Pharmacological inhibition of calcium channel modulates NF-κB-NLRP3 inflammasome axis and alters post-stroke innate immunity.

Ischemic stroke triggers a series of pathological processes where calcium overload and mitochondrial dysfunction are key mediators of neuronal damage. Mitochondria not only fail energetically under calcium excitotoxicity but also play a crucial role in alteration of innate immune response through the production of danger signals. Although innate immunity is responsible for post-stroke tissue repair, it is also involved in the amplification of neuroinflammation exacerbating neuronal injury. Indirect evidence suggests role of calcium overload in neuroinflammation, but direct mechanistic evidence is still unclear. Calcium channel inhibition may provide a promising strategy to unravel this relationship by elucidating whether calcium influx is a causal factor in immune activation. Our recent findings demonstrated that inhibiting calcium influx alleviates mitochondrial dysfunction by calcineurin and cardiolipin modulation. The present study is a further molecular expedition into the role of calcium signaling in exacerbating stroke outcomes through innate immune modulation. Stroke was induced in male Sprague Dawley rats via middle cerebral artery occlusion. Genes and proteins expression were then assessed for markers of innate immunity. Mitochondrial complex activity was measured following calcium channel inhibition. It was observed that inhibiting calcium channel altered the innate immunity associated gene and protein expression when compared to stroke. In addition, calcium channel inhibition restored mitochondrial complex activity compared to stroke. These observations offer direct evidence of the role of calcium signaling in modulation of innate immunity and related molecular mechanisms. Thus, calcium channel inhibition could be one of the potential future adjunctive therapies to improve post-stroke outcomes.