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. 43, 869–885.
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