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Measurement of Total Calcium in Neurons by Electron Probe X-ray Microanalysis
Published on: November 20, 2013
Nimodipine Blocks Histone-Induced Calcium Overload to Protect Neurons after Traumatic Brain Injury
1Department of Emergency, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, China.
Abstract:
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. 43, 869-885.
Insights
Nimodipine reduces brain damage after traumatic brain injury (TBI) by blocking calcium influx and cell death pathways. This drug improves neurological function and recovery in TBI models.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Traumatic brain injury (TBI) causes neuronal apoptosis and neurological deficits.
- Extracellular histones contribute to TBI pathology by increasing calcium influx and activating cell death pathways.
- Nimodipine's therapeutic potential in TBI beyond its vasodilatory effects requires investigation.
Purpose of the Study:
- To investigate if nimodipine alleviates TBI-induced neuronal apoptosis and neurological deficits.
- To determine if nimodipine inhibits extracellular histone-mediated calcium influx, mitochondrial damage, and Caspase pathway activation.
- To elucidate the molecular mechanisms underlying nimodipine's neuroprotective effects in TBI.
Main Methods:
- In vitro studies using cortical neurons exposed to histones.
- In vivo studies using a mouse model of TBI.
- Assessment of neuronal apoptosis, proliferation, mitochondrial function, and Caspase pathway activation.
- Behavioral tests (Morris maze, rotarod) and histological analysis of brain tissue.
- Molecular docking and transcriptomic analysis.
Main Results:
- Nimodipine reduced histone-induced calcium influx, neuronal apoptosis, and improved mitochondrial function in vitro.
- Nimodipine reversed TBI-induced neurological deficits, improved spatial memory and motor coordination in vivo.
- Nimodipine inhibited Caspase pathway activation and reduced brain lesions and neuronal loss post-TBI.
- Molecular docking confirmed nimodipine-histone binding, and transcriptomics revealed nimodipine's effects on calcium signaling, mitochondrial apoptosis, and oxidative stress pathways.
Conclusions:
- Nimodipine mitigates TBI-induced neuronal apoptosis and dysfunction by blocking extracellular histone-driven calcium overload.
- Nimodipine preserves mitochondrial integrity and suppresses Caspase activation, leading to improved functional recovery after TBI.
- This study demonstrates a novel mechanism for nimodipine's neuroprotection in TBI, targeting extracellular histone-mediated pathology.
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