Gene Expression, Oxidative Stress, and Neurotransmitters in Rotenone-induced Parkinson’s Disease in Rats: Role of Naringin from Citrus aurantium via Blocking Adenosine A2A Receptor

Background: Lack of control in voluntary movements, resting tremor, postural instability, and stiffness are the hallmarks of Parkinson's disease (PD). Objective: The current work's objective is to assess naringin isolated from Citrus aurantium L. peels as an anti-parkinsonism agent in rats. Methods: The HPLC and LC-ESI-MS analysis of Citrus aurantium L. peels methanol extract was done. The behavioral, biochemical, genetic, and histopathological analysis were evaluated in parkinsonism rats. Results: Fourteen phenolics and nine flavonoids were found in the extract, according to the HPLC analysis, while LC-ESI-MS analysis revealed the presence of twenty-six flavonoids. The dominant flavonoid subclasses were 4 aglycones, 11 monoglycosides, 5 diglycosides, and 6 polymethoxy flavonoids, beside 4 coumarines, 4 alkaloids and a limonin triterpene. Adenosine A2A receptor (A2AR) gene expression, malondialdehyde (MDA), interleukin-6 (IL-6), caspase-3 (Cas-3) and DNA fragmentation levels significantly increased in rotenone-induced rats. Dopamine (DA), norepinephrine (NE), serotonin (5-HT), reduced glutathione (GSH), succinate, and lactate dehydrogenase (SDH ) levels all significantly decreased. Treatment with naringin and A2AR antagonists enhanced the animals’ behavior and improved all the selected parameters. The brain hippocampal features confirmed our results. Conclusion: Naringin could be considered a nutraceutical agent by attenuating the neurodegeneration associated with PD via blocking adenosine A2AR.