青藤碱在戊四氮点燃大鼠中表现出抗惊厥作用和神经保护活性：涉及 NLRP1 炎性小体的抑制。

Sinomenine exerts anticonvulsant profile and neuroprotective activity in pentylenetetrazole kindled rats: involvement of inhibition of NLRP1 inflammasome.

机构信息

Department of Pharmacology, School of Basic Medical Sciences, Key Laboratory of Anti-inflammatory and Immunopharmacology, Anhui Medical University, Hefei, 230032, People's Republic of China.

Department of Psychiatry and Medical Experimental Center, Jiangxi Mental Hospital/Affiliated Mental Hospital of Nanchang University, Nanchang, 330029, People's Republic of China.

出版信息

J Neuroinflammation. 2018 May 18;15(1):152. doi: 10.1186/s12974-018-1199-0.

DOI:10.1186/s12974-018-1199-0

PMID:29776417

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5960124/

Abstract

BACKGROUND

Epilepsy is a common neurological disorder and is not well controlled by available antiepileptic drugs (AEDs). Inflammation is considered to be a critical factor in the pathophysiology of epilepsy. Sinomenine (SN), a bioactive alkaloid with anti-inflammatory effect, exerts neuroprotective activity in many nervous system diseases. However, little is known about the effect of SN on epilepsy.

METHODS

The chronic epilepsy model was established by pentylenetetrazole (PTZ) kindling. Morris water maze (MWM) was used to test spatial learning and memory ability. H.E. staining and Hoechst 33258 staining were used to evaluate hippocampal neuronal damage. The expression of nucleotide oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome complexes and the level of inflammatory cytokines were determined by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA) kits.

RESULTS

SN (20, 40, and 80 mg/kg) dose-dependently disrupts the kindling acquisition process, which decreases the seizure scores and the incidence of fully kindling. SN also increases the latency of seizure and decreases the duration of seizure in fully kindled rats. In addition, different doses of SN block the hippocampal neuronal damage and minimize the impairment of spatial learning and memory in PTZ kindled rats. Finally, PTZ kindling increases the expression of NLRP1 inflammasome complexes and the levels of inflammatory cytokines IL-1β, IL-18, IL-6, and TNF-α, which are all attenuated by SN in a dose- dependent manner.

CONCLUSIONS

SN exerts anticonvulsant and neuroprotective activity in PTZ kindling model of epilepsy. Disrupting the kindling acquisition, which inhibits NLRP1 inflammasome-mediated inflammatory process, might be involved in its effects.

摘要

背景

癫痫是一种常见的神经系统疾病，现有的抗癫痫药物（AEDs）对此控制效果不佳。炎症被认为是癫痫病理生理学中的一个关键因素。青藤碱（SN）是一种具有抗炎作用的生物活性生物碱，在许多神经系统疾病中发挥神经保护作用。然而，SN 对癫痫的影响知之甚少。

方法

戊四氮（PTZ）点燃法建立慢性癫痫模型。Morris 水迷宫（MWM）用于测试空间学习和记忆能力。H.E.染色和 Hoechst 33258 染色用于评估海马神经元损伤。Western blot、定量实时 PCR 和酶联免疫吸附试验（ELISA）试剂盒用于测定核苷酸寡聚化结构域（NOD）样受体蛋白 1（NLRP1）炎性小体复合物的表达和炎症细胞因子的水平。

结果

SN（20、40 和 80mg/kg）剂量依赖性地破坏了点燃获得过程，降低了癫痫发作评分和完全点燃的发生率。SN 还增加了癫痫发作潜伏期，减少了完全点燃大鼠的癫痫发作持续时间。此外，不同剂量的 SN 阻断了海马神经元损伤，最大限度地减少了 PTZ 点燃大鼠空间学习和记忆的损害。最后，PTZ 点燃增加了 NLRP1 炎性小体复合物的表达和炎症细胞因子 IL-1β、IL-18、IL-6 和 TNF-α 的水平，SN 以剂量依赖性方式减弱了这些变化。