Vitamin K3 alleviates brain injury and behavioral deficits by inhibiting neuroinflammation in intracerebral hemorrhage in vitro and in vivo.

Abstract

Microglia-mediated neuroinflammation is a central contributor to the pathogenesis and progression of neurological disorders, including intracerebral hemorrhage (ICH). Vitamin K comprises a family of structurally analogous vitamins crucial for blood clotting and bone integrity. Although vitamin K has demonstrated anti-inflammatory properties in vitro, its potential for mitigating neuroinflammation and providing neuroprotection, particularly within the context of intracerebral hemorrhage, remains to be elucidated. Here, we demonstrate that the synthetic vitamin K derivative vitamin K3 (VK3) exerts potent anti-inflammatory and neuroprotective effects in vitro and in vivo. In cultured microglia, VK3 and VK4 markedly suppressed lipopolysaccharide (LPS)-induced expression of pro-inflammatory mediators, whereas vitamins K1 and K2 showed minimal efficacy or greater cytotoxicity. Mechanistically, VK3 inhibited NF-κB signaling by reducing phosphorylation and nuclear translocation of the p65 subunit, thereby limiting downstream transcriptional activation of inflammatory genes. VK3 also attenuated thrombin-induced microglial activation, a key pathological trigger in ICH. The neuroprotective efficacy of VK3 was further validated in mouse models of acute and long-term ICH. Post-injury administration of VK3 significantly reduced microglial activation and neuroinflammatory responses, preserved neuronal integrity, and improved both motor and neurological performance. Notably, VK3 treatment conferred sustained functional benefits and ameliorated long-term neurological deficits following ICH. Collectively, these findings identify VK3 as a potent modulator of microglia-driven neuroinflammation and highlight short-chain vitamin K derivatives as promising therapeutic candidates for ICH and other neuroinflammatory disorders.