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The Effects of Memantine on Spatial Learning and Memory and the Expression of NMDA Receptor of PTZ-kindled Rats

Author: WangLiNa
Tutor: WangWeiPing
School: Hebei Medical University
Course: Neurology
Keywords: Pentylenetetrazole Epilepsy Learning and Memory NMDAR2B NMDAR2A Memantin
CLC: R742.1
Type: Master's thesis
Year: 2011
Downloads: 32
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Abstract


Objective : Epilepsy is a kind of common chronic dysencephalia syndrome,Its outside except seizures, often accompanied by cognitive function different degree of damage. Clinically, epilepsy with cognitive dysfunction incidence is about 30% ~ 40%, Cognitive impairments of epilepti mainly for the distraction, learning, memory loss, vocabulary expression ability to drop, digital reasoning ability damage, emotional behavior abnormalities and social adaptation ability damage, has become a declining influence with epilepsy is an important factor in the quality of life. So the cognitive impairments after Epilepsy has been extensive attention, And improve seizures in cognitive function has become another epileptic cure clinically grim requirements.We observed the learning and memory changes of PTZ-kindled epileptic rats by Morris water maze, as well as applied immunohistochemical and RT-PCR to detect and analysis the expression of NMDAR2A/2B to study the role of memantine on epileptic rats, and to explore the molecular mechanism of the cognitive impairment of epilepsy.Aims to find the role of NMDA receptors in epileptic rats and the intervention role of memantine in epileptic rats after cognitive dysfunction, in order to provide guidance and theory for Clinical treatment.Methods: 115 Adult male Sprague–Dawley (SD) rats which Weight about 200±20g were selected through Y-Maze tests and then divided into 5 groups randomly. The 25 rats in PTZ group received intraperitoneal injection of 1% pentylenetetrazol (PTZ) by 35mg/kg for consecutive 44 days. The 75 rats in memantine intervention groups received intraperitoneal injection of 1% pentylenetetrazol (PTZ) by35mg/kg for consecutive 30 days. From the 31st day on,the rats in memantine intervention groups were injected memantine intraperitoneally by 5 mg/kg、10 mg/kg、15 mg/kg 30 minutes before PTZ in the rest 14 days. The 20 rats in the normal control group (NC) were injected saline intraperitoneally (i.p) by 3.5ml/kg for consecutive 44 days. Then those rats were tested with Morris Water Maze (MWM) for the measurement of learning and memory abilities. The expression of NMDAR2A and NMDAR2B mRNA and protein levels were measured by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemical.Results:1 No seizures were found in the normal control group.Rats in the other groups beginning from day 3~day 7 on had seizures induced by repetitive PTZ, which were characterized by head shaking, squealing and crawling. 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. The numbers of the rats being fully kindled in PTZ group were, three PTZ+MMT groups were .No alteration in the frequency and stages of seizures was seen in epileptic +memantine group.2 Rats in epileptic control group spend longer time to find the hidden platform than those in normal control group. Epileptic rats treated with 5mg/kg memantine searched the hidden platform sooner than those without memantine treated(P>0.05). Epileptic rats treated with 10mg/kg and 15mg/kg memantine searched the hidden platform sooner than those without memantine treated(P<0.05). There was no significant difference in the tow groups(P>0.05).3 The ratio of NMDA2A/2B/β-actin was used to identify the expression level of NMDA2A/2B. The ratio of NMDA2A/β-actin was 0.12±0.03 in epileptic control group,0.59±0.07 in normal control group,0.26±0.09 in epileptic 5mg/kgmemantine group , 0.29±0.09 in epileptic10mg/kgmemantine group,0.62±0.08in epileptic 15mg/kgmemantine group;The ratio of NMDA2B/β-actin was 0.06±0.02 in epileptic control group,0.34±0.06 in normal control group,0.17±0.05 in epileptic 5mg/kgmemantine group ,0.23±0.05 in epielptic+10mg/kgmemantine group,0.4±0.06 in epielptic+15 mg/kgmemantine group. The results indicated that the expression of NMDAR2A/2B mRNA was decreased in epileptic control groups(P<0.05). After treated with memantine the expression of NMDAR2A/2B mRNA was increased(P<0.05). The expression level of NMDAR2A/2BmRNA increased along with the increase of the dosage .4 The number of positive cells of in rat hippocampal CA1 area with high magnification: the number of positive cells of NMDAR2A was 8.33±2.52 in epileptic control group,11.33±1.53 in epileptic and 5mg/kg memantine group,23.67±5.68 in epileptic and 10mg/kg memantine group, 28.33±1.53in epileptic and 15mg/kg memantine group,17.67±3.06 in normal control group; the number of positive cells of NMDAR2A was 13.67±3.06 in epileptic control group,23±3.61 in normal control group, 15.67±2.08 in epileptic and 5mg/kg memantine group, 30.33±5.51in epileptic and 10mg/kg memantine group, 35±3.61in epileptic 15mg/kg and memantine group.The results indicated that the expression of NMDAR2A/2B protien was decreased in epileptic control groups(P<0.05). After treated with 10mg/kg and 15mg/kg memantine the expression of NMDAR2A/2B protien was increased(p<0.05).Conclusion:1 The epileptic model kindled by PTZ in the experiment did have impairments in learning and memory abilities.2 The reducing expression of NMDAR2A/2B mRNA and protein in the hippocampus could show that NMDAR2A/2B might be involved in the pathogenesis of cognitive dysfunction after epilepsy.3 Memantine might improve spatial learning and memory of pentylene -tetrazole-kindled rats via increasing NMDAR2A and NMDAR2B expression.

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CLC: > Medicine, health > Neurology and psychiatry > Neurology > Brain diseases > Epilepsy
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