neither one nor another drug shows its vasodilator effect. The results are indicative of the interaction between excitatory and inhibitory systems on the level of cerebral vessels and once again confirm our previous conclusion about the decisive role of GABA(A) receptors in brain vessels in the implementation of anti-ischemic activity of endogenous compounds (melatonin) and well-known pharmacological substances (mexidol, afobazole), and new chemical compounds based on GABA-containing lipid derivatives.

3-O-Methyldopa inhibits astrocyte-mediated dopaminergic neuroprotective effects of L-DOPA.

BACKGROUND: We evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of L-DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and neuroprotective effects of L-DOPA in striatal astrocytes. We examined changes in the numbers of dopaminergic neurons after treatment with L-DOPA and 3-OMD or entacapone, a peripheral COMT inhibitor, using primary cultured mesencephalic neurons and striatal astrocytes. RESULTS: The number of tyrosine hydroxylase-positive dopaminergic neurons was not affected by L-DOPA treatment in mesencephalic neurons alone. However, the increase in viability of dopaminergic neurons in the presence of astrocytes was further enhanced after methyl-L-DOPA treatment (25 µM) in mixed cultured mesencephalic neurons and striatal astrocytes. The neuroprotective effect of 25 µM L-DOPA was almost completely inhibited by simultaneous treatment with 3-OMD (10 or 100 µM), and was enhanced by concomitant treatment with entacapone (0.3 µM). The uptake of L-DOPA into and the release of glutathione from striatal astrocytes after L-DOPA treatment (100 µM) were inhibited by simultaneous exposure to 3-OMD (100 µM). CONCLUSIONS: These data suggest that L-DOPA exerts its neuroprotective effect on dopaminergic neurons via astrocytes and that 3-OMD competes with L-DOPA by acting on target molecule(s) (possibly including glutathione) released from astrocytes. Since some amount of entacapone can cross the blood-brain barrier, this reagent may enhance L-DOPA transportation by inhibiting COMT and increase the astrocyte-mediated neuroprotective effects of L-DOPA on dopaminergic neurons.

Involvement of IGF-1 receptor signaling pathway in the neuroprotective effects of Icaritin against MPP(+)-induced toxicity in MES23.5 cells.

Icaritin, a natural derivative of Icariin, is the major bioactive component of Epimedium Genus. The present study tested the hypothesis that the neuroprotective effects of Icaritin against 1-Methyl-4-phenylpyridinium ion (MPP(+))-induced toxicity involved activation of the insulin-like growth factor-1 receptor (IGF-1R) signaling pathway in MES23.5 cells. Our results revealed that Icaritin pretreatment attenuated the MPP(+)-induced decrease of cell viability in a dose-dependent fashion. Co-pretreatment with phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002, mitogen-activated protein kinase (MEK) inhibitor PD98059 or IGF-1 receptor antagonist JB-1 could completely block the protective effects of Icaritin. Moreover, Icaritin pretreatment down-regulated MPP(+)-induced increase of Bax/Bcl-2 ratio transcriptionally and post-transcriptionally. Further study revealed that Icaritin pretreatment could restore the decreased protein expression of Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) induced by MPP(+) and these effects could be completely abolished by LY294002, PD98059 or JB-1. Additionally, Icaritin treatment alone time-dependently enhanced the phosphorylation of Akt and ERK1/2 in MES23.5 cells. The activation of Akt and ERK1/2 by Icaritin could be completely blocked by JB-1, LY294002 or PD98059. Taken together, our data demonstrate that IGF-1 receptor mediated activation of PI3K/Akt and MEK/ERK1/2 signaling pathways are involved in the protective effects of Icaritin against MPP(+)-induced toxicity in MES23.5 cells.

Protection against Experimental Stroke by Ganglioside GM1 Is Associated with the Inhibition of Autophagy.

UNLABELLED: Ganglioside GM1, which is particularly abundant in the central nervous system (CNS), is closely associated with the protection against several CNS disorders. However, controversial findings have been reported on the role of GM1 following ischemic stroke. In the present study, using a rat middle cerebral artery occlusion (MCAO) model, we investigated whether GM1 can protect against ischemic brain injury and whether it targets the autophagy pathway. GM1 was delivered to Sprague-Dawley male rats at 3 doses (25 mg/kg, 50 mg/kg, 100 mg/kg) by intraperitoneal injection soon after reperfusion and then once daily for 2 days. The same volume of saline was given as a control. Tat-Beclin-1, a specific autophagy inducer, was administered by intraperitoneal injection at 24 and 48 hours post-MCAO. Infarction volume, mortality and neurological function were assessed at 72 hours after ischemic insult. Immunofluorescence and Western blotting were performed to determine the expression of autophagy-related proteins P62, LC3 and Beclin-1 in the penumbra area. No significant changes in mortality and physiological variables (heart rate, blood glucose levels and arterial blood gases) were observed between the different groups. However, MCAO resulted in enhanced conversion of LC3-I into LC3-II, P62 degradation, high levels of Beclin-1, a large area infarction (26.3±3.6%) and serious neurobehavioral deficits. GM1 (50 mg/kg) treatment significantly reduced the autophagy activation, neurobehavioral dysfunctions, and infarction volume (from 26.3% to 19.5%) without causing significant adverse side effects. However, this biological function could be abolished by Tat-Beclin-1. IN CONCLUSION: GM1 demonstrated safe and robust neuroprotective effects that are associated with the inhibition of autophagy following experimental stroke.

Lithium ions attenuate serum-deprivation-induced apoptosis in PC12 cells through regulation of the Akt/FoxO1 signaling pathways.

RATIONALE: Lithium is currently used in the treatment of mental illness. We have previously reported that lithium stimulated the protein kinase B/Forkhead box O1 (Akt/FoxO1) pathway in rats. However, little information is available regarding its neuroprotective role of this pathway and underlying mechanisms. OBJECTIVES: PC12 cells treated with serum deprivation were used as a toxicity model to study the protective effect of lithium and its underlying mechanisms. METHODS: Cell viability was determined by methyl thiazolyl tetrazolium assay and Hoechst staining. FoxO1 subcellular location and its overexpression were used to study the underlying mechanisms. Various pathway inhibitors were used to investigate the possible pathways, while the phosphorylation of Akt and FoxO1 was analyzed by Western blot. RESULTS: Lithium pretreatment dose-dependently reduced PC12 cell apoptosis induced by serum starvation. The protective effect of lithium was abolished by LY294002, a PI3K-specific inhibitor, and Akt inhibitor Akt inhibitor VIII, whereas mitogen-activated protein kinase kinase (MEK kinase) inhibitor U0126 had no effect. Lithium induced the phosphorylation of Akt and FoxO1 in a time- and concentration-dependent manner. Lithium-induced phosphorylation of Akt and FoxO1 is mediated by the PI3K/Akt pathway. Serum deprivation caused nuclear translocation of FoxO1 while application of lithium reversed the effect of serum deprivation. Moreover, overexpression of FoxO1 enhanced cell apoptosis induced by serum withdrawal. Finally, lithium was found to reduce the exogenous and endogenous FoxO1 protein levels in PC12 cells in a concentration-dependent fashion. CONCLUSIONS: The protective effect of lithium against serum starvation cell death is mediated by the PI3K/Akt/FoxO1 pathway.

Rosiglitazone Suppresses In Vitro Seizures in Hippocampal Slice by Inhibiting Presynaptic Glutamate Release in a Model of Temporal Lobe Epilepsy.

Peroxisomal proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor whose agonist, rosiglitazone has a neuroprotective effect to hippocampal neurons in pilocarpine-induced seizures. Hippocampal slice preparations treated in Mg2+ free medium can induce ictal and interictal-like epileptiform discharges, which is regarded as an in vitro model of N-methyl-D-aspartate (NMDA) receptor-mediated temporal lobe epilepsy (TLE). We applied rosiglitazone in hippocampal slices treated in Mg2+ free medium. The effects of rosiglitazone on hippocampal CA1-Schaffer collateral synaptic transmission were tested. We also examined the neuroprotective effect of rosiglitazone toward NMDA excitotoxicity on cultured hippocampal slices. Application of 10 µM rosiglitazone significantly suppressed amplitude and frequency of epileptiform discharges in CA1 neurons. Pretreatment with the PPARγ antagonist GW9662 did not block the effect of rosiglitazone on suppressing discharge frequency, but reverse the effect on suppressing discharge amplitude. Application of rosiglitazone suppressed synaptic transmission in the CA1-Schaffer collateral pathway. By miniature excitatory-potential synaptic current (mEPSC) analysis, rosiglitazone significantly suppressed presynaptic neurotransmitter release. This phenomenon can be reversed by pretreating PPARγ antagonist GW9662. Also, rosiglitazone protected cultured hippocampal slices from NMDA-induced excitotoxicity. The protective effect of 10 µM rosiglitazone was partially antagonized by concomitant high dose GW9662 treatment, indicating that this effect is partially mediated by PPARγ receptors. In conclusion, rosiglitazone suppressed NMDA receptor-mediated epileptiform discharges by inhibition of presynaptic neurotransmitter release. Rosiglitazone protected hippocampal slice from NMDA excitotoxicity partially by PPARγ activation. We suggest that rosiglitazone could be a potential agent to treat patients with TLE.

A novel natural product inspired scaffold with robust neurotrophic, neurogenic and neuroprotective action.

In search for drugs to treat neuropsychiatric disorders wherein neurotrophic and neurogenic properties are affected, two neurotrophically active small molecules specially crafted following natural product leads based on 2-oxa-spiro[5.5]-undecane scaffold, have been thoroughly evaluated for their neurotrophic, neurogenic and neuroprotective potential in ex vivo primary culture and in vivo zebrafish and mouse models. The outcome of in vivo investigations suggest that one of these molecules is more neurotrophic than neurogenic while the other one is more neurogenic than neurotrophic and the former exhibits remarkable neuroprotection in a mouse acute ischemic stroke model. The molecular mechanisms of action of these compounds appear to be through the TrkB-MEK-ERK-CREB-BDNF pathway as pre-treatment with neurotrophin receptor TrkB inhibitor ANA-12 and MEK inhibitor PD98059 attenuates the neurotrophic action of compounds.

Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination.

Enhancing repair of myelin is an important but still elusive therapeutic goal in many neurological disorders. In multiple sclerosis, an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells resident within the subventricular zone are known sources of remyelinating cells. Here we characterize the contribution to remyelination of a subset of adult neural stem cells, identified by their expression of Gli1, a transcriptional effector of the sonic hedgehog pathway. We show that these cells are recruited from the subventricular zone to populate demyelinated lesions in the forebrain but never enter healthy, white matter tracts. Unexpectedly, recruitment of this pool of neural stem cells, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacological inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signalling was ineffective, indicating that the role of Gli1 both in augmenting hedgehog signalling and in retarding myelination is specialized. Indeed, inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis and is neuroprotective. Thus, endogenous neural stem cells can be mobilized for the repair of demyelinated lesions by inhibiting Gli1, identifying a new therapeutic avenue for the treatment of demyelinating disorders.

Neuroprotective effect of nicorandil through inhibition of apoptosis by the PI3K/Akt1 pathway in a mouse model of deep hypothermic low flow.

OBJECTIVE: Nicorandil exerts a protective effect on ischemia-reperfusion (I/R) injury in the brain and kidney through anti-apoptotic mechanisms. However, the mechanism by which nicorandil protects against I/R injury induced by deep hypothermic low flow (DHLF) remains unclear. METHODS: We used a cerebral I/R model induced by DHLF to determine the neuroprotective effects and possible mechanisms of nicorandil. RESULTS: Hematoxylin-eosin (HE) staining and in situ terminal deoxynucleotidyl transferase UTP nick end labeling (TUNEL) assay were used to detect changes in cell morphology and the number of apoptotic cells in hippocampus, respectively. The apoptotic regulators including Bcl-2, Bax, Akt, and p-Akt (the active, phosphorylated form of Akt) were examined by Western blot (WB). Histopathological findings showed that nicorandil significantly alleviated morphological damage in hippocampal and reduced the number of TUNEL-positive nuclei induced by DHLF. Nicorandil also increased the expression of Bcl-2 and decreased the expression of Bax, while increasing p-Akt level. Consistent with these results, nicorandil-mediated neuroprotection was reduced in the Akt1+/- mutant mice and inhibited by LY294002, a PI3K inhibitor. CONCLUSIONS: These findings showed that nicorandil provides a neuroprotective role in DHLF-induced I/R injury by inhibiting apoptosis via activation of the PI3K/Akt1 signaling pathway.

Alpha-Linolenic Acid-Induced Increase in Neurogenesis is a Key Factor in the Improvement in the Passive Avoidance Task After Soman Exposure.

Exposure to organophosphorous (OP) nerve agents such as soman inhibits the critical enzyme acetylcholinesterase (AChE) leading to excessive acetylcholine accumulation in synapses, resulting in cholinergic crisis, status epilepticus and brain damage in survivors. The hippocampus is profoundly damaged after soman exposure leading to long-term memory deficits. We have previously shown that treatment with three sequential doses of alpha-linolenic acid, an essential omega-3 polyunsaturated fatty acid, increases brain plasticity in naïve animals. However, the effects of this dosing schedule administered after a brain insult and the underlying molecular mechanisms in the hippocampus are unknown. We now show that injection of three sequential doses of alpha-linolenic acid after soman exposure increases the endogenous expression of mature BDNF, activates Akt and the mammalian target of rapamycin complex 1 (mTORC1), increases neurogenesis in the subgranular zone of the dentate gyrus, increases retention latency in the passive avoidance task and increases animal survival. In sharp contrast, while soman exposure also increases mature BDNF, this increase did not activate downstream signaling pathways or neurogenesis. Administration of the inhibitor of mTORC1, rapamycin, blocked the alpha-linolenic acid-induced neurogenesis and the enhanced retention latency but did not affect animal survival. Our results suggest that alpha-linolenic acid induces a long-lasting neurorestorative effect that involves activation of mTORC1 possibly via a BDNF-TrkB-mediated mechanism.

The role of necroptosis in neurosurgical diseases

Programmed necrosis or necroptosis is an alternative form of cell death that is executed through a caspase-independent pathway. Necroptosis has been implicated in many pathological conditions. Genetic or pharmacological inhibition of necroptotic signaling has been shown to confer neuroprotection after traumatic and ischemic brain injury. Therefore, the necroptotic pathway represents a potential target for neurological diseases that are managed by neurosurgeons. In this review, we summarize recent advances in the understanding of necroptotic signaling pathways and explore the role of necroptotic cell death in craniocerebral trauma, brain tumors, and cerebrovascular diseases.

The role of necroptosis in neurosurgical diseases.

Programmed necrosis or necroptosis is an alternative form of cell death that is executed through a caspase-independent pathway. Necroptosis has been implicated in many pathological conditions. Genetic or pharmacological inhibition of necroptotic signaling has been shown to confer neuroprotection after traumatic and ischemic brain injury. Therefore, the necroptotic pathway represents a potential target for neurological diseases that are managed by neurosurgeons. In this review, we summarize recent advances in the understanding of necroptotic signaling pathways and explore the role of necroptotic cell death in craniocerebral trauma, brain tumors, and cerebrovascular diseases.

Pterostilbene mediates neuroprotection against oxidative toxicity via oestrogen receptor α signalling pathways.

OBJECTIVES: Accumulating evidence indicated protective role of phytoestrogens against neuronal damage induced by various insults, such as amyloid beta, oxygen deprivation and mitochondrial toxins. Hydrogen peroxide (H2 O2 ) influences the mitochondrial membrane potential, which eventually results in cell apoptosis. In this study, we investigated the effects and possible mechanisms of a phytoestrogen, pterostilbene (PTER), in cell apoptosis induced by H2 O2 in human neuronal SH-SY5Y cells. We also analysed the involvement of oestrogen receptors, oestrogen receptor-α and -ß (ER-α and ER-ß) in the protective role of PTER. METHODS: The effects of PTER on H2 O2 -stimulated cell were examined using MTT and FACS analysis. The signal pathways and estrogen receptors involved in PTER's effects were investigated using MTT and Western blot analysis. KEY FINDINGS: The results showed that H2 O2 treatment significantly reduced cell viability in SY5Y cells, which was protected by PTER treatment. We also found that H2O2 inhibited the PI3K/AKT and MAPK/ERK signalling pathways, whereas PTER treatment restored these signalling pathways. We also found that the PTER effect could be largely blocked by an ER-α antagonist, 3-Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP), but not by an ER-ß antagonist, 4-[2-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a] pyrimidin-3-yl]phenol (PHTPP), suggesting that ER-α is a major player in the neuroprotective activity of PTER. CONCLUSION: Our study thus demonstrates that PTER is an effective neuroprotective agent presumably through ER-α-mediated signalling pathways.