Rehmannioside A alleviates neuroinflammation and cognitive impairments after traumatic brain injury by suppressing microglial activation via the MAPK/NF-κB pathway.

BACKGROUND: Traumatic brain injury (TBI) triggers a robust neuroinflammatory response characterized by microglial activation, which propagates secondary neuronal damage and contributes to long-term neurological deficits. Rehmannioside A (REA), a principal bioactive compound from Rehmannia glutinosa, has emerged as a candidate for neuroprotection due to its anti-inflammatory properties. However, its therapeutic potential and precise mechanisms of action in TBI remain to be fully elucidated.

METHODS: We employed a controlled cortical impact (CCI) model in mice to mimic clinical TBI. Animals were randomized into Sham/Veh, Sham/REA, TBI/Veh, and TBI/REA (40 mg/kg) groups. Neurological and cognitive functions were assessed using the modified Neurological Severity Score (mNSS) and Morris Water Maze (MWM). Cerebral edema was measured, and histopathological changes were evaluated by H&E and Nissl staining. LPS-stimulated BV2 microglial cells were used for in vitro experiments. Pro-inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA) and qRT-PCR, and activation of the MAPK/NF-κB pathway was analyzed by western blotting.

RESULTS: REA treatment significantly improved neurological scores, spatial learning and memory, and reduced cerebral edema and neuronal loss in TBI mice. REA suppressed microglial activation in vivo and dose-dependently inhibited LPS-induced pro-inflammatory mediators in vitro. These beneficial effects are associated with reduced phosphorylation of p65 (NF-κB) and p38 (MAPK) in activated microglia in vitro.

CONCLUSION: REA ameliorates functional deficits and neuropathology following TBI. The neuroprotective effect may involve suppression of microglia-mediated neuroinflammation via inhibition of the MAPK/NF-κB signaling pathway.