Transcriptomic Effects of Cannabis-Derived Therapies in a Drosophila model of ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron demise, leading to paralysis and death within approximately 3-5 years of symptom onset.Current FDA-approved therapies offer limited disease modification, highlighting the need for treatments that address neuroinflammation and excitotoxicity.Cannabis-derived compounds, particularly flavonoids like Cannflavin A (CFA), have emerged as potential neurotherapeutics due to their anti-inflammatory properties but remain unresearched.In this study, an in-vivo C9orf72 Drosophila melanogaster model of ALS, expressing toxic poly-GR dipeptide repeats, was used to evaluate the transcriptomic impact of CFA and CNR-401 (a proprietary mixture of flavonoids and terpenes).RNA-sequencing was performed on fly brains followed by differential depression analysis and functional enrichment to identify modulated molecular pathways.Both compounds were found to elicit significant transcriptional remodeling relevant to neurodegenerative pathophysiology.CNR-401 uniquely upregulated ABC transporter genes (NES = 3.17) and fatty acid metabolism (median NES = 2.7515), suggesting a shift toward lipid homeostasis, metabolic resistance, and management of neuroinflammation.CFA treatment primarily enriched gene sets associated with synaptic activity, both excitatory (Glutamatergic Synaptic Transmission NES = 3.165) and inhibitory (GABAergic Synapse NES = 2.175), suggesting a homeostatic stabilization of neurons against excitotoxicity.Both treatments suppressed glucuronidation and xenobiotic metabolism, which may enhance drug bioavailability and support endogenous neuroprotective steroids and coordinated modulation of the circadian clock.In summary, CNR-401 and CFA were shown to be strong therapeutic candidates for ALS patients.Future studies should utilize better controls and mammalian models of ALS to facilitate more accurate ortholog mapping and support gene-level claims.Deol 2