Objective: To advance understanding of striatal CaV1.3 (cacna1d) channel silencing as a therapeutic approach to reduce levodopa-induced dyskinesias (LID), a side effect of long-term escalating levodopa (LD) therapy in Parkinson’s disease (PD), acknowledging the prevalence of PD in late-middle-aged males and females.

Background: Previously, we demonstrated that silencing striatal CaV1.3 with rAAV-CaV1.3-shRNA in young (3mo) male parkinsonian rats can 1) provide near complete protection against LID induction, 2) significantly but partially reduce established severe LID, and 3) impact LID without altering levodopa (LD) motor benefit. To extend our understanding of the utility of CaV1.3 silencing in reversing LID, often considered to be refractory, we used middle-aged male and female rats to test the hypothesis that silencing aberrant CaV1.3 channel activity in the parkinsonian striatum drives reversal of LID, albeit with LD dose- and LID severity- dependent efficacy.

Method: Male and female F344 rats (15mo) were unilaterally lesioned with 6-OHDA. Rats were primed with low dose LD (3mg/kg) for 3wks resulting in low-level LID at which time they received intrastriatal rAAV-CaV1.3 or rAAV- Scr control vector. The LD dose was kept at 3mg/kg for 1mo post-vector, escalated to 6mg/kg, and then finally to 12mg/kg. Transduction of striatal volume was quantified with stereological techniques, and cacna1d transcript was quantified with confocal image analysis.

Results: LID remained low, but were not ameliorated, for the first month post-vector in both groups at the 3mg/kg dose. Escalation of LID severity at higher LD doses was prevented in aged male, but not female rats receiving rAAV-CaV1.3 compared to rAAV-Scr. However, a subpopulation (~40%) of the female rats did show therapeutic efficacy. We found no significant sex differences in the volume of striatal transduction or magnitude of striatal cacna1d knockdown.

Conclusion: The gene therapy approach of silencing striatal Cav1.3 channel expression is an effective LID modulation strategy in middle-aged male rats. While female middle-aged rats may be more resistant CaV1.3 knockdown-mediated inhibition of LID escalation, some individual rats do show profound LID inhibition. Further, investigation into the source of this observed sex difference in functional efficacy is ongoing.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/amelioration-of-levodopa-induced-dyskinesias-using-genetic-silencing-of-striatal-cav1-3-in-parkinsonian-rats-impact-of-sex-and-advancing-age/