College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
Department of Neurology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
Neurosci Bull. 2024 May;40(5):577-593. doi: 10.1007/s12264-023-01140-8. Epub 2023 Nov 16.
Neuroinflammation mediated by microglia and oxidative stress play pivotal roles in the development of chronic temporal lobe epilepsy (TLE). We postulated that kainic acid (KA)-Induced status epilepticus triggers microglia-dependent inflammation, leading to neuronal damage, a lowered seizure threshold, and the emergence of spontaneous recurrent seizures (SRS). Extensive evidence from our laboratory suggests that dextromethorphan (DM), even in ultra-low doses, has anti-inflammatory and neuroprotective effects in many animal models of neurodegenerative disease. Our results showed that administration of DM (10 ng/kg per day; subcutaneously via osmotic minipump for 4 weeks) significantly mitigated the residual effects of KA, including the frequency of SRS and seizure susceptibility. In addition, DM-treated rats showed improved cognitive function and reduced hippocampal neuronal loss. We found suppressed microglial activation-mediated neuroinflammation and decreased expression of hippocampal gp91 and p47 proteins in KA-induced chronic TLE rats. Notably, even after discontinuation of DM treatment, ultra-low doses of DM continued to confer long-term anti-seizure and neuroprotective effects, which were attributed to the inhibition of microglial NADPH oxidase 2 as revealed by mechanistic studies.
小胶质细胞介导的神经炎症和氧化应激在慢性颞叶癫痫（TLE）的发展中起着关键作用。我们假设，红藻氨酸（KA）诱导的癫痫持续状态引发小胶质细胞依赖性炎症，导致神经元损伤、癫痫发作阈值降低和自发性反复性癫痫发作（SRS）的出现。我们实验室的大量证据表明，右美沙芬（DM）即使在超低剂量下，也对许多神经退行性疾病的动物模型具有抗炎和神经保护作用。我们的结果表明，DM 的给药（每天 10ng/kg；通过皮下渗透泵持续给药 4 周）显著减轻了 KA 的残留效应，包括 SRS 的频率和癫痫易感性。此外，DM 治疗的大鼠表现出认知功能的改善和海马神经元丢失的减少。我们发现，在 KA 诱导的慢性 TLE 大鼠中，抑制小胶质细胞激活介导的神经炎症和减少海马 gp91 和 p47 蛋白的表达。值得注意的是，即使停止 DM 治疗，超低剂量的 DM 仍继续发挥长期的抗癫痫和神经保护作用，这归因于通过机制研究发现抑制小胶质细胞 NADPH 氧化酶 2。
