Fisetin Ameliorates Levodopa Induced Dyskinesia in Experimental Model Parkinson's Disease: Role of Mitochondrial Activities and Monoamines Turnover (vol 17, 2022)

Background: Levodopa (or l-DOPA) is the current standard of care for the management of Parkinson's disease (PD), but its chronic administration has been associated with the development of LID (l-DOPA-induced dyskinesia). Fisetin is a dietary flavonoid known for its neuroprotective efficacy. Aim: To determine the neuroprotective potential of fisetin in 6-hydroxydopamine (6-OHDA)-lesioned LID animals. Methods: 6-OHDA (12 mu g and L-ascorbic acid [10 mu L]) was injected in a substantial nigra of Sprague-Dawley rat to develop PD followed by l-DOPA (20 mg/kg and benserazide HCl [5 mg/kg], 42 days) to induce LID. Rats were concomitantly administered with vehicle or amantadine (40 mg/kg), or fisetin (5, 10, and 25 mg/kg, p.o.) for 42 days with l-DOPA. Results: Chronic l-DOPA administration resulted in progressive abnormal involuntary movements (AIMs viz. axial, forelimb, and orolingual), akinesia (forelimb adjusting steps, FAS), muscular rigidity (catalepsy bar test), muscular coordination, and neurological impairments. Fisetin at doses of 10 and 25 mg/kg effectively reduced (P < .05) these LID-induced AIMs and behavioral changes. Furthermore, fisetin treatment markedly (P < .05) attenuated LID-induced diminished striatal mitochondrial complex activities, striatal monoamines (serotonin [5-HT] and dopamine [DA]), elevated monoamines turnover (DA: DOPAC and 5-HT: 5-HIAA). In addition, fisetin treatment effectively (P < .05) reversed the upregulated expressions of striatal cFOS, FosB, Homer, Nurr-77, Parkin, and Pdyn. Conclusion: Our study demonstrated that fisetin offered neuroprotection via amelioration of striatum mitochondrial dysfunction and monoamine (5-HT and DA) turnover to halt further development of abnormal involuntary movement and dyskinesia.