Preclinical evaluation of cannabidiolic acid as a neuroprotective agent in TDP-43 transgenic mice, an experimental model of amyotrophic lateral sclerosis

Plant-derived cannabinoids, including Δ⁹-THC, cannabinol, and Sativex-like combinations, have shown neuroprotection in preclinical ALS models. However, minor phytocannabinoids like cannabidiolic acid (CBDA) remain unexplored. This study evaluated the neuroprotective effects of CBDA, cannabidivarin, CBD, Δ⁹-THC, and Δ⁹-tetrahydrocannabidivarin in Prp-hTDP-43(A315T) transgenic male mice from early symptomatic (day 65) to advanced stages (day 90). CBDA proved the most effective, improving motor coordination (rotarod test) and reducing neuronal cell death, gliosis, microglial reactivity, and pro-inflammatory mediators in the spinal cord. A dose-response study confirmed that 10 mg/kg CBDA improved motor performance and preserved motor neurons, while lower doses were less effective and higher doses caused toxicity. Flow cytometry revealed a shift from an M1 proinflammatory to an M2 anti-inflammatory phenotype in microglial cells after CBDA treatment, mirroring effects in BV2 cells exposed to LPS. Comparing CBDA with riluzole (standard ALS therapy), CBDA showed superior neuroprotection, except for rotarod performance, where no improvement was observed. A combination of CBD and riluzole failed to enhance efficacy and even weakened microglial response benefits. In conclusion, CBDA was the most effective of the five phytocannabinoids studied and outperformed riluzole in ALS models. These findings support further clinical evaluation of CBDA for ALS treatment.