HDAC6 Inhibition Attenuates Early Brain Injury After Experimental Subarachnoid Hemorrhage and Suppresses Neuroinflammatory Responses.

Abstract

Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is closely associated with microglia-driven neuroinflammation, yet effective therapeutic strategies remain limited. Histone deacetylase 6 (HDAC6) has been implicated in neuroinflammatory regulation, but its role in microglial inflammatory activation after SAH remains unclear. In the present study, we investigated whether HDAC6 targeting attenuates SAH-induced EBI through modulation of microglia-associated neuroinflammation. A mouse prechiasmatic cistern blood-injection model of SAH and an Hb-stimulated primary microglia model were used to evaluate the effects of compound 13-7, an HDAC6-targeting inhibitor. We found that HDAC6 expression was significantly upregulated after SAH and was predominantly localized in microglia and neurons. Treatment with compound 13-7 increased α-tubulin acetylation in microglia, reduced brain edema, improved neurological deficits, and decreased neuronal apoptosis. In addition, compound 13-7 attenuated microglial inflammatory activation, reduced pro-inflammatory gene expression, decreased brain tissue levels of TNF-α, IFN-γ, and IL-6, and increased IL-4, IL-5, and IL-10 levels. In vitro, compound 13-7 protected neurons primarily through modulation of microglia-mediated inflammatory responses rather than by directly acting on neurons. Mechanistically, compound 13-7 reduced the p-P65/P65 ratio and suppressed NF-κB-related inflammatory gene expression in Hb-stimulated microglia. Collectively, these findings demonstrate that HDAC6 targeting attenuates SAH-induced EBI and improves neurological outcomes, at least partly by suppressing microglia-associated neuroinflammation and restoring inflammatory cytokine balance. Inhibition of NF-κB signaling may contribute to the anti-inflammatory effects of compound 13-7, highlighting HDAC6 as a potential therapeutic target for SAH-induced EBI.