Anticonvulsant Effect Of MK-801 And Other Drugs On Tetramine-induced Seizure

Objective On the establishment of tetramine (TET) caused status epileptics (SE) model in rats, antiepileptic effects of MK-801, diazepam and phencynonate hydrochloride on seizures induced by TET in rats were evaluated and compared. Methods To establish TET-induced SE model in rats, anticonvulsant effects of N-methyl-D-aspartate(NMDA) receptor antagonist MK-801(3,5mg/kg), gamma-aminobutyric acid(GABA) receptor agonist diazepam(10,20mg/kg), as well as anticholinergic phencynonate hydrochloride (8, 12mg/kg) on TET-caused SE were examined and compared by behavior, electrophysiology, neuropathology, and 24h survival rate. Results 1. 3min after TET (0.4 mg/kg) toxication, animals began to show rest less and gradually developed into wet dog shake, facial twitching, nodding like movement; then followed by bilateral forelimb clonic convulsions, stiff tail and tail bending.10-25min since TET poisoning, the clonic convulsion eventually developed into persistent generalized tonic seizure, continuously high-frequency and high-amplitude spikes wave in cortex and hippocampus were shown by EEG. 2. Behavioral and EEG results revealed that MK-801(3,5mg/kg) had significantly anticonvulsant and anti-lethal effects on TET-induced SE (P<0.05); diazepam (20mg/kg) also could notably antagonize the seizure induced by TET whereas phencynonate hydrochloride totally lost its anticonvulsant effect on the choose dose. 3. 24h since SE onset, the HE stain displayed that cells were reduced obviously in cortex and hippocampus CA1 region, followed by the cellular swelling, plasmatorrhexis, dislimn and derangement. MK-801 could obviously inhibit the cortex and hippocampus damage induced by TET, its neuroprotection was much better than those of diazepam and phencynonate hydrochloride. Conclusion. MK-801 had significantly anticonvulsant effect on TET-induced SE, it could also increase the 24h survival rate and inhibit the neuropathological injuries of SE animals; the anti-seizure, anti-lethal and neuroprotective effects of MK-801 were much stronger than those of diazepam and phencynonate hydrochloride. Our research first demonstrated the potential use of NMDA receptor MK-801 on the treatment of TET-induced SE in rats.[Abstract] Objective To examine the expression of NMDA receptor subunits at different time point during SE development induced by TET and investigate the relationship between the expression of NMDAR and the SE, as well as the corresponding brain damage. Methods 42 SD rats were randomly divided into seven groups including: normal control group; 4h, 8h, 12h, 24h, 48h and 72h since TET-poisoned group. On the establishment of TET (0.4mg/kg, ig) induced SE model, the expression of mRNA and protein of NR2A and NR2B were tested by real-time quantitative polymerase chain reaction (RT-PCR) and Western blotting in rats cortex and hippocampus at different time points since SE onset. Results 1. Compared with the normal control group, the levels of the mRNA and protein of NR2A decreased significantly at 4h and 12h and kept down-regulating until 72h(P<0.05, P<0.01) since SE onset though the tendency of up-regulating . 2. Compared with the normal control group, the levels of NR2B mRNA kept unchanged at all the test point though the tendency of down-regulating. Different from mRNA, the level of NR2B protein down-regulated 72h(P<0.05) since SE onset. Conclusion The down regulation of NR2A and NR2B may be the cause of TET induced SE.Compared with NR2B, the down-regulation of NR2A may have the close relation to SE and the corresponding brain damage induced by TET.Part 3 Inhibitory effect of MK-801 on the expression of the cortex and hippocampus NMDAR subunits on tetramine-induced SE in rats [Abstract] Objective On the establishment of TET-caused SE model in rats, inhibitory effect of MK-801 on the expression of NMDAR subunit NR2A, NR2B in rats cortex and hippocampus were tested. Methods 40 SD rats were randomly divided into 4 groups including: Normal control group, SE group, MK-801 (5mg/kg) treatment group and diazepam (20mg/kg) treatment. In addition to Normal control group, the other animal were received TET (0.4mg/kg, ig) to establish TET induced SE model. Immediately after TET poisoning, each TET treatment group was injected MK-801 5 mg/kg, diazepam 20 mg/kg and the same volume of saline respectively. 24h since TET toxication, the cortex and hippocampus were detached as fast as possible. Using RT-PCR and Western blotting, the expression of NR2A and NR2B was determined. Results 1. 24h since TET toxication, compared with the normal control group, the expression of NR2A and NR2B subunits were remarkably reduced in cortex and hippocampus 2. MK-801 could down-regulate the mRNA and protein of NR2A and NR2B subunit expression significantly at dose of 5mg/kg (P<0.05) whereas diazepam had no effect. Conclusion 1.24h since TET toxication,the levels of mRNA and protein of NR2A decreased significantly in cortex and hippocampus. 2. MK-801 could obviously inhibit the expression of NR2A and NR2B subunit in rats cortex and hippocampus and this inhibitory effects may be closely correlated to its excellently anti-seizure and neuroprotective effects.