Impact of Oxidative Stress and Neuroinflammation on Sarco/Endoplasmic Reticulum Ca2+-ATPase 2b Downregulation and Endoplasmic Reticulum Stress in Temporal Lobe Epilepsy

Abstract

Epilepsy is one of the most common neurological disorders. Calcium dysregulation and neuroinflammation are essential and common mechanisms in epileptogenesis. Sarco/endoplasmic reticulum (ER) Ca²⁺-ATPase 2b (SERCA2b), a crucial calcium regulatory pump, plays pathological roles in various calcium dysregulation-related diseases. However, the link between SERCA2b and neuroinflammation in epilepsy remains undetermined. This study aimed to establish the relationship between SERCA2b, oxidative stress, and neuroinflammation in epilepsy to elucidate the underlying molecular mechanism in epileptogenesis. Neuroinflammation and oxidative stress were induced in N2a cells using lipopolysaccharide (LPS) and hydrogen peroxide (H₂O₂). However, experimental temporal lobe epilepsy (TLE) was induced in mice using pilocarpine. Further, effects of oxidative stress and neuroinflammation on SERCA2b and ER stress markers were assessed at protein and mRNA levels. Calcium imaging was employed to determine intracellular calcium levels. SERCA2b expression significantly decreased after LPS, H₂O₂, and pilocarpine exposure at both mRNA and protein levels, mediated by upregulating neuroinflammation. This downregulation of SERCA2b was associated with increased production of reactive oxygen species and elevated intracellular calcium levels, leading to elevated ER stress markers. Our findings highlight a link between oxidative stress, neuroinflammation and SERCA2b in TLE. The results suggest that targeting SERCA2b could restore calcium homeostasis and ER stress processes, potentially providing a therapeutic option for TLE. This study underscores the importance of SERCA2b in the pathophysiology of epilepsy and its potential as a therapeutic target.