| Objective:Monocyte chemoattractant protein-1(MCP-1)is regarded as a considerable virulence factor of HIV-1-associated neurocognitive disorder(HAND).This research aims to investigate the effects of MCP-1 on spatial learning and memory deficits,cognitive impairment and oxidative stress in rats and explore the role of NMDA receptors involved in it via injected MCP-1 directly into hippocampus bilaterally of rats to establish a cognitive impairment rat model.Our study provided a basis for assessing the role of NMDA receptors in neurodegenerative diseases.Methods:1.Effect of different doses of MCP-1 on spatial learning and memory,cognition in rats,and the morphology of hippocampal neuronsThe rats were randomly divided into 6 groups: control group,sham group,and model groups which including MCP-1 groups of 5ng,50 ng,150ng and 300 ng.A rat model of cognitive impairment was established by bilateral injection of MCP-1 into the hippocampus.Morris water maze was used to assess the learning and memory abilities,the novel object recognition test was employed to detect the cognition,and HE staining was used to observe the morphological structure of rat hippocampal neurons.2.Effects of NMDA receptor antagonists on behavior change of the ratsThe rats were randomly divided into 5 groups: control group,sham group,and model group(5ng MCP-1 group)and drug treatment groups(memantine group and ifenprodil group).The rats of memantine group and ifenprodil group were treated with drugs 10mg/kg/day by intraperitoneal injection(i.p)for consecutive 3 days(the rats of the control group,sham group,and model group were treated with the equal volume of normal saline)before hippocampal injection.In the last day,30 min after drug administration,the models were treated with bilateral hippocampus injection with 2.5?L per side,the shams were given an equal volume of sterilized double-distilled water and the rats of the control group were not treated.The Morris water maze was used to assess the learning and memory abilities of rats,and the novel object recognition test was performed to detect the cognition of rats.3.Effects of NMDA receptor antagonists on oxidative stress in ratsAfter the novel object recognition test,the hippocampal tissues of rats were separated and the activity of superoxide dismutase(SOD)and glutathione(GSH)and the content of malondialdehyde(MDA)were detected by ELISA according to commercial kits.Results:1.Effect of different doses of MCP-1 on spatial learning and memory,cognition in rats,and morphology of the hippocampal neuronsThe results of Morris water maze show that in the navigation test,compared with sham group,the Escape Latency of each model group has significant difference,which the 5ng and 50 ng MCP-1 groups were more significantly(P <0.01)than the 150 ng and 300 ng MCP-1 groups(P <0.05).The cumulative distances of rats in the 5ng,50 ng,and 300 ng MCP-1 groups were significantly greater than the sham group(P <0.01 or P <0.05),but there was no statistical difference with the cumulative distance of rats between 150 ng MCP-1 group and sham group.Among all groups,the swimming speed has no difference(P >0.05).In the spatial probe trial,compared with the sham group,the number of crossing times in the 5ng MCP-1 group was significantly decreased(P <0.05),and the percentage of distance and time in target quadrant had no significant difference(P >0.05),but there was still a decreasing tendency.The three indicators in the spatial probe trial of 50 ng and 300 ng MCP-1 groups were significantly decreased compared with the sham group(P <0.05 or P <0.01),and the percentage of distance and time in target quadrant of the 150 ng MCP-1 group was significantly decreased compared with the sham group(P <0.05),but there was no statistical difference in the number of crossings to the former platform position(P >0.05).The results of novel object recognition test showed that compared with the sham operation group,the discrimination index(DI)of 5ng and 50 ng MCP-1 groups were statistically significantly lower(P <0.05),while DI in 150 ng MCP-1 group and 300 ng MCP-1 group decreased compared with sham group,but there was no statistical difference(P >0.05).The results of HE staining showed that all of the doses of MCP-1 could impair the hippocampal neurons.The hippocampal neurons in the rats of each model group arranged abnormally,with a large number of neurons showing pycnotic nucleus,cytoplasm of deep stained,cells shrinking,distorting and dislocation.The nucleus of some cells dissolved to form ghost cells.2.Effects of NMDA receptor antagonists on behavior change of ratsThe results of Morris water maze show that compared with the model group(5ng MCP-1 group),the escape latency and cumulative distances of rats in the memantine group and ifenprodil group were significantly reduced(P <0.01)in the navigation test.In the spatial probe trial,compared with the model group,the above indicators in memantine group had no statistically significant difference(P >0.05),although there was an increasing trend.However,the results of ifenprodil group were almost equal to those of 5ng MCP-1 group,and there was no statistical difference(P >0.05).The results of novel object recognition test showed that the discrimination index DI of memantine group was significantly higher than model group(P <0.05),while there was no significant difference in ifenprodil group(P >0.05).3.Effects of NMDA receptor antagonists on oxidative stress in ratsCompared with the model group,the activity of SOD in the hippocampus of memantine group and ifenprodil group were significantly increased(P <0.01),GSH activity(P <0.001)and MDA content(P <0.05)were significantly decreased.Conclusions:1.Intrahippocampal injection of 5ng,50 ng,150ng and 300 ng of 4 different concentrations of MCP-1 in both hippocampus could induce learning and memory impairment and cognitive dysfunction in rats and impaired the hippocampal neuronal structure in rats.Of the four concentrations explored,5ng and 50 ng of MCP-1 were effective in successfully preparing a rat model of cognitive impairment.2.Both non-selective NMDAR antagonist memantine and selective NR2 BR antagonist ifenprodil improved MCP-1-induced learning and memory impairment and cognitive dysfunction in rats,suggesting that NMDA receptors were involved in learning and memory impairment and cognitive dysfunction.3.Both memantine and ifenprodil increased the antioxidant capacity of MCP-1 cognitive dysfunction rats,suggesting that NMDA receptors participated in the oxidative stress process of the central nervous system.Previous studies about excitatory post-synaptic currents have shown that evoked oxidative stress and excitatory damage are two ways that NMDA receptors cause learning and memory impairment and cognitive dysfunction. |
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