Selegiline increases on time without exacerbation of dyskinesia in 6-hydroxydopamine-lesioned rats displaying l-Dopa-induced wearing-off and abnormal involuntary movements

Abstract

3,4-Dihydroxy-l-phenylalanine (l-Dopa) remains the most effective drug for treating the motor symptoms of Parkinson's disease (PD). However, its long-term use is limited due to motor complications such as wearing-off and dyskinesia. A clinical study in PD patients with motor complications has demonstrated that selegiline, a monoamine oxidase type B inhibitor, is effective in reducing off time without worsening dyskinesia, although another study has shown worsening dyskinesia. Here, using unilateral 6-hydroxydopamine-lesioned rats showing degeneration of nigrostriatal dopaminergic neurons and l-Dopa-induced motor complications, we determined the efficacy of selegiline in controlling l-Dopa-induced motor fluctuations and exacerbated dyskinesia. Repeated administration of l-Dopa/benserazide (25/6.25 mg/kg, intraperitoneally, twice daily for 22 days) progressively shortened rotational response duration (on time) and augmented peak rotation in lesioned rats. Single subcutaneous injection of selegiline (10 mg/kg) extended l-Dopa-induced shortened on time without augmenting peak rotation. Furthermore, l-Dopa/benserazide (25/6.25 mg/kg, intraperitoneally, once daily for 7 days) progressively increased abnormal involuntary movements (l-Dopa-induced dyskinesia, LID) and peak rotation. Single subcutaneous injection of selegiline (10 mg/kg) did not exacerbate LID or alter mRNA expression of prodynorphin (PDy) and activity-regulated cytoskeleton-associated protein (Arc), both mRNAs associated with LID in the lesioned striatum. Despite undetectable plasma concentrations of selegiline and its metabolites at 24 h post-administration, these on time and LID effects did not decrease, suggesting involvement of irreversible mechanisms. Altogether, these results indicate that selegiline is effective in increasing on time without worsening dyskinesia.

The Rodent Models of Dyskinesia and Their Behavioral Assessment

“…The interpretation of rotation has always been the focus of debate. For a long time, the intensity of rotation was regarded to be a correlative index of the degree of neurotoxin-induced DA denervation for screening well-lesioned animals, as well as an indicator for evaluating the anti-akinetic efficiency of antiparkinsonian drugs (12, 58, 59). An inherent contradiction of this theory lies in the following reasoning: if the intensity of rotation is equivalent to the therapeutic effects, then the sensitization of rotational behavior should naturally be interpreted as an enhanced therapeutic action, which is apparently inconsistent with the clinical fact that the efficacy of L-DOPA always decreases gradually as the medication persists (12).…”

“…Moreover, L-DOPA-induced rotation is a purposeless movement that is poorly correlated with the improvement of motor function as determined by cylinder test or rotarod test (28, 60), as sensitive measures of motor impairments in hemiparkinsonian rodents. Presently, majority of studies have reached a consensus that the measure of rotation should not be included in the AIM score (29, 49, 61, 62), and the shortened duration of rotation response should be viewed as a behavioral index of “wearing-off” like phenomenon (59, 61), but the behavioral significance of rotation requires further clarification.…”