Baicalein ameliorates cognitive impairment of vascular dementia rats via suppressing neuroinflammation and regulating intestinal microbiota.

Neuroinflammation induced by chronic cerebral hypoperfusion (CCH) plays a crucial role in the pathophysiologic mechanisms of vascular dementia (VD). A growing body of research has found that intestinal microbiota is associated with a variety of central nervous system disorders and that there is a relationship between intestinal microbiota dysbiosis and cognitive dysfunction and inflammatory responses. Baicalein belongs to the class of flavonoids and has a variety of biological functions, including anti-inflammatory, antioxidant and anti-apoptotic. Baicalein has a significant improvement in memory and learning, and can be used as a potential drug for the protection and treatment of central nervous system disorders. Whether baicalein has an ameliorative effect on cognitive impairment in VD, and whether its mechanism is related to the inhibition of inflammatory response and regulation of intestinal microbiota has not been reported. We used bilateral common carotid artery occlusion (BCCAO) to establish a VD rat model. Morris water maze (MWM) test showed that baicalein improved cognitive dysfunction in VD rats. We applied HE staining, immunofluorescence and ELISA to observe that baicalein treatment significantly improved CCH-induced neuronal damage in the CA1 region of the hippocampus, and reduced glial cell activation and release of pro-inflammatory factors. Western blot showed that baicalein inhibited the activation of the TLR4/MyD88/NF-κB signaling pathway in VD rats. We applied 16 S rDNA sequencing to analyze the composition of the intestinal microbiota. The results showed that baicalein modulated the diversity and composition of the intestinal microbiota, and suppressed the relative abundance of inflammation-associated microbiota in VD rats. In conclusion, this study found that baicalein ameliorated cognitive impairment, attenuated hippocampal inflammatory responses, inhibited the TLR4/MyD88/NF-κB signaling pathway, and modulated intestinal microbiota in VD rats.

Edaravone Dexborneol Alleviates Neuroinflammation by Reducing Neuroglial Cell Proliferation and Suppresses Neuronal Apoptosis/Autophagy in Vascular Dementia Rats.

More and more evidence shows that the pathological mechanism of vascular dementia (VD) is closely related to oxidative stress injury, cell apoptosis, autophagy, inflammatory response, excitatory amino acid toxicity, synaptic plasticity change, calcium overload, and other processes. Edaravone dexborneol (EDB) is a new type of neuroprotective agent that can improve the neurological damage caused by an ischemic stroke. Previous studies showed that EDB has effects on synergistic antioxidants and induces anti-apoptotic responses. However, it remains unclear whether EDB can affect apoptosis and autophagy by activating the PI3K/Akt/mTOR signaling pathway and its impact on the neuroglial cells. In this study, we established the VD model of rats by bilateral carotid artery occlusion to explore the neuroprotective effect of EDB and its mechanism. Morris Water Maze test was applied to assess the cognitive function of rats. H&E and TUNEL staining were applied to observe the cellular structure of the hippocampus. Immunofluorescence labeling was used to observe the proliferation of astrocytes and microglia. ELISA was applied to examine the levels of TNF-α, IL-1ß and IL-6, and RT-PCR was applied to examine their mRNA expression levels. Western blotting was applied to examine apoptosis-related proteins (Bax, Bcl-2, Caspase-3), autophagy-related proteins (Beclin-1, P62, LC3B), PI3K/Akt/mTOR signaling pathway proteins and their phosphorylation levels. The results indicated that EDB ameliorates learning and memory in rats subjected to the VD model, alleviates neuroinflammatory response by reducing the proliferation of the neuroglial cell and inhibits apoptosis and autophagy, which may be mediated by the PI3K/Akt/mTOR signaling pathway.

Systemic Immune-Inflammation Index is Associated with Cerebral Small Vessel Disease Burden and Cognitive Impairment.

Objective: This study sought to explore the associations of the systemic immune-inflammation index (SII) with total cerebral small vessel disease (CSVD) burden and cognitive impairment. Methods: We enrolled 201 patients in the retrospective study with complete clinical and laboratory data. The SII was calculated as platelet count × neutrophil count/lymphocyte count. Cognitive function was evaluated by the Mini-Mental State Examination (MMSE). Total CSVD burden was assessed based on magnetic resonance imaging. We performed logistic regression models, Spearman correlation, and mediation analysis to evaluate the associations of SII with CSVD burden and cognitive impairment. Results: After adjustment for confounding factors in the multivariate binary logistic regression model, elevated SII (odds ratio [OR], 3.263; 95% confidence interval [CI], 1.577-6.752; P = 0.001) or severe CSVD burden (OR, 2.794; 95% CI, 1.342-5.817; P = 0.006) was significantly associated with the risk of cognitive impairment. Correlation analyses revealed that SII levels were negatively associated with MMSE scores (rs = -0.391, P < 0.001), and positively associated with the total CSVD burden score (rs = 0.361, P < 0.001). Moreover, SII was significantly related to the severity of the CSVD burden (OR, 2.674; 95% CI, 1.359-5.263; P = 0.004). The multivariable-adjusted odds ratios (95% CI) in highest tertile versus lowest tertile of SII were 8.947 (3.315-24.145) for cognitive impairment and 4.945 (2.063-11.854) for severe CSVD burden, respectively. The effect of higher SII on cognitive impairment development was partly mediated by severe CSVD burden. Conclusion: Elevated SII is associated with severe CSVD burden and cognitive impairment. The mediating role of severe CSVD burden suggests that higher SII may contribute to cognitive impairment through aggravating CSVD burden.

Baicalin facilitates remyelination and suppresses neuroinflammation in rats with chronic cerebral hypoperfusion by activating Wnt/ß-catenin and inhibiting NF-κB signaling.

One main factor contributing to the cognitive loss in vascular dementia (VD) is white matter lesions (WMLs) carried on by chronic cerebral hypoperfusion (CCH). A secondary neuroinflammatory response to CCH accelerates the loss and limits the regeneration of oligodendrocytes, leading to progressive demyelination and insufficient remyelination in the white matter. Thus, promoting remyelination and inhibiting neuroinflammation may be an ideal therapeutic strategy. Baicalin (BAI) is known to exhibit protective effects against various inflammatory and demyelinating diseases. However, whether BAI has neuroprotective effects against CCH has not been investigated. To determine whether BAI inhibits CCH-induced demyelination and neuroinflammation, we established a model of CCH in rats by occluding the two common carotid arteries bilaterally. Our results revealed that BAI could remarkably ameliorate cognitive impairment and mitigate CA1 pyramidal neuron damage and myelin loss. BAI exhibited enhancement of remyelination by increasing the expression of myelin basic protein (MBP) and oligodendrocyte transcription factor 2 (Olig2), inhibiting the loss of oligodendrocytes and promoting oligodendrocyte regeneration in the corpus callosum of CCH rats. Furthermore, BAI modified microglia polarization to the anti-inflammatory phenotype and inhibited the release of pro-inflammatory cytokines. Mechanistically, BAI treatment significantly induced phosphorylation of glycogen synthase kinase 3ß (GSK3ß), enhanced the expression of ß-catenin and its nuclear translocation. Simultaneously, BAI reduced the expression of nuclear NF-κB. Collectively, our results suggest that BAI ameliorates cognitive impairment in CCH-induced VD rats through its pro-remyelination and anti-inflammatory capacities, possibly by activating the Wnt/ß-catenin and suppressing the NF-κB signaling.

Dulaglutide Improves Gliosis and Suppresses Apoptosis/Autophagy Through the PI3K/Akt/mTOR Signaling Pathway in Vascular Dementia Rats.

Dulaglutide is a new type of hypoglycemic agent that agonizes glucagon-like peptide-1 receptor (GLP-1RA). It can be concluded from previous studies that a GLP-1RA can reduce apoptosis and regulate autophagy in the nervous system, while related research on dulaglutide in vascular dementia (VD) has not been reported. In our study, the VD rat model was established by bilateral carotid artery occlusion, and the results of the Morris water maze test (MWM) and open-field test showed that the application of dulaglutide could effectively reduce the cognitive decline of VD rats without changing the behavior in the open-field test, which was used to assess an anxiety-like phenotype. We applied HE staining and immunofluorescence labeling to show that dulaglutide treatment significantly alleviated neuronal damage in the hippocampal region of VD rats, and reduced microglial and astrocyte proliferation. Western blot results showed that dulaglutide reduced VD-induced neuronal apoptosis (BCL2/BAX, c-caspase3) and autophagy (P62, LC3B, Beclin-1), and upregulated phosphorylation of PI3K/Akt/mTOR signaling pathway. KEGG pathway analysis of RNA-Sequence results showed that the differentially expressed genes in the dulaglutide treatment group were significantly enriched in the mTOR signaling pathway, and the repressor of mTOR, Deptor, was down-regulated. In conclusion, this study suggested that dulaglutide may alleviate learning and memory impairment and neuron damage in VD rats by attenuating apoptosis, regulating autophagy, and activating the PI3K/Akt/mTOR signaling pathway in neurons, which may make it a promising candidate for the simultaneous treatment of VD and diabetes.

Cerebral small vessel disease mediates the association between homocysteine and cognitive function.

Objective: To investigate the relations of serum total homocysteine (tHcy) with cerebral small vessel disease (CSVD) and cognitive function and evaluate whether CSVD mediates the effect of serum tHcy on cognitive function. Methods: A total of 1,033 consecutive eligible participants who received serum tHcy, brain magnetic resonance imaging (MRI), and neuropsychological assessment were included in this retrospective study. White matter hyperintensity, lacune, cerebral microbleed, and enlarged perivascular space were evaluated based on brain MRI. We used multivariate binary logistic regression analysis, multivariate ordinal logistic regression analysis, and mediation analyses to assess the relations of serum tHcy with CSVD and cognitive function. Results: Serum tHcy levels were higher in patients with cognitive impairment than those with no cognitive impairment. Logistic regression analyses showed elevated serum tHcy was associated with cognitive impairment [odds ratio (OR): 10.475; 95% confidence interval (CI): 4.522 to 24.264; p < 0.001] and a higher CSVD burden score (OR: 17.151; 95% CI: 8.785 to 33.921; p < 0.001) after adjusting potential confounders. Compared with the lowest tHcy quartile, the multivariable-adjusted OR of the highest quartile was 4.851 (95% CI: 3.152 to 7.466; p for the trend < 0.001) for cognitive impairment, 3.862 (95% CI: 2.467 to 6.047; p for the trend < 0.001) for a severe CSVD burden score. Mediation analyses showed significant moderating effects (9.3-23.6%) by different imaging markers of CSVD on the association between higher serum tHcy levels and cognitive impairment. Conclusion: Elevated serum tHcy is associated with cognitive impairment and the development of CSVD. A proportion of the association between elevated serum tHcy and cognitive impairment may be attributed to the presence of different imaging markers of CSVD, especially the severe CSVD burden score.

Dl-3-n-Butylphthalide Improves Neuroinflammation in Mice with Repeated Cerebral Ischemia-Reperfusion Injury through the Nrf2-Mediated Antioxidant Response and TLR4/MyD88/NF-κB Signaling Pathway.

Increasing evidence shows that oxidative stress and neuroinflammation play a crucial role in the pathology of vascular dementia (VD). Previously, we have found that Dl-3-n-butylphthalide (NBP) has antioxidant and anti-inflammatory activities in VD, whereas little is known about its mechanism. Therefore, the objective of our study was to explore the contribution of nuclear factor erythroid-2 related factor 2 (Nrf2) to NBP and its effects on anti-inflammatory activity in a mouse model of VD. Our studies revealed that NBP could effectively mitigate cognitive deficits, neuron cell loss, and apoptosis in mice subjected to repeated cerebral ischemia-reperfusion (RCIR). Additionally, NBP promoted both the expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) in hippocampus tissue. NBP exhibited antioxidant activity by enhancing Nrf2 nuclear accumulation, increasing HO-1 and NQO1 expression, enhancing SOD activity, and inhibiting RCIR-induced MDA and 8-iso PGF2α generation in the hippocampus. NBP also significantly inhibited TLR4/MyD88/NF-κB signaling and suppressed microglial proliferation and the production of proinflammatory mediators in RCIR mice. Importantly, the antioxidant, antineuroinflammatory, and neuroprotective effects of NBP above were abolished by Nrf2 knockout. Collectively, these results indicated the effects of NBP on neuroinflammation were strongly associated with the Nrf2 pathway. Modulation of TLR4/MyD88/NF-κB pathway by Nrf2 is involved in the neuroprotective effect of NBP against VD induced by RCIR injury. With antioxidant and anti-neuroinflammatory properties, NBP could be a promising drug candidate for the prevention and/or treatment of VD and other neuroinflammatory disorders.

Past Exposure to Cigarette Smoke Aggravates Cognitive Impairment in a Rat Model of Vascular Dementia via Neuroinflammation.

Smoking is a risk factor for dementia. Cognitive function can be partially restored after quitting smoking, but still lower than never smoked group. The underlying mechanisms still remain unclear. The effects of smoking cessation combined with cerebral chronic hypoperfusion (CCH) on cognitive function have never been described. Here, we established a cigarette smoking cessation model, a CCH model, and a cigarette smoking cessation plus CCH model. We investigated cognitive function in these models and the mechanisms of the neuroinflammation, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3)/cysteine aspartate-specific proteinase (caspase-1)/interleukin- 1ß (IL-1ß) pathway, and eucaryotic initiation factor 2α (eIF2α) /autophagy pathway. We used morris water maze (MWM) and novel object recognition (NOR) test to evaluate cognitive function in rats. Nissl staining was performed to observe cell morphology in the hippocampal CA1 area. A neuroinflammatory marker (glial fibrillary acidic protein, GFAP) was assessed by Western blot analysis and immunohistochemistry staining. IL-1ß levels were detected by ELISA. The protein levels of NLRP3/caspase-1/ IL-1ß and eIF2α/autophagy pathway were evaluated by Western blot analysis. LC3 was assessed by immunofluorescence staining. CCH can affect cognitive function by influencing neuroinflammation, NLRP3/caspase-1/IL-1ß pathway, and eIF2α/autophagy pathway. Past exposure to cigarette smoke can also affect cognitive function by influencing neuroinflammation and NLRP3/caspase-1/IL-1ß pathway, which may be induced by smoking and may not be alleviated after smoking cessation. Past exposure to cigarette smoke does not influence autophagy, which may be increased by smoking and then decrease to normal levels after smoking cessation. Past exposure to smoking can further aggravate cognitive impairment and neuroinflammation in VaD animals: cognitive impairment induced by CCH via neuroinflammation, NLRP3/caspase-1/IL-1ß, and eIF2α/autophagy pathway and cognitive impairment induced by past exposure to cigarette smoke via neuroinflammation and NLRP3/caspase-1/IL-1ß pathway. The combined group had the worst cognitive impairment because of harmful reasons.

Long-Term Use of Metformin Is Associated With Reduced Risk of Cognitive Impairment With Alleviation of Cerebral Small Vessel Disease Burden in Patients With Type 2 Diabetes.

Objective: Type 2 diabetes (T2D) is a risk factor for cognitive impairment and cerebral small vessel disease (CSVD). The relation of metformin use and cognitive impairment or CSVD is not clear. The objective of this study was to investigate the cross-sectional effects of long-term use of metformin on total CSVD burden and cognitive function in patients with T2D. Methods: A total of 234 participants with T2D from the memory clinic in Hebei General Hospital were enrolled in this retrospective study. Duration of metformin use and dosage were recorded. Along with cerebral magnetic resonance imaging (MRI) examination, Mini-Mental State Examination (MMSE) was also performed to assess their cognitive status. We determined the validated total CSVD score (ranging from 0-4) by combining four markers of CSVD that were visually rated. We used binary logistic regression analysis, ordinal logistic regression analysis and mediation analysis to assess the relation of long-term use of metformin with CSVD burden and cognitive function. Results: Binary logistic regression analysis showed long-term use of metformin was associated with reducing the risk of cognitive impairment (OR: 0.446; 95% Confidence Interval (CI): 0.249 to 0.800; P = 0.007), after adjustment of potential confounders, such as total CSVD burden score, age, HbA1c, hypertension, history of stroke, homocysteine, body mass index, TG and HDL-C. Ordinal logistic regression analysis suggested that long-term use of metformin was associated with alleviation of total CSVD burden score (OR: 0.583; 95% CI: 0.359 to 0.943; P = 0.027), after adjusting for age, HbA1c, hypertension, history of stroke, homocysteine, body mass index, TG and HDL-C. Mediation analysis showed significant mediation by the presence of severe CSVD burden score for long-term use of metformin in relation to cognitive impairment. Conclusion: Long-term use of metformin was associated with lower rates of cognitive impairment and lower total CSVD burden score in patients with T2D. A proportion of the relation between long-term use of metformin and cognitive impairment may be attributable to alleviation of CSVD burden.

Lithium chloride ameliorated spatial cognitive impairment through activating mTOR phosphorylation and inhibiting excessive autophagy in the repeated cerebral ischemia-reperfusion mouse model.

Lithium has been previously demonstrated to alleviate cognitive impairment caused by neurodegenerative diseases and acute brain injuries; however, the specific mechanism remains elusive. In the present study, the C57BL/6 mouse model of spatial cognitive impairment induced by repeated cerebral ischemia-reperfusion was established. Morris water maze test was performed to evaluate the levels of spatial cognitive impairment. Nissl staining was used to observe any morphological alterations, whilst western blotting was performed to measure the expression levels of microtubule-associated protein light chain 3 (LC3) and Beclin1 in addition to mTOR phosphorylation. LiCl was found to significantly improve spatial learning and memory impairments according to data from the Morris water maze test. Nissl staining indicated that LiCl inhibited neuronal damage in the CA1 region of the hippocampus. Additionally, LiCl increased mTOR phosphorylation, reduced beclin1 expression and reduced the LC3 II/I expression ratio. Taken together, these findings suggest that LiCl may alleviate the spatial cognitive impairment induced by repeated cerebral ischemia-reperfusion. This observation may be attributed to the inhibition of excessive autophagy by LiCl through mTOR signaling activation.

DL-3-n-butylphthalide alleviates vascular cognitive impairment induced by chronic cerebral hypoperfusion by activating the Akt/Nrf2 signaling pathway in the hippocampus of rats.

Oxidative stress induced by chronic cerebral hypoperfusion (CCH) plays an important role in the pathogenesis of vascular cognitive impairment (VCI). The Akt/Nrf2 signaling pathway is one of the most important antioxidative stress pathways. To explore whether NBP (DL-3-n-butylphthalide) could alleviate VCI induced by CCH via activating the Akt/Nrf2 signaling pathway and modifying the levels of apoptosis-related proteins, adult male Sprague-Dawley rats were subjected to permanent occlusion of bilateral common carotid arteries (BCCAO) and treated either with vehicle or NBP (applied in two doses, 40 mg/kg and 80 mg/kg) while sham operated animals were treated with vehicle. Treatments were administered daily for 28 days. The obtained results indicate that both administrated doses of NBP significantly ameliorated the spatial learning and memory impairments as indicated by the Morris water maze test while Hematoxylin-Eosin staining revealed that morphological defects in the CA1 area of hippocampus were improved. Moreover, NBP reversed the BCCAO-induced downregulation of investigated oxidative stress-related proteins (p-Akt, t-Nrf2, n-Nrf2 and HO-1) along with the upregulation of pro-apoptotic molecule, Bax and reduction of the expression of anti-apoptotic protein, Bcl-2. According to presented results, NBP may have a protective effect against cognitive and morphological impairments induced by CCH via activation of Akt/Nrf2 signaling pathway and inhibition of apoptotic cascade.

Edaravone attenuates oxidative stress induced by chronic cerebral hypoperfusion injury: role of ERK/Nrf2/HO-1 signaling pathway.

Objectives The potential protective effects and mechanisms of edaravone have not been well elucidated in vascular dementia (VaD) induced by chronic cerebral hypoperfusion (CCH). The aim of this study was to investigate whether edaravone could improve cognitive damage in rats induced by CCH, and whether the effects of edaravone were associated with ERK/Nrf2/HO-1 signaling pathway. Methods CCH was induced by bilateral common carotid arteries occlusion (BCCAO). Sprague-Dawley (SD) rats were randomly divided into four groups: sham (sham-operated) group, vehicle (BCCAO + normal saline) group, edaravone3.0 group and edaravone6.0 group. The edaravone3.0 and edaravone6.0 group rats were provided 3.0 mg/kg and 6.0 mg/kg of edaravone, respectively, intraperitoneal (i.p.) injection twice daily following the first day after BCCAO. In this experiment, the spatial learning and memory were assessed using the Morris water maze. The malondialdehyde (MDA) contents and superoxide dismutase (SOD) activities in the hippocampus were measured biochemically. And, the levels of total ERK1/2 (t-ERK1/2), Phospho-ERK1/2 (p-ERK1/2), total Nrf2 (t-Nrf2), nuclear Nrf2 (n-Nrf2), and HO-1 were assessed by western blot. Results The results showed that the treatment with edaravone significantly improved CCH-induced cognitive damage, and boosted endogenous antioxidants SOD activity and HO-1 level, decreased MDA contents in the hippocampus by activating Nrf2 signaling pathway which was related to ERK1/2. We also found that the neuronal morphology of the hippocampal CA1 area significantly improved and the number of Nrf2 positive cells markedly increased in the edaravone treatment groups. Conclusion Our results demonstrated a neuroprotective effect of edaravone on hippocampus against oxidative stress and cognitive deficit induced by CCH. The mechanism may be related to the enhancement of antioxidant defense system by activating ERK/Nrf2/HO-1 signaling pathway.

Cerebrolysin alleviates cognitive deficits induced by chronic cerebral hypoperfusion by increasing the levels of plasticity-related proteins and decreasing the levels of apoptosis-related proteins in the rat hippocampus.

The incidence of vascular dementia (VaD) has rapidly increased over the past few decades. Although officially approved medications for VaD remain limited, cerebrolysin (CBL) had preventive and treatment effects on VaD in some clinical trials. However, the underlying mechanisms have not been determined. The aim of this study was to determine whether CBL protects against cognitive deficits in a rat model of VaD induced by chronic cerebral hypoperfusion by increasing the levels of plasticity-related proteins and decreasing the levels of apoptosis-related proteins. In our study, adult male Sprague-Dawley rats were subjected to bilateral common carotid artery occlusion (BCCAO) surgery. The animals were randomly divided into four groups after the operation: Sham, Vehicle, L-CBL (2.5ml/kg), and H-CBL (5ml/kg). CBL was administered after the operation daily for 28 days. The CBL treatment significantly decreased the escape latency and increased the percentage of time the rat spent in the target quadrant of the Morris water maze (MWM) task. Pathological changes in the hippocampus, such as reduced cell count numbers and obvious pyknosis, were observed using haematoxylin-eosin (HE) staining. Furthermore, CBL significantly increased the expression of plasticity-related synaptic proteins, such as postsynaptic density protein 95 (PSD-95), protein kinase C subunit gamma (PKCγ), phosphorylated cAMP response element binding protein (p-CREB), and decreased the expression of apoptosis-related proteins in the hippocampus. In summary, CBL likely protects against cognitive deficits by improving synaptic plasticity and decreasing apoptosis.

Lipoxin A4 methyl ester alleviates vascular cognition impairment by regulating the expression of proteins related to autophagy and ER stress in the rat hippocampus.

Since autophagy and endoplasmic reticulum stress mechanisms are involved in some neurodegenerative and cerebral vascular diseases, we suspected that similar mechanisms might participate in vascular cognitive impairments induced by chronic cerebral hypoperfusion. Lipoxin A4 methyl ester (LXA4 ME) is an inflammation inhibitor that exhibits potent protective effects in experimental stroke models. In an earlier study, we found that LXA4 ME improved cognitive deficit in a rat model of vascular cognitive impairment created using bilateral common carotid artery ligation (BCCAL) and two-vessel occlusion (2VO). In this study, LXA4 ME treatment of 2VO rats improved brain morphological defects. We found that LXA4 ME reduced the expression of some autophagy- and ERS-related factors in the hippocampus of 2VO rats, namely C/EBP homologous protein, beclin1 and the ratio of microtubule-associated protein light chain 3 II (LC3-II) to LC3-I. By contrast, LXA4 ME upregulated the protein expression of phospho-mTOR, total-mTOR, glucose-regulated protein 78 and spliced and unspliced X-box binding protein-1 mRNA. Differential protein regulation by LXA4 ME might underlie its ability to protect cognition after chronic cerebral hypoperfusion.

Lithium chloride administration prevents spatial learning and memory impairment in repeated cerebral ischemia-reperfusion mice by depressing apoptosis and increasing BDNF expression in hippocampus.

Lithium has been reported to have neuroprotective effects, but the preventive and treated role on cognition impairment and the underlying mechanisms have not been determined. In the present study, C57Bl/6 mice were subjected to repeated bilateral common carotid artery occlusion to induce the learning and memory deficits. 2 mmol/kg or 5 mmol/kg of lithium chloride (LiCl) was injected intraperitoneally per day before (for 7 days) or post (for 28 days) the operation. This repeated cerebral ischemia-reperfusion (IR) induced dynamic overexpression of ratio of Bcl-2/Bax and BDNF in hippocampus of mice. LiCl pretreatment and treatment significantly decreased the escape latency and increased the percentage of time that the mice spent in the target quadrant in Morris water maze. 2 mmol/kg LiCl evidently reversed the morphologic changes, up-regulated the survival neuron count and increased the BDNF gene and protein expression. 5 mmol/kg pre-LiCl significantly increased IR-stimulated reduce of Bcl-2/Bax and p-CREB/CREB. These results described suggest that pre-Li and Li treatment may induce a pronounced prevention on cognitive impairment. These effects may relay on the inhibition of apoptosis and increasing BDNF and p-CREB expression.