Lasmiditan ameliorates cortico-hippocampal pathology and improves cognition in aging parkinsonian mice

While the etiopathology of Parkinson's disease (PD) is complex, mitochondrial dysfunction is established to have a central role. Thus, mitochondria have emerged as targets of therapeutic interventions aiming to slow or modify PD progression. We have previously identified serotonergic 5-HT1F receptors as novel mediators of mitochondrial biogenesis (MB) - the process of producing new mitochondria. Given this, here, we assessed the therapeutic potential of the FDA-approved 5-HT1F receptor agonist, lasmiditan, in a chronic progressive PD model (Thy1-aSyn ‘line 61’ mice). It was observed that systemic lasmiditan exhibited robust brain penetration and reversed cognitive deficits in young (4–5.5 months old) Thy1-aSyn mice (1 mg/kg, every other day). Anxiety-like behavior was also improved while motor function remained unaffected. These behavioral changes were associated with enhanced MB and mitochondrial function and reduced alpha-synuclein aggregation particularly in cortico-hippocampal regions. In older (10–11.5 months old) mice, although the effects were milder, daily lasmiditan administration increased MB and bettered cognitive abilities. In essence, these findings indicate that repurposing lasmiditan could be a potential strategy to address PD-related cognitive decline.