Nimodipine Blocks Histone-Induced Calcium Overload to Protect Neurons after Traumatic Brain Injury.

Aims: To investigate if nimodipine alleviates traumatic brain injury (TBI)-induced neuronal apoptosis and neurological deficits by inhibiting extracellular histone-mediated Ca²⁺ influx, mitochondrial damage, and Caspase pathway activation. Results: In vitro, nimodipine significantly reduced histone-induced Ca²⁺ influx in cortical neurons, reversed by Ca²⁺ activator A23187. It restored neuronal proliferation (↑3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, ↑Ki67+ cells), reduced apoptosis (↓Annexin V/propidium iodide), improved mitochondrial function (↑ΔΨm/adenosine triphosphate, ↓reactive oxygen species/malondialdehyde, ↑Glutathione Peroxidase), and modulated apoptosis markers (↓Bax, ↑Bcl-2). These effects were blocked by A23187 or Caspase activator AD-2646, which increased Cleaved Caspase-3/9 and PARP1. Molecular docking confirmed nimodipine-histone binding. Transcriptomics revealed nimodipine reversed histone-induced dysregulation of Ca²⁺ signaling, mitochondrial apoptosis, and oxidative stress pathways, with Caspase-3 as a key protein-protein interaction node. In vivo, nimodipine improved spatial memory (Morris maze), neurological function (↓modified neurological severity score), and motor coordination (↑rotarod) in TBI mice. It reduced brain lesions (2,3,5-triphenyltetrazolium chloride), neuronal loss (hematoxylin and eosin/Nissl), Ca²⁺ accumulation, and proapoptotic protein expression and restored ΔΨm. Histone coadministration attenuated these benefits. Innovation: First demonstration that nimodipine directly targets extracellular histone-induced Ca²⁺ influx-a key TBI pathology mechanism-preserving mitochondrial integrity and inhibiting the Caspase cascade, extending beyond its known vasodilatory effects. Conclusion: Nimodipine mitigates post-TBI neuronal apoptosis and dysfunction by blocking extracellular histone-driven Ca²⁺ overload, preventing mitochondrial damage, and suppressing Caspase activation, significantly improving functional recovery. Antioxid. Redox Signal. 00, 000-000.