“Background: Cognitive impairment is a major complication of traumatic brain injury (TBI), yet effective therapies remain lacking. As a natural compound extracted from Cannabis sativa, cannabidiol (CBD) possesses antioxidant properties and has shown neuroprotective potential in several neurological disorders. However, its effects in cognitive impairment after TBI remain unclear.
Purpose: This study aimed to investigate the therapeutic effects of CBD on cognitive impairment after TBI and elucidate its underlying molecular mechanisms.
Study design: In vitro H2O2 model and in vivo TBI model were used to evaluate the neuroprotective effects of CBD.
Methods: Neuronal oxidative stress models induced by H2O2 and controlled cortical impact model were used to detect the neuroprotective effects of CBD. Western blotting, histological staining, and biochemical assays were employed to investigate the effects of CBD on oxidative stress and apoptosis in neurons. RNA-Seq analysis, co-immunoprecipitation, molecular dynamics simulations, CETSA, SPR and immunofluorescence were performed to elucidate the molecular mechanisms.
Results: CBD can inhibit neuronal oxidative stress and apoptosis both in vivo and in vitro. Mechanistically, we identify a novel SET/PP2A/Akt signaling axis, in which CBD directly bound to SET, induced conformational changes in its nuclear localization signal and promoted its retention in the cytoplasm. Elevated cytoplasmic SET suppresses PP2A activity, activates Akt signaling pathway, and inhibits oxidative stress and pro-apoptotic cascades, promoting neuronal survival.
Conclusion: CBD exerts its neuroprotective effects by inhibiting neuronal oxidative stress and apoptosis through SET/PP2A/Akt signaling axis. These findings provide a novel potential drug target for the treatment of cognitive impairment after TBI.”
https://pubmed.ncbi.nlm.nih.gov/41512358
“Cannabidiol alleviates cognitive impairment after traumatic brain injury in mice.”
“This work not only enhances understanding of post-TBI pathophysiology but also provides mechanistic insights supporting the potential clinical application of CBD in post-TBI cognitive impairment.”
https://www.sciencedirect.com/science/article/abs/pii/S0944711326000061?via%3Dihub