Cannabidiol preserves astrocyte viability and attenuates injury-induced glial stress responses across zebra finch song control nuclei.

Chronic neuroinflammation following traumatic brain injury (TBI) increases the risk of affective disorders and early-onset dementias. Existing anti-inflammatory therapies are limited by systemic side effects with chronic use and by poor brain penetration of newer biologics. Cannabidiol (CBD), a non-euphorigenic phytocannabinoid with a favorable safety profile and multi-target neuroprotective actions, is a promising alternative. Using a songbird microlesion model of learned vocal recovery after targeted damage to the premotor nucleus HVC, we previously showed that systemic CBD (10 mg/kg/day) reduces vocal disruption, inflammatory cytokines, oxidative stress, and synaptic loss. Here we tested the hypothesis that these benefits involve astrocytes. CBD (10 mg/kg/day IM for 7 days) preserved astrocyte viability, attenuated injury-induced lysosomal stress, suppressed reactivity markers (C3, S100A10, aromatase), and upregulated key metabolic and antioxidant transcripts (glutamine synthetase and GCLM) across the interconnected song-control nuclei HVC, RA, and Area X. These changes were accompanied by reduced neuronal apoptosis in lesioned HVC. The results identify astrocyte-associated responses as a candidate cellular substrate of CBD's circuit-wide protective effects and support its translational potential to mitigate secondary injury and communication deficits after TBI.