The link between spreading depolarization and innate immunity in the central nervous system.

Spreading depolarization (SD) is a complex event that induces significant cellular stress in the central nervous system, leading to a robust inflammatory response without causing cell death in healthy tissues which may be called as neuro-parainflammation. Research has established a clear link between SD and the activation of pro-inflammatory pathways, particularly through the release of cytokines like interleukin-1β and tumor necrosis factor-α, and the involvement of inflammatory mediators such as cyclooxygenase-2 and high mobility group box 1 (HMGB1). Mechanistically, the opening of pannexin-1 (Panx1) channels and the activation of the (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome play critical roles in this process, facilitating the release of inflammatory signals that can exacerbate conditions like migraine. Furthermore, the interplay between neurons and glial cells, particularly astrocytes and microglia, underscores the intricate nature of neuroinflammation triggered by SD. Importantly, these findings indicate that these inflammatory processes may also have systemic implications, affecting immune responses beyond the central nervous system. Overall, this body of work highlights the need for further exploration of the mechanisms underlying SD-induced inflammation and potential therapeutic targets to mitigate neuroinflammatory disorders. Inflammation extends beyond the central nervous system to peripheral structures, including the meninges and trigeminovascular system, which are critical for headache initiation. Genetic factors, particularly familial hemiplegic migraine (FHM), exacerbate neuroinflammatory responses to SD, leading to increased susceptibility and prolonged headache behaviors. Collectively, these findings underscore the complex cellular interactions and innate inflammatory processes underlying SD and their relevance to migraine mechanisms, suggesting potential avenues for therapeutic intervention.