Vitamin D Protects against Traumatic Brain Injury via Modulating TLR4/MyD88/NF-κB Pathway-Mediated Microglial Polarization and Neuroinflammation

Abstract

Vitamin D (VD) deficiency is associated with neuroinflammation and neurocognitive deficits in patients with traumatic brain injury (TBI). The present study was aimed at investigating the therapeutic effects of VD and the molecular mechanisms after TBI. After the intraperitoneal injection of VD (1 μg/kg), sensorimotor and cognitive function was assessed via a series of behavioral tests in TBI rats. Traumatic outcomes were investigated by brain edema, blood-brain barrier (BBB) disruption, and morphologic staining. In vitro, cellular viability and cytotoxicity in primary hippocampal neurons were detected via the MTT method and LDH release. Hippocampal oxidative stress-related enzymes and proinflammatory mediators and the serum concentration of VD were analyzed by ELISA. The expression of VDR, TLR4, MyD88, and NF-κB p65 was measured by Western blot. Furthermore, the levels of M1/M2 microglial markers were quantified using real-time PCR and Western blot. VD treatment significantly increased the serum level of VD and the hippocampal expression of VDR. VD not only effectively alleviated neurocognitive deficits, brain edema, and BBB disruption but also promoted hippocampal neuronal survival in vivo and in vitro. Moreover, VD therapy prevented excessive neuroinflammation and oxidative stress caused by TBI. Mechanically, the hippocampal expression of TLR4, MyD88, and nuclear NF-κB p65 was elevated in the TBI group but robustly restrained by VD treatment. Taken together, VD provides an important neuroprotection through modulating hippocampal microglial M2 polarization and neuroinflammation via the TLR4/MyD88/NF-κB pathway.