Dantrolene Protects Hippocampal Neurons Against Amyloid-β₁₋₄₂-Induced Calcium Dysregulation and Cell Death

The accumulation of amyloid-β₁₋₄₂ (Aβ₁₋₄₂) in the brain is a hallmark of Alzheimer's disease (AD), contributing to intracellular calcium dysregulation and neuronal death. Ryanodine receptors (RyRs), located in the endoplasmic reticulum (ER), play a pivotal role in intracellular calcium release and homeostasis. In this study, we employed an in vitro model of AD using cultured rat hippocampal neurons treated with Aβ₁₋₄₂ to investigate the effects of dantrolene, a RyR antagonist, on calcium signaling and neuronal viability. Dantrolene significantly reduced basal cytosolic calcium levels and attenuated stimulus-induced calcium transients in response to depolarizing solution, electrical field stimulation, and caffeine application. These findings indicate that dantrolene stabilizes intracellular calcium signaling by limiting calcium release from ER stores. Furthermore, co-application of dantrolene with Aβ₁₋₄₂ increased neuronal survival from 26 to 76% and significantly reduced the proportions of apoptotic and necrotic cells. These results demonstrate that RyRs contribute to calcium overload and neurotoxicity under AD-like conditions and that dantrolene effectively counteracts Aβ₁₋₄₂-induced calcium dysregulation. Altogether, our findings support the calcium hypothesis of AD and highlight dantrolene as a potential disease-modifying agent targeting ER-mediated calcium homeostasis.