Alpha Lipoic Acid Mitigates TBI-Induced Neuroinflammation by Regulating S100B/STIM Signaling via NF-ƙB Pathway

Alpha-lipoic acid (ALA) is a natural compound present in plants, animals, and humans. It provides neuroprotection through its antioxidant action, reducing oxidative stress and inflammation via pathways such as the Nrf-2 signalling pathway. It has shown protective effect against neuronal damage in Alzheimer's disease and Parkinson's disease. The traumatic brain injury (TBI) is a major cause of cognitive and motor impairments. TBI primarily initiates a series of secondary injury pathways, with glutamate excitotoxicity being a critical factor in neuronal degeneration. In this study, we investigated the protective effects of ALA on TBI induced by controlled cortical impact (CCI) in the cerebral cortex (CC) and hippocampus (HC) regions of the Wistar rats. TBI parameters were analysed using behavioural assays, including the Barnes maze test (BMT), beam balance test, grip strength, and Y-maze test (YMT). In addition, we measured brain water content, and analyzed histological alterations by light microscopy, microglial changes by the immunofluorescence technique, and ultrastructural changes by the transmission electron microscopy (TEM). Expression of markers of glutaminergic and calcium (Ca²⁺) pathways was analysed by qRT-PCR and western blotting. ALA was administered following TBI induction in rats. It was shown that ALA downregulated S100B and the N-methyl-D-aspartate (NMDA) receptor subunit 2B (GRIN2B) mRNA expression. However, TBI-dependent alterations in excitatory amino acid transporter (EAAT) expression were downregulated in the CC region of adult rats with TBI. Protein expression of S100B, stromal interaction molecule (STIM), ubiquitin C-terminal hydrolase L1 (UCHL1), nuclear factor kappa (NF-ƙB), and glial fibrillary acidic protein (GFAP) was increased in the TBI group, as analysed by immunoblotting. Furthermore, expression of Iba1⁺, a marker of microglial activation, was increased in TBI and mitigated by ALA. Overall, this study helps us understand the role of ALA as a mitigating compound in the TBI-induced rat model.