Regulation of the p75 neurotrophin receptor attenuates neuroinflammation and stimulates hippocampal neurogenesis in experimental Streptococcus pneumoniae meningitis.

BACKGROUND: Streptococcus pneumoniae meningitis is a destructive central nervous system (CNS) infection with acute and long-term neurological disorders. Previous studies suggest that p75NTR signaling influences cell survival, apoptosis, and proliferation in brain-injured conditions. However, the role of p75NTR signaling in regulating pneumococcal meningitis (PM)-induced neuroinflammation and altered neurogenesis remains largely to be elucidated. METHODS: p75NTR signaling activation in the pathological process of PM was assessed. During acute PM, a small-molecule p75NTR modulator LM11A-31 or vehicle was intranasally administered for 3 days prior to S. pneumoniae exposure. At 24 h post-infection, clinical severity, histopathology, astrocytes/microglia activation, neuronal apoptosis and necrosis, inflammation-related transcription factors and proinflammatory cytokines/mediators were evaluated. Additionally, p75NTR was knocked down by the adenovirus-mediated short-hairpin RNA (shRNA) to ascertain the role of p75NTR in PM. During long-term PM, the intranasal administration of LM11A-31 or vehicle was continued for 7 days after successfully establishing the PM model. Dynamic changes in inflammation and hippocampal neurogenesis were assessed. RESULTS: Our results revealed that both 24 h (acute) and 7, 14, 28 day (long-term) groups of infected rats showed increased p75NTR expression in the brain. During acute PM, modulation of p75NTR through pretreatment of PM model with LM11A-31 significantly alleviated S. pneumoniae-induced clinical severity, histopathological injury and the activation of astrocytes and microglia. LM11A-31 pretreatment also significantly ameliorated neuronal apoptosis and necrosis. Moreover, we found that blocking p75NTR with LM11A-31 decreased the expression of inflammation-related transcription factors (NF-κBp65, C/EBPß) and proinflammatory cytokines/mediators (IL-1ß, TNF-α, IL-6 and iNOS). Furthermore, p75NTR knockdown induced significant changes in histopathology and inflammation-related transcription factors expression. Importantly, long-term LM11A-31 treatment accelerated the resolution of PM-induced inflammation and significantly improved hippocampal neurogenesis. CONCLUSION: Our findings suggest that the p75NTR signaling plays an essential role in the pathogenesis of PM. Targeting p75NTR has beneficial effects on PM rats by alleviating neuroinflammation and promoting hippocampal neurogenesis. Thus, the p75NTR signaling may be a potential therapeutic target to improve the outcome of PM.

Notch1 Signaling Pathway Promotes Proliferation and Mediates Differentiation Direction in Hippocampus of Streptococcus pneumonia Meningitis Rats.

BACKGROUND: Streptococcus pneumonia meningitis (PM) is a major cause of childhood neurological deficits. Although the Notch1 signaling pathway regulates neurogenesis and neuroinflammation, we know little about its expression or influence on hippocampal neurogenesis and gliogenesis during PM. METHODS: We used immunofluorescence and Western blots to detect Notch1 signaling expression during experimental PM. Through double-labeling immunofluorescence, we investigated proliferation and differentiation in the dentate gyrus (DG) in PM before and after treatment with exogenous Notch1 activator (Jagged1) and inhibitor (IMR-1). RESULTS: Our results showed that Notch1 was activated after 24 hours in PM. Compared with the phosphate-buffered saline (PBS) control, Jagged1 increased the proliferation of neural stem cells and progenitor cells (NS/PCs) in DG. After 14 and 28 days of meningitis, astrocyte differentiation increased compared with control. Astrocyte differentiation was higher in the Jagged1 versus the PBS group. In contrast, IMR-1 increased neuronal differentiation but decreased astrocyte differentiation compared with dimethyl sulfoxide treatment. CONCLUSIONS: Under PM, Notch1 signaling promotes NS/PC proliferation and astrocyte differentiation in DG, while decreasing neuronal differentiation. Transient activation of the Notch1 signaling pathway explains the reactive gliogenesis and limited neuronal differentiation observed in PM.

Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis.

BACKGROUND: Streptococcus pneumoniae meningitis is a serious inflammatory disease of the central nervous system (CNS) and is associated with high morbidity and mortality rates. The inflammatory processes initiated by recognition of bacterial components contribute to apoptosis in the hippocampal dentate gyrus. Brain-derived neurotrophic factor (BDNF) has long been recommended for the treatment of CNS diseases due to its powerful neuro-survival properties, as well as its recently reported anti-inflammatory and anti-apoptotic effects in vitro and in vivo. METHODS: In this study, we investigated the effects of BDNF-related signaling on the inflammatory response and hippocampal apoptosis in experimental models of pneumococcal meningitis. Pretreatment with exogenous BDNF or the tropomyosin-receptor kinase B (TrkB) inhibitor k252a was performed to assess the activation or inhibition of the BDNF/TrkB-signaling axis prior to intracisternal infection with live S. pneumoniae. At 24 h post-infection, rats were assessed for clinical severity and sacrificed to harvest the brains. Paraffin-embedded brain sections underwent hematoxylin and eosin staining to evaluate pathological severity, and cytokine and chemokine levels in the hippocampus and cortex were evaluated by enzyme-linked immunosorbent assay. Additionally, apoptotic neurons were detected in the hippocampal dentate gyrus by terminal deoxynucleotidyl transferase dUTP-nick-end labeling, key molecules associated with the related signaling pathway were analyzed by real-time polymerase chain reaction and western blot, and the DNA-binding activity of nuclear factor kappa B (NF-κB) was measured by electrophoretic mobility shift assay. RESULTS: Rats administered BDNF exhibited reduced clinical impairment, pathological severity, and hippocampal apoptosis. Furthermore, BDNF pretreatment suppressed the expression of inflammatory factors, including tumor necrosis factor α, interleukin (IL)-1ß, and IL-6, and increased the expression of the anti-inflammatory factor IL-10. Moreover, BDNF pretreatment increased TrkB expression, activated downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, and inhibited the myeloid differentiation primary response gene 88 (MyD88)/NF-κB-signaling pathway. CONCLUSIONS: These data suggested that BDNF administration exerted anti-inflammatory and anti-apoptotic effects on an experimental pneumococcal meningitis model via modulation of MyD88/NF-κB- and PI3K/AKT-signaling pathways. Our results indicated that treatment with exogenous BDNF might constitute a potential therapeutic strategy for the treatment of bacterial meningitis.

A predictive risk model for medical intractability in epilepsy.

OBJECTIVE: This study aimed to investigate early predictors (6 months after diagnosis) of medical intractability in epilepsy. METHODS: All children <12 years of age having two or more unprovoked seizures 24 h apart at Xinhua Hospital between 1992 and 2006 were included. Medical intractability was defined as failure, due to lack of seizure control, of more than 2 antiepileptic drugs at maximum tolerated doses, with an average of more than 1 seizure per month for 24 months and no more than 3 consecutive months of seizure freedom during this interval. Univariate and multivariate logistic regression models were performed to determine the risk factors for developing medical intractability. Receiver operating characteristic curve was applied to fit the best compounded predictive model. RESULTS: A total of 649 patients were identified, out of which 119 (18%) met the study definition of intractable epilepsy at 2 years after diagnosis, and the rate of intractable epilepsy in patients with idiopathic syndromes was 12%. Multivariate logistic regression analysis revealed that neurodevelopmental delay, symptomatic etiology, partial seizures, and more than 10 seizures before diagnosis were significant and independent risk factors for intractable epilepsy. The best model to predict medical intractability in epilepsy comprised neurological physical abnormality, age at onset of epilepsy under 1 year, more than 10 seizures before diagnosis, and partial epilepsy, and the area under receiver operating characteristic curve was 0.7797. This model also fitted best in patients with idiopathic syndromes. CONCLUSION: A predictive model of medically intractable epilepsy composed of only four characteristics is established. This model is comparatively accurate and simple to apply clinically.

The responsiveness of TrkB to exogenous BDNF in frontal cortex during antibiotic treatment of Streptococcus pneumoniae meningitis.

Our previous studies suggested that the expression of TrkB and BDNF decreased concomitantly in brain during Streptococcus pneumoniae meningitis after antibiotic treatment, and that adjuvant administration of exogenous BDNF could rescue neurons from S. pneumoniae meningitis. In this study, we investigated the responsiveness of TrkB to exogenous BDNF treatment in frontal cortex during antibiotic treatment of S. pneumoniae meningitis. We found that adjuvant administration of exogenous BDNF led to increased number of survived neurons, improved the conduction of central auditory pathway and neurological disfunction, and up-regulated TrkB expression at the mRNA level in the frontal cortex of rats under S. pneumonia meningitis (P < 0.01). When treated with placebo, on the contrary, neurons in the frontal cortex of control rats were seriously damaged and the TrkB expression was remarkably decreased. These findings indicated that exogenous BDNF could up-regulate TrkB expression and thus played a neuroprotective role in frontal cortex injury from S. pneumoniae meningitis. They further confirmed our previous report that the decrease of intrinsic BDNF and TrkB expression is involved in the pathogenesis of neurological brain damage during S. pneumoniae meningitis after antibiotic treatment.

SEEG-RFTC in patients with refractory focal epilepsy: real-world outcomes from 121 cases.

OBJECTIVE: Radiofrequency thermocoagulation (RFTC) has emerged as an effective and safe treatment method for patients with refractory focal epilepsy, when stereo-electroencephalography (SEEG) is implanted. Although real-world research results are still limited, a considerable number of patients have shown favorable outcomes with this less invasive method. This study aims to describe the outcomes and predictive factors of SEEG-RFTC in real-world research. METHODS: A retrospective observational study was conducted on patients in the authors' epilepsy center. In total, 121 patients who underwent RFTC were included in the study. Post-RFTC outcomes were evaluated using the seizure-free rate and response rate (seizure frequency reduction more than 50%). Predictive factors influencing post-RFTC outcome were considered by comparing different variables. RESULTS: The mean follow-up period was 18.3 months. Eighty-two patients (67.8%) were responders and 54 (44.6%) were seizure free. In 36 patients with malformation of cortical development, the seizure-free rate and the response rate were 69.44% and 83.33%, respectively. In 20 patients with hippocampal sclerosis, 19 patients were responders and 14 (70%) patients were seizure free at the last follow-up. The MRI feature and etiology of epilepsy are correlated with the outcome. MR-positive is a predictive factor for seizure freedom (p < 0.01) and responders (p < 0.01). Other factors have no predictive value for post-RFTC outcome. INTERPRETATION: SEEG-RFTC is a safe procedure and yields favorable outcomes in numerous cases of focal DRE. The MRI feature and etiology of epilepsy are correlated with the seizure-free rate and response rate. And MRI positivity is the predictor for good RFTC outcome.

Quantification of Hypsarrhythmia in Infantile Spasmatic EEG: A Large Cohort Study.

Infantile spasms (IS) is a neurological disorder causing mental and/or developmental retardation in many infants. Hypsarrhythmia is a typical symptom in the electroencephalography (EEG) signals with IS. Long-term EEG/video monitoring is most frequently employed in clinical practice for IS diagnosis, from which manual screening of hypsarrhythmia is time consuming and lack of sufficient reliability. This study aims to identify potential biomarkers for automatic IS diagnosis by quantitative analysis of the EEG signals. A large cohort of 101 IS patients and 155 healthy controls (HC) were involved. Typical hypsarrhythmia and non-hypsarrhythmia EEG signals were annotated, and normal EEG were randomly picked from the HC. Root mean square (RMS), teager energy (TE), mean frequency, sample entropy (SamEn), multi-channel SamEn, multi-scale SamEn, and nonlinear correlation coefficient were computed in each sub-band of the three EEG signals, and then compared using either a one-way ANOVA or a Kruskal-Wallis test (based on their distribution) and the receiver operating characteristic (ROC) curves. The effects of infant age on these features were also investigated. For most of the employed features, significant ( ) differences were observed between hypsarrhythmia EEG and non-hypsarrhythmia EEG or HC, which seem to increase with increased infant age. RMS and TE produce the best classification in the delta and theta bands, while entropy features yields the best performance in the gamma band. Our study suggests RMS and TE (delta and theta bands) and entropy features (gamma band) to be promising biomarkers for automatic detection of hypsarrhythmia in long-term EEG monitoring. The findings of our study indicate the feasibility of automated IS diagnosis using artificial intelligence.

EEG Signal Epilepsy Detection With a Weighted Neighbor Graph Representation and Two-Stream Graph-Based Framework.

Epilepsy is one of the most common neurological diseases. Clinically, epileptic seizure detection is usually performed by analyzing electroencephalography (EEG) signals. At present, deep learning models have been widely used for single-channel EEG signal epilepsy detection, but this method is difficult to explain the classification results. Researchers have attempted to solve interpretive problems by combining graph representation of EEG signals with graph neural network models. Recently, the combination of graph representations and graph neural network (GNN) models has been increasingly applied to single-channel epilepsy detection. By this methodology, the raw EEG signal is transformed to its graph representation, and a GNN model is used to learn latent features and classify whether the data indicates an epileptic seizure episode. However, existing methods are faced with two major challenges. First, existing graph representations tend to have high time complexity as they generally require each vertex to traverse all other vertices to construct a graph structure. Some of them also have high space complexity for being dense. Second, while separate graph representations can be derived from a single-channel EEG signal in both time and frequency domains, existing GNN models for epilepsy detection can learn from a single graph representation, which makes it hard to let the information from the two domains complement each other. For addressing these challenges, we propose a Weighted Neighbour Graph (WNG) representation for EEG signals. Reducing the redundant edges of the existing graph, WNG can be both time and space-efficient, and as informative as its less efficient counterparts. We then propose a two-stream graph-based framework to simultaneously learn features from WNG in both time and frequency domain. Extensive experiments demonstrate the effectiveness and efficiency of the proposed methods.

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy.

AIM: To establish a population pharmacokinetics (PPK) model for lamotrigine (LTG) in Chinese children with epilepsy in order to formulate an individualized dosage guideline. METHODS: LTG steady-state plasma concentration data from therapeutic drug monitoring (TDM) were collected retrospectively from 284 patients, with a total of 404 plasma drug concentrations. LTG concentrations were determined using a HPLC method. The patients were divided into 2 groups: PPK model group (n=116) and PPK valid group (n=168). A PPK model of LTG was established with NONMEM based on the data from PPK model group according to a one-compartment model with first order absorption and elimination. To validate the basic and final model, the plasma drug concentrations of the patients in PPK model group and PPK valid group were predicted by the two models. RESULTS: The final regression model for LTG was as follows: CL (L/h)=1.01*(TBW/27.87)(0.635)*e(-0.753*VPA)*e(0.868*CBZ)*e(0.633*PB), Vd (L)= 16.7*(TBW/27.87). The final PPK model was demonstrated to be stable and effective in the prediction of serum LTG concentrations by an internal and external approach validation. CONCLUSION: A PPK model of LTG in Chinese children with epilepsy was successfully established with NONMEM. LTG concentrations can be predicted accurately by this model. The model may be very useful for establishing initial LTG dosage guidelines.

Harvesting random embedding for high-frequency change-point detection in temporal complex systems.

Recent investigations have revealed that dynamics of complex networks and systems are crucially dependent on the temporal structures. Accurate detection of the time instant at which a system changes its internal structures has become a tremendously significant mission, beneficial to fully understanding the underlying mechanisms of evolving systems, and adequately modeling and predicting the dynamics of the systems as well. In real-world applications, due to a lack of prior knowledge on the explicit equations of evolving systems, an open challenge is how to develop a practical and model-free method to achieve the mission based merely on the time-series data recorded from real-world systems. Here, we develop such a model-free approach, named temporal change-point detection (TCD), and integrate both dynamical and statistical methods to address this important challenge in a novel way. The proposed TCD approach, basing on exploitation of spatial information of the observed time series of high dimensions, is able not only to detect the separate change points of the concerned systems without knowing, a priori, any information of the equations of the systems, but also to harvest all the change points emergent in a relatively high-frequency manner, which cannot be directly achieved by using the existing methods and techniques. Practical effectiveness is comprehensively demonstrated using the data from the representative complex dynamics and real-world systems from biology to geology and even to social science.

[Diagnostic value of neuronal nitric oxide synthase antibody for clinically suspected Becker muscular dystrophy].

OBJECTIVE: Immunohistochemistry using antibodies to dystrophin is the pathological basis for the differential diagnosis of Duchenne and Becker muscular dystrophy (DMD and BMD). In rare cases, however, labelling dystrophin on sarcolemma is equivocal and similar to that observed in controls. This makes the diagnosis of BMD difficult. This study aimed to explore the diagnostic value of neuronal nitric oxide synthase (nNOS) antibody for clinically suspected BMD. METHODS: Immunohistochemical staining was performed on muscle specimens of 5 cases of BMD with positive expression of Dys-C (3 cases had a confirmed diagnosis of BMD, 2 cases were clinically suspected as BMD) by using dystrophin and nNOS antibodies. Normal muscle specimens from the children with fracture were used as controls. RESULTS: Compared with the controls, the expression of Dys-R, Dys-C and Dys-N was markedly reduced and nNOS was not expressed on sarcolemma in the three cases of definitely diagnosed BMD. The two cases of clinically suspected as BMD had a complete absence of sarcolemmal nNOS, even if had a similar expression of dystrophin on sarcolemma to the controls. CONCLUSIONS: nNOS antibody staining can be used for a definite diagnosis in children with clinically suspected BMD who have the almost normal expression of dystrophin.

Rate Distortion Optimization: A Joint Framework and Algorithms for Random Access Hierarchical Video Coding.

This paper revisits the problem of rate distortion optimization (RDO) with focus on inter-picture dependence. A joint RDO framework which incorporates the Lagrange multiplier as one of parameters to be optimized is proposed. Simplification strategies are demonstrated for practical applications. To make the problem tractable, we consider an approach where prediction residuals of pictures in a video sequence are assumed to be emitted from a finite set of sources. Consequently the RDO problem is formulated as finding optimal coding parameters for a finite number of sources, regardless of the length of the video sequence. Specifically, in cases where a hierarchical prediction structure is used, prediction residuals of pictures at the same prediction layer are assumed to be emitted from a common source. Following this approach, we propose an iterative algorithm to alternatively optimize the selections of quantization parameters (QPs) and the corresponding Lagrange multipliers. Based on the results of the iterative algorithm, we further propose two practical algorithms to compute QPs and the Lagrange multipliers for the RA(random access) hierarchical video coding: the first practical algorithm uses a fixed formula to compute QPs and the Lagrange multipliers, and the second practical algorithm adaptively adjusts both QPs and the Lagrange multipliers. Experimental results show that these three algorithms, integrated into the HM 16.20 reference software of HEVC, can achieve considerable RD improvements over the standard HM 16.20 encoder, in the common RA test configuration.

Novel CDKL5 mutations were found in patients in China: retrospective investigation in cases of CDKL5-related disorders.

OBJECTIVE: CDKL5-related disorders (CDD) is an epileptic encephalopathy resulted of gene mutations of CDKL5. This study aimed to explore the development process of CDD and to expand its mutation spectrum. METHODS: Clinic datawas collected about three infantile epileptic encephalopathy cases diagnosed at Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine. Next generation sequencing technology was used to find three de novo mutations of CDKL5. We searched published literatures about CDKL5 in pubmed and made an analysis about our clinic data and the related literatures. RESULTS: The three patients were all girls. Their average onset age of seizures was around 2 months, and all of them have intractable epileptic seizures, severe intellectual disability, and hypotension. Among them, two presented infantile spasm and high arrhythmia in EEG, and the other manifested clonic seizure and broad epileptiform discharge in EEG. Extracerebral space widening in cranial MRIs was demonstrated in two cases. Visual evoked potential was abnormal in two cases. Seizures were resistant to all kinds of antiepileptic drugs (AEDs). Gene tests showed three de novo mutations of CDKL5: one was a truncated mutation (c.2254A > T,P.R752X, stop279), which was pathogenic according to the ACMG guide, the other two were missense mutations (c.377G > T,p.Cys126Phe) and a frameshift mutation (c.362-362insG(p.Ala122GlyfsTer7), which were likely pathogenic according to the ACMG. CONCLUSIONS: All three de novo mutations are first reported. Based on the combined related literature and the manifestations observed, we diagnosed the three children as CDKL5-related disorders, and concluded that the de novo CDKL5 mutations are the reason for their epilepsy.

Anti-N-methyl-D-aspartate receptor encephalitis associated with reactivated Epstein-Barr virus infection in pediatric patients: Three case reports.

RATIONALE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most frequent autoimmune encephalitis in children, and its presentation is various. The disease can be triggered by various infections. PATIENT CONCERNS: Case 1 was a 7-year-old female with the presentation of seizure, repeated fever, language disorder, and decreased muscle strength of the right limbs; Case 2 was a 7-year-old male with the manifestation of repeated emesis, headache, involuntary movement, altered personality, seizures, and cognitive impairment; Case 3 was a 2-year-old female with repeated fever, emesis, seizures, coma, and decreased muscle strength of limbs. Anti-NMDAR antibody was identified in cerebrospinal fluid (CSF) in the 3 cases, confirming the diagnosis of anti-NMDAR encephalitis. Pathogenic examinations revealed positive serum Epstein-Barr virus (EBV)-nuclear antigen and EBV-capsid antigen (CA)-IgG antibodies in the 3 cases, as well as positive EBV-early antigen (EA)-IgG antibody in CSF. Case 1 also had positive EBV-CA-IgA antibody; Case 3 also had positive EBV-CA-IgA and EBV-CA-IgG antibodies. DIAGNOSES: Anti-NMDAR antibody and EBV-EA-IgG antibody in CSF were tested positive in the 3 cases. Thus, they were diagnosed as anti-NMDAR encephalitis associated with reactivated EBV infection. INTERVENTIONS: All of the 3 cases received immunoglobulin, corticosteroid, and ganciclovir treatment. Cases 2 and 3 also received antiepileptic drugs due to repeated seizures. In addition, Case 3 also received assistant respiration, plasma exchange, and rituximab. OUTCOMES: The 3 cases were substantially recovered after treatment. Repeat CSF analysis showed decreased titer of the anti-NMDAR antibody. LESSONS: Reactivated EBV infection may trigger anti-NMDAR encephalitis in children, which has not been reported previously. Related possible virology tests should be completed while diagnosing the disease.

Exogenous BDNF increases neurogenesis in the hippocampus in experimental Streptococcus pneumoniae meningitis.

BACKGROUND: Despite the effective use of antibiotics, occurrences of mortality and neurological sequelae following Streptococcus pneumoniae meningitis remain high. METHODS: We investigated the neurogenesis of endogenous neural stem cells (NSCs) after inoculation with exogenous brain-derived neurotrophic factor (BDNF) in the hippocampus dentate gyrus following experimental S. pneumoniae meningitis using a double-labeling immunofluorescence analysis with 5-bromo-2'-deoxyuridine (BrdU), Nestin, DCX and NeuN. RESULTS: Our results showed that 7days after inoculation, the number of BrdU & Nestin co-labeled cells increased in the hippocampus in meningitis rats compared with control rats (p<0.05). But the number of DCX-positive cells decreased in the dentate gyrus of infected rats treated with saline (p<0.05). However, these cell numbers returned to close to normal-control levels in infected rats treated with BDNF (p>0.05). After treatment with exogenous BDNF, the number of BrdU & Nestin co-labeled cells increased in the hippocampus in both the meningitis rats and normal control rats (p<0.05), but this increase was more significant in the former (p<0.05). We found that the percentage of BrdU & DCX/BrdU co-labeled cells increased in infected rats treated with BDNF both 7days and 14days after inoculation in a greater proportion compared to other groups (p<0.05). No significant differences were found in the percentage of BrdU & NeuN/BrdU 28days after inoculation among all of the groups (p>0.05). CONCLUSION: Our findings suggest that S. pneumoniae meningitis activates the proliferation of endogenous NSCs, but impairs their early differentiation. Administration of exogenous BDNF might improve the neurogenesis of endogenous NSCs in the hippocampus and may provide a promising therapy after bacterial meningitis.

Geranylgeranylacetone protects against cerebral ischemia and reperfusion injury: HSP90 and eNOS phosphorylation involved.

Cerebral ischemia and reperfusion (I/R) can trigger a cytotoxic cascade with overflow of reactive oxygen species, paradoxically causing neurological dysfunction, redox imbalance, inflammation and apoptosis. The present study aims to investigate the effect of geranylgeranylacetone(GGA) on cerebral I/R injury and the underlying mechanism. The results demonstrated that cerebral I/R increased the neurological function abnormality, brain edema, inflammation and oxidative injury in rats as well as the cognitive impairment, which was significantly reversed by GGA in a dose-dependent manner. GGA also suppressed the cell injury and apoptosis caused by cerebral I/R. Moreover, the protective effect of GGA was found to involve heat shock protein 90 (HSP90) and phosphorylated endothelial nitric oxide synthase (eNOS) expression and activity. Both the HSP90 and eNOS inhibitor abolished the effect of GGA. The data showed that GGA could protect rats against cerebral I/R injury, which may be related to the induction of HSP90 and activation of eNOS.