Cannabinoids originating from plants, such as Δ9-tetrahydrocannabinol (Δ9-THC), cannabinol, and formulations resembling Sativex, have demonstrated neuroprotective properties in various preclinical models of amyotrophic lateral sclerosis (ALS).

Nevertheless, the therapeutic potential of lesser-known phytocannabinoids, including cannabidiolic acid (CBDA), has not been extensively investigated. The present investigation examined the neuroprotective capabilities of CBDA, alongside cannabidivarin, cannabidiol (CBD), Δ9-THC, and Δ9-tetrahydrocannabidivarin, in male mice carrying the Prp-hTDP-43(A315T) transgene, spanning from the onset of symptoms at postnatal day 65 through to late-stage progression at day 90. Among these compounds, CBDA exhibited the greatest efficacy, as evidenced by enhanced motor coordination in the rotarod assay and diminished neuronal loss, astroglial proliferation, microglial activation, and levels of proinflammatory cytokines within the spinal cord tissue.

Subsequent dose-escalation experiments substantiated that administration of CBDA at 10 mg/kg optimized motor function and safeguarded motor neuron integrity, whereas suboptimal doses yielded diminished benefits and elevated doses induced adverse toxic effects. Analyses via flow cytometry indicated a transition in microglial polarization from a proinflammatory M1 state to an anti-inflammatory M2 profile following CBDA exposure, a phenomenon recapitulated in lipopolysaccharide-stimulated BV2 microglial cells. When juxtaposed with riluzole, the established pharmacological intervention for ALS, CBDA conferred enhanced neuroprotective outcomes across multiple parameters, albeit without discernible amelioration in rotarod performance metrics. Notably, co-administration of CBD and riluzole did not augment therapeutic efficacy and, in fact, attenuated the advantageous modulation of microglial responses.

In summary, CBDA emerged as the most potent among the evaluated phytocannabinoids and surpassed riluzole in mitigating ALS-associated pathology in this model. These observations advocate for the advancement of CBDA into clinical trials as a prospective therapeutic modality for ALS.

Keywords: Amyotrophic lateral sclerosis; Cannabidiolic acid; Neurodegenerative processes; Plant-derived cannabinoids; Riluzole; Transgenic TDP-43 mice.

Declaration of Competing Interests

The authors LGT, CRC, AF, JFR, and EdL affirm no competing interests, while WH is affiliated with Jazz Pharmaceuticals Research Ltd, receiving compensation and equity holdings therein.

https://pubmed.ncbi.nlm.nih.gov/40580876