[+]-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats
[+]-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats
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DOI：
10.1016/j.cbi.2008.05.023
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发表时间：
2008-09-25
影响因子：
5.1
通讯作者：
Nambiar, Madhusoodana P.
中科院分区：
文献类型：
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作者：
Coleman, Brian R.;Ratcliffe, Ruthie H.;Nambiar, Madhusoodana P.
有机磷（OP）神经毒剂的毒性归因于其对乙酰胆碱酯酶（AChE）的不可逆抑制，导致乙酰胆碱（ACh）过度积累，随后释放兴奋性氨基酸（EAA）。 EAA 会因过度刺激 N-甲基-D-天冬氨酸 (NMDA) 受体而维持癫痫发作并诱发神经病理学。 Huperzine A (Hup A) 是一种可渗透血脑屏障的选择性可逆 AChE 抑制剂，已被证明可以通过干扰原代神经元培养物中的谷氨酸受体门控离子通道来减少 EAA 诱导的细胞死亡。虽然 [-]-Hup A（天然异构体）抑制 AChE 的效力比 [+]-Hup A 大约强 38 倍，但 [-]- 和 [+]-Hup A 都类似地阻断 NMDA 通道。在这里，我们在大鼠模型中评估了 [+]-Hup A 对 NMDA 诱导的癫痫发作的保护功效。植入无线电遥测探针以记录脑电图（EEC）、心电图（ECG）、体温和身体活动的大鼠被给予不同剂量的[+]-Hup A（肌内），并在20-30分钟后用20μg/kg NMDA（脑室内）治疗。对于暴露后，在NMDA（20μg/kg）1分钟后用[+]-Hup A（3mg/kg，肌肉注射）处理大鼠。我们的数据表明，暴露前和暴露后，[+]-Hup A (3 mg/kg) 可以保护动物免受 NMDA 诱发的癫痫发作。此外，给予 NMDA 的动物在 [+]-Hup A 治疗后表现出存活率增加。 [+]-Hup A 对脑电图、心率、体温、体力活动没有明显影响，表明副作用、毒性或相关病理的风险降低。我们的结果表明，[+]-Hup A 通过阻断 NMDA 诱导的体内兴奋性毒性来预防癫痫发作和癫痫持续状态 (SE)。我们认为，[+]-Hup A 或 [+]- 和 [-]-Hup A 的独特组合可能被证明对于致命剂量的 OP 诱导的神经毒性的暴露前和暴露后治疗有效。由爱思唯尔爱尔兰有限公司出版
The toxicity of organophosphorous (OP) nerve agents is attributed to their irreversible inhibition of acetylcholinesterase (AChE), which leads to excessive accumulation of acetylcholine (ACh) and is followed by the release of excitatory amino acids (EAA). EAAs sustain seizure activity and induce neuropathology due to over-stimulation of N-methyl-D-aspartate (NMDA) receptors. Huperzine A (Hup A), a blood-brain barrier permeable selective reversible inhibitor of AChE, has been shown to reduce EAA-induced cell death by interfering with glutamate receptor-gated ion channels in primary neuronal cultures. Although [-]-Hup A, the natural isomer, inhibits AChE approximately 38-fold more potently than [+]-Hup A, both [-]- and [+]-Hup A block the NMDA channel similarly. Here, we evaluated the protective efficacy of [+]-Hup A for NMDA-induced seizure in a rat model. Rats implanted with radiotelemetry probes to record electroencephalography (EEC), electrocardiography (ECG), body temperature, and physical activity were administered various doses of [+]-Hup A (intramuscularly) and treated with 20 mu g/kg NMDA (intracerebroventricular) 20-30 min later. For post-exposure, rats were treated with [+]-Hup A (3 mg/kg, intramuscularly) 1 min after NMDA (20 mu g/kg). Our data showed that pre- and post-exposure, [+]-Hup A (3 mg/kg) protects animals against NMDA-induced seizures. Also, NMDA-administered animals showed increased survival following [+]-Hup A treatment. [+]-Hup A has no visible effect on EEG, heart-rate, body temperature, OF physical activity, indicating a reduced risk of side effects, toxicity, or associated pathology. Our results suggest that [+]-Hup A Protects against seizure and status epilepticus (SE) by blocking NMDA-induced excitotoxicity in vivo. We propose that [+]-Hup A, or a unique combination of [+]- and [-]-Hup A, may prove to be effective for pre- and post-exposure treatment of lethal doses of OP-induced neurotoxicity. Published by Elsevier Ireland Ltd