Biology subjects

Meredith, J. R.

Publications and source records attributed to Meredith, J. R..

3 recordsLinked to original sources

bioRxiv2026

The anti-dyskinetic and the anti-parkinsonian effects of sub-anesthetic ketamine are also present in female preclinical models

Biological sex is an important determinant of neuropharmacological response, yet females remain underrepresented in preclinical studies of Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). We previously demonstrated that sub-anesthetic ketamine reduces established LID, attenuates dyskinesia development, and produces anti-parkinsonian effects in male unilateral 6-hydroxydopamine (6-OHDA) rat models. However, whether these therapeutic effects extend to females remained unknown. Here, we evaluated the anti-dyskinetic and anti-parkinsonian effects of sub-anesthetic ketamine in female Sprague-Dawley rats using the attenuation and established models of LID. In the attenuation paradigm, unilateral 6-OHDA-lesioned females received repeated L-DOPA administration with either ketamine (20 mg/kg, i.p.; 10-h dosing paradigm) or vehicle. Ketamine significantly attenuated the progressive development of dyskinesia, indicating that early intervention modified the trajectory of LID expression. In the established LID paradigm, ketamine produced robust significant acute reductions in abnormal involuntary movements (AIMs) after dyskinesia had fully developed, and these significant effects persisted for up to 49 days following treatment, demonstrating sustained suppression of dyskinesia severity. To determine whether ketamine altered therapeutic motor function, forelimb adjusting steps testing was performed in female unilateral 6-OHDA rats. Ketamine did not impair L-DOPA-mediated motor improvement suggesting compatibility with the gold standard medication. Ketamine was also by itself associated with significantly improved stepping performance during ketamine treatment conditions, indicating acute anti-parkinsonian motor benefit. Together, these findings demonstrate that the anti-dyskinetic and anti-parkinsonian effects of ketamine extend to female preclinical models and strengthen the translational rationale for repurposing sub-anesthetic ketamine as a potential therapeutic strategy for individuals with LID.

neuroscience↗

bioRxiv2026

Dyskinesia induced by a dopamine 2 receptor-like agonist, but not a dopamine 1 receptor-like agonist, is blocked by sub-anesthetic ketamine

L-DOPA remains the most effective symptomatic treatment for Parkinson's disease, but chronic administration is frequently complicated by L-DOPA-induced dyskinesia (LID). Our prior work has established that sub-anesthetic ketamine can reduced LID acutely and has a long-lasting neuroplastic effect. This study tested whether low-dose ketamine reduces dyskinesia induced specifically by dopamine D2R-like or D1R-like receptor activation. Male Sprague Dawley rats were primed with daily L-DOPA to establish dyskinesia and then challenged with quinpirole, a D2R-like receptor agonist, or SKF-81297, a D1R-like receptor agonist, to induce abnormal involuntary movements (AIMs). After stable AIM baselines were established, animals received agonist plus vehicle or agonist plus ketamine. Limb, axial, and orolingual AIMs were scored on the acute treatment day (D0) and after washout on D4 and D7. Quinpirole and SKF-81297 reliably produced stable total LAO AIM scores following L-DOPA priming. Ketamine significantly reduced only quinpirole-induced, but not SKF-81297-induced, total AIMs compared with vehicle on D0, demonstrating an acute anti-dyskinetic effect. This reduction persisted after washout, with ketamine-treated animals continuing to show significantly lower AIMs on D4 and D7. Time-course analyses further showed reduced AIMs expression across the post-quinpirole observation period on D0 and at multiple time points on D7. These findings demonstrate that ketamine suppresses quinpirole-induced dyskinesia in L-DOPA-primed male rats and suggest that D2R-like receptor-mediated or indirect pathway-related mechanisms, but not direct pathway-related mechanisms, may contribute to ketamine's anti-dyskinetic effects. Together, these results extend prior work on ketamine by linking its sustained anti-dyskinetic effects to dyskinesia driven by D2R-like receptor stimulation in vivo.

neuroscience↗

bioRxiv2025

The 5-HT1F Receptor Agonist Lasmiditan improves Cognition and Ameliorates Associated Cortico-Hippocampal Pathology in Aging Parkinsonian Mice

While the etiopathology of Parkinsons 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 (1mg/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, paired with reduced alpha-synuclein aggregation particularly in cortico-hippocampal regions. Furthermore, 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 potent strategy to address PD-related cognitive decline.

neuroscience↗