Anti-epileptic and Neuroprotective Effects of Ultra-low Dose NADPH Oxidase Inhibitor Dextromethorphan on Kainic Acid-induced Chronic Temporal Lobe Epilepsy in Rats
Jing‑Jing Yang1,2,3 · Ying‑Xin Liu1,3 · Yan‑Fang Wang1,3 · Bi‑Ying Ge3 · Ying Wang2 · Qing‑Shan Wang3,4 · Sheng Li1,3 · Jian‑Jie Zhang1,2 · Ling‑Ling Jin3 · Jau‑Shyong Hong5 · Sheng‑Ming Yin1,3 · Jie Zhao1,31 College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
2 Department of Neurology, The First Afliated Hospital of Dalian Medical University, Dalian 116011, China
3 National and Local Joint Engineering Research Center for Drug Research and Development of Neurodegenerative Diseases, Dalian 116044, China
4 School of Public Health, Dalian Medical University, Dalian 116044, China
5 Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC 27709, USA
Abstract
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 gp91phox and p47phox 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.
Keywords
Temporal lobe epilepsy; Dextromethorphan; NADPH oxidase; Ultra-low dose
