| Objective: Epilepsy is a common neurological disease, with repeated episodes of clinical features, In clinical observation, it had been found that patients with epilepsy not only had seizures symptoms, but also accompanied by memory loss, attention deficit disorder and other cognitive impairment in performance, which seriously affected the life and work of patients. Activity regulation of cytoskeleton associated protein (Arc) / Activity regulation of gene 3.1 protein homolog (Arg3.1), is an unique immediate early gene (IEG). In neurons, Arc can be transiently and rapidly induced in response to physiological and pathological stimuli, and it has a significant effect on synaptic plasticity and stability, also, it is closely related with long-term potentiation (LTP) in the hippocampus. LTP reflects the stored procedures of information on the synaptic level, and that is considered to be the molecular basis of learning and memory. In this experiment, we established the stable rat models of chronic epilepsy with pentylenetetrazole (PTZ), and given memantine (MMT), a NMDA receptor antagonist to intervene, then used Morris water maze to test the learning and memory changes in epileptic rats. Followed of it, we detected the expression of Arc/Arg3.1 in rats hippocampus by immunohistochemistry to explore the mechanism of the cognitive impairment of epilepsy and observed the role of memantine in the treatment of cognitive impairment followed with epilepsy.Methods: Healthy and clean adult male Sprague-Dawley (SD) rats (115), weighing approximately 200±20g, were randomly divided into normal control group(NC)(15), PTZ group(25), PTZ + MMT (5 mg / kg) group(25), PTZ + MMT ( 10 mg / kg) group(25), PTZ + MMT (15mg/kg) group(25). The first step was model preparation. Weighting the rats before administration, PTZ group and intervention group of memantine were injected intraperitoneally of 1% PTZ 35 mg / kg every day, after injecting every day, observed the rats about 1h, NC group were injected normal saline 3.5 ml / kg every day, continuous infusion for 30 days, After the modeling, since the 31 days, PTZ group were injected normal saline 3.5 ml / kg 15 min before the injection of PTZ every day, memantine treatment group, according to different dose groups, were given MMT 5 mg / kg (low dose), 10 mg / kg (medium dose), 15mg/kg (high dose) injection intraperitoneally 15min before the injection of PTZ every day, NC group were injected intraperitoneally normal saline 3.5 ml / kg 15min before the injection of physiological saline 3.5 ml / kg. There are a total of 14 days of intervention. Then used Morris water maze to test the learning and memory changes in epileptic rats, and detected the positive cell of Arc/Arg3.1 in rats hippocampus by immunohistochemistry.Results:1.Behavior modeling stage we observed in rats after PTZ injection of 6 ~ 10 days that the rats began to nod, staring, wash-like the face repeatly, twitch the facial and head, afterwards, the symptoms increased day by day. Moreover, loss of righting reflex and generalized tonic–clonic convulsions were seen on day 18~day 24, which indicated reaching the kindling standard. Rats were regarded as fully kindled when they exhibited seizure stagesⅣ~Ⅴin 3 times continuously. On day 30, in addition to the dead rats, the total number of the rats being fully kindled were 68, in PTZ group were 16, in PPT+MMT5 group were 17, in PPT+MMT10 group were 18, in PPT+MMT15 group were 17.No seizures were found in the NC group.2.Place navigation results in Morris water maze test: We compared the mean of the escape latency each day. The results showed: The PTZ group was prolonged to the NC group in the time of finding the platform(escape latency), and there was a statistical difference between the two groups(P<0.05); the escape latency of PTZ+MMT5 group was shorten than the PTZ group, but there was no statistical difference between them(P>0.05); the escape latency of PTZ+MMT10 group showed no difference comparing with PTZ+MMT15 group(P>0.05),but these two group escape latencies were all shorten than the PTZ group, and showed statistically differences((P>0.05).3.Arc-positive cell in the CA1 area of rats hippocampals detected by Immunohistochemistry showed that PTZ group (27.601±2.073)was lower than the NC group (37.802±1.303), the difference was statistically significant (P<0.05); Compared with PTZ group , PTZ + MMT5 group (28.798±2.387) was no significant difference (P>0.05); PTZ + MMT10 group(32.001±2.000)was higher than the PTZ group(P<0.05); PTZ+MMT15 group was higher than the PTZ group, (P<0.05); PTZ+MMT10 and PTZ+MMT15 were higher than PTZ+MMT5, (P<0.05), but between PTZ+MMT10 group and PTZ+MMT15 group , there was no significant difference (P> 0.05).Conclusion: In this study, the chronic epileptic models kindled by PTZ indeed had learning and memory abilities impairments. We found that the number of Arc-positive cells in the hippocampus of the chronic epileptic rats kindled by PTZ reduced, suggesting that the cognitive dysfunction of epilepsy may be associated with Arc. Memantine may regulate the expression level of Arc in the hippocampus to improve learning and memory ability in rats with epilepsy, and the improved degree may be associated with the dose of memantine.
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