Spinal bulbar muscular atrophy (SBMA) is an adult-onset, slowly progressive motor neuron disease caused by abnormal CAG repeat expansion in the androgen receptor (AR) gene. Although ligand (testosterone)-dependent mutant AR aggregation has been shown to play important roles in motor neuronal degeneration by the analyses of transgenic mice models and in vitro cell culture models, the underlying disease mechanisms remain to be fully elucidated because of the discrepancy between model mice and SBMA patients. Thus, novel human disease models that recapitulate SBMA patients’ pathology more accurately are required for more precise pathophysiological analysis and the development of novel therapeutics. Here, we established disease specific iPSCs from four SBMA patients, and differentiated them into spinal motor neurons. To investigate motor neuron specific pathology, we purified iPSC-derived motor neurons using flow cytometry and cell sorting based on the motor neuron specific reporter, HB9 e438 ::Venus , and proceeded to the genome-wide transcriptome analysis by RNA sequences. The results revealed the involvement of the pathology associated with synapses, epigenetics, and endoplasmic reticulum (ER) in SBMA. Notably, we demonstrated the involvement of the neuromuscular synapse via significant upregulation of Synaptotagmin, R-Spondin2 (RSPO2), and WNT ligands in motor neurons derived from SBMA patients, which are known to be associated with neuromuscular junction (NMJ) formation and acetylcholine receptor (AChR) clustering. These aberrant gene expression in neuromuscular synapses might represent a novel therapeutic target for SBMA.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.

BACKGROUND:Deposition of the amyloid β protein (Aβ) into neuritic plaques is the neuropathological hallmark of Alzheimer's Disease (AD). Aβ is generated through the cleavage of the Amyloid Precursor Protein (APP) by β-secretase and γ-secretase. Currently, the evaluation of APP cleavage by β-secretase in experimental settings has largely depended on models that do not replicate the physiological conditions of this process.OBJECTIVE:To establish a novel live cell-based β-secretase enzymatic assay utilizing a novel chimeric protein that incorporates the natural sequence of APP and more closely replicates its cleavage by β-secretase under physiological conditions.METHODS:We have developed a chimeric protein construct, ASGβ, incorporating the β-site cleavage sequence of APP targeted by β-secretase and its intracellular trafficking signal into a Phosphatase-eGFP secreted reporter system. Upon cleavage by β-secretase, ASGβ releases a phosphatase-containing portion that can be measured in the culture medium, and an intracellular fraction that can be detected through Western Blot. Subsequently, we have generated a cell line stably expressing ASGβ that can be utilized to assay β-secretase in real time.RESULTS:ASGβ is specifically targeted by β-secretase, being cleaved exclusively at the site responsible for the generation of Aβ. Dosage response to β-secretase inhibitors shows that β-secretase activity can be positively correlated to phosphatase activity in culture media.CONCLUSION:Our findings suggest this system could be a high-throughput tool to screen compounds that aim to modulate β-secretase activity and Aβ production under physiological conditions, as well as evaluating factors that regulate this cleavage.

Recent epidemiological studies have noted that type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease (AD). In a previous study, we utilized a mouse model of T2DM/AD and demonstrated that beta-alanyl-L-histidine, endogenous dipeptide existed in muscle and brain, ameliorated cognitive deficit observed in this T2DM/AD model mouse. Our goal in this study was to elucidate mechanism for the amelioration by the treatment of this dipeptide. For this purpose, we utilized a micro-array analysis of expressed gene in the hippocampus of this model mouse either in the absence or the presence of beta-alanyl-L-histidine treatment. B6C3-Tg (APP swe/PSEN1dE9) 85Dbo/J AD purchased from Jackson Laboratories (Bar Harbor, Maine, USA) was utilized for this study. Animals were fed with high fat diet (HFD-32, containing 32% of fat; CLEA, Japan) from 4 month of age for 8 weeks. For the treatment group, animals were treated with beta-alanyl-L-histidine through drinking bottle at the concentration of 1 g/L (approximately 5 mg/body/day). This treatment was started 2 weeks after the initial feeding with HFD and kept until the end of the experiments. Control animals had access to regular de-ionized autoclaved drinking water. Animals were tested for contextual fear conditioning task. Twenty-four hours after the behavioral test, mice were sacrificed and perfused transcardially with saline. Then, the right hippocampus was dissected from the brain and was homogenized in TRIzol reagent and stored at -80 °C. Gene expression of individual hippocampus was evaluated with SurePrint G3 Mouse GE 8x60K Microarray Kit (Agilent Technologies) under the entrustment of Cell Innovator Co., Fukuoka, Japan. Other sets of animals were utilized for immunohistochemical analysis or animal MRI analysis as described by Chin et al., (2013) J. Neuroinflammation. In this T2DM/AD model, we have observed the decline in spatial memory performance, as detected by the measurement of freezing time in contextual fear conditioning task. We did not detect any change in the amount of beta amyloid plaque between the treatment and the control group, but observed differences in the neuroinflammatry response between the two groups. The beta-alanyl-L-histidine treatment significantly blocked the increase in the neuroinflammatory response as revealed by immnohistochemistry and by diffusion MRI analysis. As a result from microarray analysis of the hippocampal samples (n = 3 in each group), to our surprise, we detected a substantial decrease in the expression of both astrocytic GABA-transpoters in the treatment group in comparison to the control group (GAT2 (Slc6a13): ratio (treat / control) = 0.36 p=0.0006; BGT1 (Slc6a12): ratio = 0.27, p = 0.0007). In addition, we observed decrease in the expression of BMP7 (ratio 0.52, P = 0.0009) and GFAP (ratio 0.54, P = 0.006) in the treatment group. In conclusion, we can propose a new model for the effect of beta-alanyl-L-histidine on the amelioration of cognitive decline observed in T2DM/AD through the inhibition of the expression of astrocytic GABA transporters. Since, beta-alanine, a cleaved product of this dipeptide, is a substrate of the two astrocytic GABA transporters. We can speculate that beta-alanine, a catabolite of beta-alanyl-Lhistidine by carnosinase, promotes the down-modulation of genes expressing astroytic GABA-transporters after transferred into the central nervous system from the blood flow by taurine / beta-alanine transporter (Slc6A6) at the blood brain barrier. In the affected astrocytes, this cellular event may lead to the inhibition of BMP7 expression then the suppression of astrocytic activation, gliosis. Further study must be definitely required to assist this hypothesis of the suppression of gliosis by the treatment of beta-alanyl-L-histidine.

Down Syndrome (DS) patients develop characteristic Alzheimer's Disease (AD) neuropathology after their middle age. Prominent neuronal loss has been observed in the cortical regions of AD brains. However, the underlying mechanism leading to this neuronal loss in both DS and AD remains to be elucidated. Calcium overloading and oxidative stress have been implicated in AD pathogenesis. Two major isoforms of regulator of calcineurin 1 (RCAN1), RCAN1.1 and RCAN1.4, are detected in human brains. In this report we defined the transcriptional regulation of RCAN1.1 and RCAN1.4 by two alternative promoters. Calcium overloading upregulated RCAN1.4 expression by activating RCAN1.4 promoter through calcineurin-NFAT signaling pathway, thus forming a negative feedback loop in isoform 4 regulation. Furthermore, RCAN1.4 overexpression exacerbated calcium overloading-induced neuronal apoptosis, which was mediated by caspase-3 apoptotic pathway. Our results suggest that downregulating RCAN1.4 expression in neurons could be beneficial to AD patients.

Adult neurogenesis and hippocampal function are both regulated by neuronal activity, particularly by GABAergic signals. Recently, it has been reported that an imbalance of the GABAergic 　 transmission impairs adult neurogenesis in Alzheimer's disease (AD). This GABAergic signal is modulated by several endogenous molecules. Diazepam binding inhibitor is a small cytosolic polypeptide which is an inverse agonist of GABA A receptor. Thus, we researched the expression and the effect of diazepam binding inhibitor (DBI) on neurogenesis in the hippocampus by using AD model mice. In this study, we used AD model mice which the early onset of the symptoms of AD was induced. Our recent study showed that feeding with High Fat Diet is a viable method for inducing the early onset of the symptoms of AD in B6C3-Tg (APPswe/PSEN1dE9)85Dbo/J Alzheimer's Disease Model Transgenic mice. Using these mice, we performed DBI knockdown experiment and immunostaing of DBI to investigate a functional role of DBI in dentate gyrus. To evaluate the effect of DBI knockdown for differentiation we observed the number and morphology of doublecortin (DCX; immature neuron marker) positive cells. We immunostained DBI and dyed senile plaques to compare the expression of DBI in AD model and control mice. As a result, we observed a tendency of increased DBI expression in the hippocampus in AD model mice. Commonly, DBI is expressed in neural stem cells, however, it was also expressed in glial cell in AD model mice. Furthermore, expression of DBI was observed in astrocytes surrounding senile plaques in AD model mice. This result corroborates the report that the Aβ peptide stimulates DBI biosynthesis in cultured rat astrocytes. The impairment of maturation of immature neuron in AD model mice was repaired by the inhibition of DBI expression in the dentate gyrus. These results suggest that increased DBI in the hippocampus inhibit normal maturation in AD model mice. This increased DBI is derived from astrocyte activated by Aβ. DBI produced by astrocyte and released in the dentate gyrus cause disorder in neurogenesis in AD mice via GABA A receptor.

Our goal in this study was to determine whether or not feeding young (4 months old) Alzheimer's disease model transgenic mice with a high fat diet (HFD), consisting of 32% fat, is capable of causing cognitive decline and whether treatment with β-alanyl-L-histidine (carnosine) is capable of reducing these effects. Carnosine is an endogenous antioxidant and antiglycating agent that is abundantly present in the brain and muscle tissues of vertebrates. After 8 weeks of feeding with HFD, we observed a significant decline in the contextual memory in transgenic mice fed with HFD as compared to transgenic mice fed with a normal diet as well as to normal diet-wild type mice. Treatment with carnosine at a dose of 5 mg/day for 6 weeks was effective in preventing cognitive decline, as the transgenic group fed with HFD and treated with carnosine displayed a level of cognition comparable to controls. No differences in senile plaque load were observed between all groups. However, we observed an increase in the expression of RAGE in blood vessels as well as increased microglial activation in the hippocampus of animals fed with HFD, effects that were reversed when treated with carnosine. Given these results, there is a possibility that inflammation and cerebrovascular abnormalities might be the cause of cognitive decline in this model.

Oxygen-glucose deprivation (OGD) in brain cells increases extracellular glutamate concentration leading to excitotoxicity. Glutamate uptake from the synaptic cleft is carried out by glutamate transporters, which are likely to be modulated by oxidative stress. Therefore, oxidative stress is associated with reduced activity of glutamate transporters and glutamine synthetase, thus increasing extracellular glutamate levels that may aggravate damage to brain cells. Atorvastatin, a cholesterol-lowering agent, has been shown to exert neuroprotective effects. The aim of this study was to investigate if in vivo atorvastatin treatment would have protective effects against hippocampal slices subjected to OGD, ex vivo. Atorvastatin pretreatment promoted increased cell viability after OGD and reoxygenation of hippocampal slices. Atorvastatin-induced neuroprotection may be related to diminished oxidative stress, since it prevented OGD-induced decrement of non-proteic thiols (NPSH) levels and increase in the production of reactive oxygen species (ROS). Atorvastatin pretreatment also prevented the OGD-induced decrease in glutamate uptake and glutamine synthetase activity, although it had no effect on OGD-induced excitatory aminoacids release. Addition of cholesterol before OGD and reoxygenation, abolished the protective effect of atorvastatin on cellular viability as well as on glutamate uptake and glutamine synthetase activity. Therefore, atorvastatin is capable of preventing OGD-induced cell death, an effect achieved due to modulation of glutamate uptake and glutamine synthetase activity, and associated with diminished oxidative stress. Additionally, atorvastatin effects were dependent on its action on cholesterol synthesis inhibition. Thus, atorvastatin might be a useful strategy in the prevention of glutamate exitotoxicity involved in brain injuries such as vascular disorders. (C) 2013 Elsevier Ltd. All rights reserved.

Searching for new therapeutic strategies through modulation of glutamatergic transmission using effective neuroprotective agents is essential. Glutamatergic excitotoxicity is a common factor to neurodegenerative diseases and acute events such as cerebral ischemia, traumatic brain injury, and epilepsy. This study aimed to evaluate behavioral and electroencephalographic (EEG) responses of mice cerebral cortex and hippocampus to subconvulsant and convulsant application of NMDA and quinolinic acid (QA), respectively. Moreover, it aimed to evaluate if EEG responses may be related to the neuroprotective effects of NMDA. Mice were preconditioned with NMDA (75 mg/kg, i.p.) and EEG recordings were performed for 30 min. One day later, QA was injected (36.8 nmol/site) and EEG recordings were performed during 10 min. EEG analysis demonstrated NMDA preconditioning promotes spike-wave discharges (SWDs), but it does not display behavioral manifestation of seizures. Animals that were protected by NMDA preconditioning against QA-induced behavioral seizures, presented higher number of SWD after NMDA administration, in comparison to animals preconditioned with NMDA that did display behavioral seizures after QA infusion. No differences were observed in latency for the first seizure or duration of seizures. EEG recordings after QA infusion demonstrated there were no differences in the number of SWD, latency for the first seizure or duration of seizures in animals pretreated with saline or in animals preconditioned by NMDA that received QA. A negative correlation was identified between the number of NMDA-induced SWD and QA-induced seizures severity. These results suggest a higher activation during NMDA preconditioning diminishes mice probability to display behavioral seizures after QA infusion.

Alzheimer's disease (AD) is the most prevalent form of dementia associated with old age in our present society. Recently, obesity and hypercholesterolemia have been lauded as major risk factors for the early onset of its symptoms. We are researching a new model of early-onset AD utilizing a high-fat diet (HFD) as a means of inducing the metabolic syndrome observed as a common risk factor for AD. This model of diet-induced obesity has been previously shown to be able to induce the insulin resistance and inflammatory responses observed in the metabolic syndrome and inhibit hippocampal neurogenesis. Our objective in the present study was to evaluate whether feeding with a HFD is capable of evoking an early onset of the symptoms observed in an animal model for AD, and evaluate whether a treatment with Carnosine, an endogenous antioxidant, is capable of reverting this cognitive decline. For this study we utilized 4 month-old APP/Swe AD model transgenic mice, and fed them with a HFD for a period of 2 months in order to induce obesity and hypercholesterolemia. Animals were treated with Carnosine (1g/L), administered through their drinking water for 6 weeks, starting on the third week of feeding. On the last 3 days of feeding, the animals were subjected to cognitive testing carried out using a Conditioned Fear Response protocol. 24 hours after the cognitive testing, animals were sacrificed for the collection of brain samples for further analyses. Feeding with a HFD was capable of causing significant contextual and cued memory impairments in APP/Swe mice when compared to age and diet-matched controls. Chronic treatment with Carnosine has proven effective in countering the adverse effects on cognition caused by feeding with HFD. Histochemical evaluation has shown no difference in the deposition of the Aβ peptide in any of the groups. Feeding with HFD is an effective method for causing the early onset of cognitive decline observed in AD. Treatment with Carnosine proved effective in countering this decline, suggesting that oxidative stress and Advanced Glycation Endproducts might be underlying this decline, given the antioxidant and antiglycating properties of Carnosine.

Preconditioning by N-methyl-d-aspartate (NMDA) may be promoted in vivo by the administration of a sub-convulsing dose of NMDA, with a neuroprotective effect against seizures and neuronal death induced by the infusion of quinolinic acid (QA) in mice. This study aimed to evaluate the participation of protein kinase C (PKC), cyclic AMP-dependent protein kinase (PKA), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK), Ca2+/calmodulin dependent protein kinase II (CaMKII) and phosphatidilinositol-3 kinase (PI3K) signaling pathways in this neuroprotection model. Adult Swiss male mice were preconditioned with NMDA 24 h before the infusion of QA, and were treated with inhibitors of the aforementioned signaling pathways either 15 min before the preconditioning or infusion of QA. Inhibition of the PKA and PI3K pathways abolished the protection evoked by NMDA, and inhibition of the MEK pathway significantly diminished this protection. Treatment with PKC and CaMKII inhibitors did not alter the protection rate. Inhibition of the MEK and PKC pathways resulted in an increased mortality rate when followed by the infusion of QA, or NMDA preconditioning and QA infusion, respectively. These results suggest that the PKA, PI3K and MEK pathways have a crucial role in the achievement of a neuroprotective state following preconditioning.

Certain dietary patterns, specifically high-fat diets (HFD), increase the risk of developing sporadic Alzheimer's disease and cognitive decline. However, no specific therapy has been developed to ameliorate the negative effects of HFD on cognition. Carnosine (beta-alanyl-L-histidine) is a dipeptide found at up to 20 mM in muscle and nerve tissues in humans, and is a quencher of cytotoxic unsaturated aldehydes from the degradative oxidative pathway of endogenous lipids. HFD may cause lipid peroxidation, and its products such as unsaturated aldehydes could be mediators for HFD-related cognitive decline. Therefore, there is a possibility that carnosine treatment is capable of impeding neuronal degeneration in sporadic Alzheimer's disease and cognitive decline. APPswe/PSEN1dE9 (B6C3-Tg (APPswe, PSEN1dE9)85Dbo/J) hemizygous mice 4 months old were randomly assigned to one of three diets/treatments: normal diet-no treatment (ND), HFD-no treatment (n=5), or HFD-carnosine treatment (carnosine at 1 g/L in drinking bottle; n=5). Mice were fed with either ND or HFD (HFD-32; Clea Japan) for 8 weeks. HFD is rich in fatty acids (32g/100g diet) and in cholesterol (12.9 mg/100 g). Two weeks after the start of the HFD, HFD-carnosine group mice were treated with carnosine for 6 weeks. At the end of treatment, the cognitive function of mice was assessed by a behavioral test. Cognitive testing consisted of the Fear Conditioning Behavioral test, which aims to test the contextual and cued fear responses to the experimental environment and an aural stimulus. Cognitive testing was carried out on the last 3 days of the experiment. In the first day of testing the animals were introduced to a closed apparatus and given 3 consecutive 0.75mA electric shocks accompanied by a tone, in order to induce a fear response to the tone and the experimental environment. Twenty-four hours after the conditioning the animals were introduced once more to the apparatus and the fear response to the experimental environment was evaluated in order to assess the contextual memory of the animals. Twenty-four hours after the contextual text, the environment of the apparatus was changed prior to the introduction of the animals, and their fear response to a continuous tone was evaluated in order to assess their cued memory as described previously (Corcoran et al., 2002). Data collection was carried out by means of computerized video recording system (Med Associates). Since our goal was to identify a treatment protocol for those people who already present signs for metabolic syndrome and bear the risk of sporadic Alzheimer's disease, we constructed a study design with the 2 weeks of HFD feeding followed by the 6 weeks of treatment by utilizing an Alzheimer's disease mouse model, APPswe/PSEN1dE9 double transgenic. To assess the effect of HFD on cognitive performance of APPswe/PSEN1dE9 double transgenic mice, we used the context and the tone fear-conditioning test. Cognitive performance of APPswe/PSEN1dE9 double transgenic mice fed HFD for 8 weeks, treated with carnosine or vehicle, was compared to age-matched APPswe/PSEN1dE9 mice on a normal diet. Neither HFD nor carnosine treatment increased mortality, nor decreased the locomotor activity. In contrast, HFD caused an increase in body weight, which was not affected by the treatment with carnosine. As illustrated in the Figure, carnosine treatment ameliorates the cognitive decline in HFD as evaluated in the contextual test (P < 0.05; 0-128 sec); however, we did not see any significant difference between groups in the tone-test (not shown). From these results, we conclude that HFD worsens hippocampal dependent-memory performance, while the carnosine treatment restores cognitive performance to the control level.

Traumatic brain injury (TBI) causes impairment of fine motor functions in humans and nonhuman mammals that often persists for months after the injury occurs. Neuroprotective strategies for prevention of the sequelae of TBI and understanding the molecular mechanisms and cellular pathways are related to the glutamatergic system. It has been suggested that cellular damage subsequent to TBI is mediated by the excitatory neurotransmitters, glutamate and aspartate, through the excessive activation of the N-methyl-D-aspartate (NMDA) receptors. Thus, preconditioning with a low dose of NMDA was used as a strategy for protection against locomotor deficits observed after TBI in mice. Male adult mice CF-1 were preconditioned with NMDA (75 mg/kg) 24 hr before the TBI induction. Under anesthesia with O(2)/N(2)O (33%: 66%) inhalation, the animals were subjected to the experimental model of trauma that occurs by the impact of a 25 g weight on the skull. Sensorimotor gating was evaluated at 1.5, 6, or 24 hr after TBI induction by using footprint and rotarod tests. Cellular damage also was assessed 24 hr after occurrence of cortical trauma. Mice preconditioned with NMDA were protected against all motor deficits revealed by footprint tests, but not those observed in rotarod tasks. Although mice showed motor deficits after TBI, no cellular damage was observed. These data corroborate the hypothesis that glutamatergic excitotoxicity, especially via NMDA receptors, contributes to severity of trauma. They also point to a putative neuroprotective mechanism induced by a sublethal dose of NMDA to improve motor behavioral deficits after TBI.

l-arginine, the substrate for endothelial nitric oxide synthase, is essential for normal endothelial function. Aim of the present study was to investigate in healthy smokers the effect of a short-term daily l-arginine administration on vascular function.We studied the effect of a 3-day oral administration of l-arginine in 10 healthy smokers (24.3 ± 0.73 years old) on 3 occasions (day0, day1 and day3). The study was carried out on two separate arms, one with l-arginine (7 gr/d) and one with placebo according to a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before, immediately after (Sm0) and 20 min after (Sm20) cigarette smoking. Endothelial function was evaluated by flow-mediated dilatation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as a measure of arterial wave reflections.Compared to placebo, l-arginine led to an increase of FMD (p < 0.05 at day 2), indicating a favorable effect on endothelial function, which however lost significance at day 3. l-arginine induced a progressive decrease of PWV and AIx at both day 2 and day 3 (p < 0.01 vs baseline for all). l-arginine blunted the acute smoking-induced increase of AIx at both day 1 (p < 0.05) and day 3 (p < 0.01), and there was a trend to protect the smoking-induced change of PWV at day 3 (p < 0.1).Short-term daily administration of l-arginine improves arterial performance in healthy smokers and abrogates the smoking-induced increase in arterial stiffness and wave reflections in these individuals.

In this study, diffusion tensor MRI was used to examine the restoration of the cerebral white matter of macaque monkeys after unilateral cerebral multiple microinfarctions. Post-stroke, the monkeys showed deficits in several neurological functions, including motor functions, but most of the deficits resolved within 6 weeks. Very interestingly, the fractional anisotropy (a value determined by diffusion tensor MRI), of the monkeys’ affected motor pathways dropped transiently, indicating a damage in the neural tracts. However, it returned to normal levels within 6 weeks after the stroke, concomitant with the gradual recovery of motor functions at subacute phase.

Statins are cholesterol-lowering agents due to the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Recent studies have shown statins possess pleiotropic effects, which appear to be independent from its cholesterol-lowering action. In this study, we investigated whether atorvastatin would have protective effects against hippocampal cell death promoted by quinolinic acid (QA)-induced seizures in mice. Mice were pretreated with Atorvastatin (1 or 10 mg/kg) or vehicle (saline, 0.9%), orally, once a day for 7 days before the intracerebroventricular (i.c.v.) QA infusion (36.8 nmol/site). Atorvastatin treatment with 1 mg/kg/day did not significantly prevent QA-induced seizures (13.34%). However, administration of atorvastatin 10 mg/kg/day prevented the clonic and/or tonic seizures induced by QA in 29.41% of the mice. Additionally, administration of atorvastatin 10 mg/kg/day significantly prevented QA-induced cell death in the hippocampus. Atorvastatin treatment promoted an increased Akt phosphorylation, which was sustained after QA infusion in both convulsed and non-convulsed mice. Moreover, atorvastatin pretreatment prevented the reduction in glutamate uptake into hippocampal slices induced by QA i.c.v. infusion. These results show that atorvastatin attenuated QA-induced hippocampal cellular death involving the Akt pathway and glutamate transport modulation. Therefore, atorvastatin treatment might be a useful strategy in the prevention of brain injury caused by the exacerbation of glutamatergic toxicity in neurological diseases such as epilepsy.