| Background:Human immunodeficiency virus associated dementia (HAD), which belongs to subcortical dementia, is also known as the AIDS-Dementia Complex (ADC). Learning and memory dysfunction is one of the core symptoms of HAD. It's reported that the occurrence of ADC and neuroinflammation is related to activation of macrophages/microglia. Adenosine triphosphate (Adenosine Triphosphate ATP) as a signal molecule to regulate microglial cell function, impaired nerve cells to release the ATP stimulate the surrounding glial cells release ATP and other chemicals chemoattractant, and the ATP-induced chemotaxis of microglia can be excited driven by P2X7 receptor. Because P2X7 receptors are not only involved in the regulation of microglia function, but also involved in inflammation and immune response, and is closely related to neurodegenerative diseases, P2X7 receptors may be a new target for the prevention and treatment of HAD. Naringin is a kind of natural flavonoids, which have anti-inflammatory and anti oxidative stress effect. At present, whether P2X7 receptor involved in ADC is unclear; there is no research at home or abroad reporting that naringin has effect on ADC prevention and treatment by supressing P2X7 receptor.Objective:The research aims to investigated the effects of naringin on the HIV-1 envelope glycoprotein gp120 (gp120)-induced cognitive dysfunction of rats via establish HAD model, and the effects of expression of P2X7 receptors and p65 protein in the hippocampus was observed, exploring the improvement of naringin on gp120-induced cognitive deficits mediated by P2X7 receptor in rats and its possible role mechanism.Methods:Health Sprague-Dawley (SD) rats, weight 125-175g, male and female half, SD rats were randomly divided into control group (Ctrl), sham operation group (Sham), gp120 group (gp120 50ng/d), naringin treatment group (gp120+Naringin, namely gp120 50ng/d+Naringin 30 mg/kg-d) and P2X7 receptor antagonist BBG group (gpl20+BBG, namely gp120 50ng/d+BBG 50mg/kg), with 6 rats in each group. AIDS dementia animal model was established by lateral ventricle infusion with gp120, and six arm water maze test was utilized to observe the behavioral changes on learning and memory deficits caused by intracerebroventricular perfusion of gp120 and the ameliorative function of naringin. And Western Blot, immunohistochemistry, RT-PCR, qPCR and other molecular biological methods were applied to detecting the expression of P2X7 receptor protein/mRNA and P65 protein in the hippocampus of each group rats.Results:1. The six arm water maze behavior test repeated measure analysis of variance showed that the escape latency and the number of errors to find the target platform of different gp120 concentration groups was of time efficiency (P<0.01), With the increase of water maze test days, the rats escape latency gradually shortened and the number of errors to find the target platform gradually reduced; At the same time, there was an interaction effect between the time and the gp120 factor (P<0.01); As the result of one-way analysis of variance showed, there were differences in the escape latency and number of errors among different group rats, and the escape latency and number of errors of different gp120 concentration group rats increased obviously when compared with control group(P<0.01), indicating that intracerebroventricular infusion of gpl20 can cause the disorder of learning and memory in rats, quasi AIDS dementia animal model was successfully established.2. The results of western blot, immunohistochemistry and PCR showed that P2X7 receptor protein and mRNA expression in the hippocampus of every gp120 concentration group rats had increased compared with that of control group (P<0.01), indicating that gp120 induced cognitive impairment is related to the P2X7 receptor in the hippocampus of rats.3. The behavioral results found the escape latency and the number of errors to find the target platform of each naringin treatment group rats had reduced when compared with the gp120 model group (P<0.01),indicating that naringin could exert ameliorative effects on gp120-induced learning and memory deficits; there existed no significant difference in the escape latency and the number of errors between naringin treatment group rats and the gp120+BBG group rats (P>0.05). At the same time, the P2X7 receptor protein and mRNA expression of different naringin dosage treatment groups were decreased compared with the model group (P<0.01), while no difference in the expression of P2X7 receptor protein and mRNA was observed when naringin treatment group was compared with BBG group (P>0.05), indicating that naringin can inhibit P2X7 receptor-mediated learning and memory deficits induced by gp120.4. The results of Western Blot showed that the expression of P65 protein in gp120 group rats hippocampus was higher than the control group (P<0.05), however, there was no difference between naringin treatment group and gp120+BBG group (P<0.05), showed that the P65 protein involved in the pathological process of naringin improves P2X7 receptor mediated cognitive dysfunction in gp120 rats.Conclusion:HIV gp120 intracerebroventricular infusion can be prepared to establish HIV dementia animal model; P2X7 receptors may be involved in the pathological process of gp120 induced learning and memory deficits of rats; Naringin can improve the learning and memory deficits caused by intracerebroventricular infusion of gp120, the mechanism of which may be related to the confrontation of P2X7 receptors and the upregulation of p65 expression. Indicating that P65 protein may be involved in gp120 mediated P2X7 receptor expression process. |
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