Applying vinpocetine to reverse synaptic ultrastructure by regulating BDNF-related PSD-95 in alleviating schizophrenia-like deficits in rat.

BACKGROUND: Schizophrenia is a mental disorder characterized by hyperlocomotion, cognitive symptoms, and social withdrawal. Brain-derived neurotrophic factor (BDNF) and postsynaptic density (PSD)-95 are related to schizophrenia-like deficits via regulating the synaptic ultrastructure, and play a role in drug therapy. Vinpocetine is a nootropic phosphodiesterase-1 (PDE-1) inhibitor that can reverse ketamine-induced schizophrenia-like deficits by increasing BDNF expression. However, the effects of vinpocetine on alleviating schizophrenia-like deficits via reversing the synaptic ultrastructure by regulating BDNF-related PSD-95 have not been sufficiently studied. METHODS: In this study, the schizophrenic model was built using ketamine (30 mg/kg) for 14 consecutive days. The effect of vinpocetine on reversing schizophrenia-like behaviors was examined via behavioral testing followed by treatment with certain doses of vinpocetine (20 mg/kg, i.p.). The BDNF and PSD-95 levels in the posterior cingulate cortex (PCC) were measured using biochemical assessments. In addition, the synaptic ultrastructure was observed using transmission electron microscopy (TEM). RESULTS: Ketamine induced drastic schizophrenia-like behaviors, lower protein levels of BDNF and PSD-95, and a change in the synaptic ultrastructure in the PCC. After treatment, the vinpocetine revealed a marked amendment in schizophrenia-like behaviors induced by ketamine, including higher locomotor behavior, lower cognitive behavior, and social withdrawal defects. Vinpocetine could increase the PSD-95 protein level by up-regulating the expression of BDNF. In addition, the synaptic ultrastructure was changed after vinpocetine administration, including a reduction in the thickness and curvature of the synaptic interface, as well as an increase in synaptic cleft width in the PCC. CONCLUSION: Vinpocetine can reverse the synaptic ultrastructure by regulating BDNF-related PSD-95 to alleviate schizophrenia-like deficits induced by ketamine in rats.

Role of RAGE in Alzheimer's Disease.

Receptor for advanced glycation end products (RAGE) is a receptor of the immunoglobulin super family that plays various important roles under physiological and pathological conditions. Compelling evidence suggests that RAGE acts as both an inflammatory intermediary and a critical inducer of oxidative stress, underlying RAGE-induced Alzheimer-like pathophysiological changes that drive the process of Alzheimer's disease (AD). A critical role of RAGE in AD includes beta-amyloid (Aß) production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration. The steady-state level of Aß depends on the balance between production and clearance. RAGE plays an important role in the Aß clearance. RAGE acts as an important transporter via regulating influx of circulating Aß into brain, whereas the efflux of brain-derived Aß into the circulation via BBB is implemented by LRP1. RAGE could be an important contributor to Aß generation via enhancing the activity of ß- and/or γ-secretases and activating inflammatory response and oxidative stress. However, sRAGE-Aß interactions could inhibit Aß neurotoxicity and promote Aß clearance from brain. Meanwhile, RAGE could be a promoting factor for the synaptic dysfunction and neuronal circuit dysfunction which are both the material structure of cognition, and the physiological and pathological basis of cognition. In addition, RAGE could be a trigger for the pathogenesis of Aß and tau hyper-phosphorylation which both participate in the process of cognitive impairment. Preclinical and clinical studies have supported that RAGE inhibitors could be useful in the treatment of AD. Thus, an effective measure to inhibit RAGE may be a novel drug target in AD.

Effects of rosuvastatin in combination with nimodipine in patients with mild cognitive impairment caused by cerebral small vessel disease.

BACKGROUND: To investigate the clinical efficiency and safeness of the combination of rosuvastatin and nimodipine in treating mild cognitive impairment of cerebral small vessel disease (CSVD) patients. METHODS: A total of 120 patients with mild cognitive impairment caused by CSVD were divided randomly into two groups: an observation group and a control group, each of which had 60 patients. In the observation group, patients were given rosuvastatin in combination with nimodipine, and other patients were given nimodipine in the control group. For the two groups, the course of treatment was six months. Before and after treatments, levels of total cholesterol (TC), triacylglycerol (TG), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), MMP-9 and high sensitivity C reactive protein (hs-CRP) were measured. Montreal Cognitive Assessment (MoCA) and activities of daily living (ADL) were also evaluated. Incidence of adverse reactions were compared between two groups. RESULTS: The levels of TG, TC and LDL-C were decreased after treatment in the observation group (P<0.01), and these after-treatment levels were lower than the control group. Additionally, after treatment, the levels of MMP-9 and hs-CRP were significant lower in the observation group than the control group. The MoCA and ADL scores were higher in the observation group than the control group after treatment (P<0.05). Moreover, the overall effective rate were higher in the observation group (91.7%) than the control group (65.0%) (P<0.01), while there was no significant difference of the rate of adverse reactions between the observation group and the control one (10.0% vs. 8.3%) (P>0.05). CONCLUSIONS: The combination of rosuvastatin and nimodipine was safe and effective in treating mild cognitive impairment of CSVD patients.

Rho kinase regulates neurite outgrowth of hippocampal neurons via calcium dependent cytoskeleton regulation.

OBJECTIVE: To investigate whether calcium is involved in downstream signal transduction in neurite outgrowth regulated by Rho kinase. METHODS: In vitro primary hippocampal neurons were cultured and treated with Rho kinase agonist (LPA) or antagonist (Y-27632). Then, the cytoskeleton and neurite outgrowth were observed. After addition of calcium antagonist BAPTA/AM to reduce intracellular calcium, the cytoskeleton distribution and neurite outgrowth were observed. RESULTS: The activation or inhibition of Rho kinase could significantly alter the number and length of neurites of hippocampal neurons. Rho kinase regulated the cytoskeleton to regulate the neurite outgrowth, and LPA could significantly increase intracellular calcium. After BAPTA/AM treatment, the length and branch number of neurites of neurons reduced markedly. BAPTA/AM was able to reduce intracellular calcium and decrease neuronal cytoskeleton. Treatment with both BAPTA/AM and LPA could stop the retraction of neurites, but the length and branch number of neurites remained unchanged after treatment with Y-27632 and LPA. CONCLUSION: Calcium may affect the cytoskeleton arrangement to regulate neurite outgrowth, and calcium is involved in the downstream signal transduction of Rho kinase regulated neurite outgrowth of hippocampal neurons.

Three polymorphisms of ALOX5AP and risk of ischemic stroke in Chinese: evidence from a meta-analysis.

The impacts of three polymorphisms (SG13S114A/T, SG13S89A/G and SG13S32A/C) of 5-lipoxygenase activating protein (ALOX5AP) on the risk of ischemic stroke (IS) have been extensively studied for Chinese people, while conflicting results have been reported. The aim of meta-analysis was to further explore the associations to get a more robust conclusion. We researched the databases of Medline, Embase and Wangfang with latest update of August 1st, 2013. Odds ratio and corresponding 95% confidence interval (OR and 95%CI) were used to present the strength of the associations. Eleven case-control studies with 11,037 Chinese peoples (5361 IS cases and 5676 controls) were included. Overall, combined analysis indicated that AA genotype of ALOX5AP SG13S114A/T was significantly associated with increased risk of IS incidence compared with TT genotype [OR and 95%CI: 1.47 (1.13-1.91), P=0.005]. In addition, when subgroup analysis was conducted by subtypes of IS (atherothrombotic- or small artery disease-IS, AHS- or SAD-IS), A allele of SG13S114A/T was found to be associated with increased risk of AHS-IS compared with T allele [OR and 95%CI: 1.51 (1.28-1.79), P<0.01 for AA vs. TT, and 1.12 (1.03-1.22), P=0.010 for A carriers v. T carriers]. However, SG13S89A/G and SG13S32A/C were not overall associated with IS incidence. Due to limited number of included studies, subgroup analyses were not conducted for SG13S89A/G and SG13S32A/C polymorphisms. Sensitivity analyses indicated the robustness of all combined analyses, and publication bias was not found. In conclusion, ALOX5AP SG13S114A/T, rather SG13S89A/G and SG13S32A/C, was significantly associated with risk of IS development for Chinese. More studies were required to warrant the findings of this study.