Optimizing L-DOPA treatment through treadmill controlled exercise in a hemi-parkinsonian rat model

Parkinson's Disease (PD) is a movement disorder characterized by the loss of nigrostriatal dopamine (DA) neurons. Early-stage PD motor symptoms are typically controlled with the DA replacement therapy, levodopa (L-DOPA). However, chronic use of this treatment causes abnormal involuntary movements (AIMs) called L-DOPA-induced dyskinesia (LID). Accumulating research suggests that exercise can modify the course of PD by modulating DA signaling, thereby improving movement, and thus may also slow LID progression. This study evaluated these phenomena in hemiparkinsonian rats that display severe unilateral DA loss. Sprague-Dawley rats received unilateral 6-hydroxydopamine (6-OHDA) lesions of the left medial forebrain bundle and were then counterbalanced into equally lesioned exercise or sedentary groups. Thereafter, rats underwent 3 weeks of treadmill exercise or exposure, respectively. One-hour post-treadmill, all animals received a 4 mg/kg subcutaneous (s.c.) injection of L-DOPA. All rats were rated weekly for LID using the AIMs test. Rotarod performance was conducted 24 h before or following AIMs. Following the 4-week exercise regimen, forepaw adjusting steps (FAS) and rotarod were conducted 60 min after L-DOPA to assess group differences in L-DOPA efficacy. Results revealed lesion-induced decrements in motor performance were significantly better within exercised subjects after L-DOPA treatment. Moreover, exercise reduced the severity of LID. Post-mortem analyses showed severe DA loss in the nigrostriatal pathway of both groups while 5-HIAA, 5-HT and DA turnover were significantly higher in the lesioned striatum (STR) of exercised animals. Thus, treadmill exercise optimized L-DOPA while reducing LID. Although exercise may not restore DA in cases of severe loss, enhanced functional compensation may support its benefits when paired with DA replacement therapy.