Exploring the Therapeutic Potentials of Highly Selective Oxygenated Chalcone Based MAO-B Inhibitors in a Haloperidol-Induced Murine Model of Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative disorder of dopaminergic, noradrenergic, and serotonergic systems, in which dopamine, noradrenaline, and serotonin levels are depleted and lead to the development of motor and non-motor symptoms such as tremor, bradykinesia, weight changes, fatigue, depression, and visual hallucinations. Therapeutic strategies place much focus on dopamine replacement and the inhibition of dopamine metabolism. The present study was based on the known abilities of chalcones to act as molecular scaffolds that selectively inhibit MAO-B with the added advantage of binding reversibly. Recently, we synthesized a series of 26 chalcone compounds, amongst which (2E)-1-(2H-1,3-benzodioxol-5-yl)-3-(4-fluorophenyl)prop-2-en-1-one (O10) and (2E)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(4-fluorophenyl)prop-2-en-1-one (O23) most inhibited MAO-B. Hence, the present study was performed to explore the molecular mechanisms responsible for the neuroprotective effect ofO10andO23at varying doses such as 10, 20, and 30 mg/kg each in a haloperidol-induced murine model of PD. Both compounds were effective (thoughO23was the more effective) at ameliorating extrapyramidal and non-motor symptoms in the model and improved locomotory and exploratory behaviors, reduced oxidative stress markers, and enhanced antioxidant marker and neurotransmitter levels. Furthermore, histopathological studies showedO10andO23both reduced neurofibrillary tangles and plaques to almost normal control levels.