Unraveling the Role of α2δ-1 in Cerebral Hemorrhage: Calcium Overload, Endoplasmic Reticulum Stress, and Microglial Apoptosis

Abstract

Abstract Background Cerebral hemorrhage is a severe condition associated with high morbidity and mortality. Understanding the underlying pathogenesis is crucial for developing effective therapeutic strategies. This study aimed to investigate the role of the dysregulated α2δ-1 protein in cerebral hemorrhage. Methods Immunofluorescence and Western blot analyses were performed on cerebral hemorrhage tissue and peripheral tissue samples obtained from patients with intracerebral hemorrhage. In BV2 cells, we investigated the effects of α2δ-1-mediated calcium overload on intracellular calcium concentration, phosphorylation of PLCr and IP3R, ERS response, and BV2 microglia apoptosis. Results We observed a significant upregulation of α2δ-1 in cerebral hemorrhage tissue. Knockdown of α2δ-1 resulted in decreased intracellular calcium concentration and reduced phosphorylation of PLCr and IP3R in the presence of calcium. Additionally, α2δ-1-mediated calcium overload induced ERS in BV2 microglia, accompanied with increased phosphorylation of PERK and decreased ERS-related proteins levels. Furthermore, α2δ-1 knockdown significantly inhibited BV2 microglia apoptosis and downregulated apoptosis-related proteins in the presence of calcium. Conclusions Our study indicates the involvement of α2δ-1 in calcium-mediated signaling, endoplasmic reticulum stress, and BV2 microglia apoptosis. The findings provide a basis for considering α2δ-1 as a potential therapeutic target in neuroinflammatory and neurodegenerative conditions associated with calcium dysregulation.