Neuroprotective Effect of Cannabidiol Against Rotenone in Hippocampal Neuron Culture.

(-)-Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has been suggested to provide protective effects in neuronal systems. This work investigates its neuroprotective effect against rotenone, a mitochondrial complex I inhibitor that causes neuronal toxicity, using primary hippocampal neurons. Rotenone treatment reduces neuronal viability with marked neurite degeneration in a concentration-dependent manner (LC50 = 189.1 nM). Administration of 2.5 µM CBD significantly increases viability to 69.9%, compared with 45.6% observed under 200 nM rotenone treatment. Neuronal morphology is preserved under both CBD pre-treatment and co-treatment conditions, with confocal analyses further confirming the maintenance of axonal branching and overall structural integrity. Antagonist experiments reveal that TRPV1 inhibition markedly reduces the protective effect of CBD, whereas blockade of 5-HT1AR has only a minor influence. These findings demonstrate that CBD protects primary hippocampal neurons from rotenone-induced toxicity, with TRPV1 playing a central role in the mechanism.