The impact of folic acid deficiency on ischemic stroke: Role of inflammation and long noncoding RNA H19

It has been validated that folic acid deficiency (FD) is associated with an increased risk of stroke and a worse prognosis. However, the specific mechanisms by which FD exerts its detrimental effects on ischemic stroke (IS) have not been fully understood. The results of this case-control study indicated that patients with IS had a decreased serum folate level, along with up-regulated long non-coding RNA H19 (lncRNA H19) and enhanced inflammatory responses. Meanwhile, it was corroborated that the serum folate level was negatively correlated with H19 expression and the systemic immune-inflammation index (SII). Similarly, FD was demonstrated to exacerbate neurological injury in the middle cerebral artery occlusion/reperfusion (MCAO/R) rats by up-regulating the expression of inflammatory cytokines and H19 in both peripheral blood and brain tissue. Notably, the alterations in the expression of these factors in peripheral blood were consistent with those observed in brain tissue. Additionally, in a co-culture of N2a neurons and BV2 microglia, FD promoted the transition of BV2 cells towards a pro-inflammatory state by up-regulating the expression of H19, which aggravated neuronal injury. Moreover, blocking H19 in BV2 cells mitigated inflammation and partially reversed the injury in N2a cells exacerbated by FD after the treatment with oxygen-glucose deprivation and reperfusion (OGD/R). These findings provide a more in-depth insight into the regulatory role of H19-mediated systemic inflammatory responses in the context of FD, suggesting the potential clinical utility of folic acid in managing ischemic brain injury.