Objective: This study aims to validate the protective effect of citrus extract A (CEA) against loss of dopamine neurons in PD by dual targeting of ROS and mitochondrial respiration with citrus extract A (CEA) in vitro and in vivo. And, we address the beneficial effect of CEA administration to relieve motor symptoms in PD model.

Background: Dopamine neuronal loss in Parkinson’s disease (PD) is caused by mitochondrial dysfunction and increase of reactive oxygen species (ROS). Progressive loss of dopamine neurons fails to maintain physiologic level of dopamine, which aggravates motor dysfunction. However, current therapeutics of PD targets relief of symptoms such as rigidity, tremor and bradykinesia by supplementing levodopa or dopamine agonist, instead of directly modulating mitochondrial function. Although, genetic or pharmacologic inhibition of mitochondrial respiration improve cellular function and decrease ROS production in peripheral tissues, in dopamine neuron is unclear. Therefore, we use CEA, which specifically targets mitochondrial respiration and inhibits ROS, exploring the mechanism and potency of CEA for protection of dopamine neuronal loss.

Methods: 1) cell viability of rotenone- treated cells was measured by SRB assay with or without CEA

2) Improvement of movement disorder was validated by open-field test and grid test after injection of CEA to MPTP induced PD

Results: Pretreatment of CEA to dopamine cell line, SN4741 significantly increased cell viability and reduced mitochondrial ROS with induction of antioxidant enzymes after rotenone administration compared to vehicle treated cells. Oxygen consumption rate and cellular ATP were decreased by CEA treatment. Blockade of mitochondrial respiration by CEA was confirmed by western blotting. As we expected, CEA injection to MPTP-induced PD mice showed mild improvement of movement. CEA injected mice showed increased number of dopamine neuron in SN region of MPTP mice. 

Conclusions: These results demonstrated that CEA dual targets mitochondrial respiration and ROS to protect dopamine neuronal loss. The induction of antioxidant enzymes by CEA is indispensable for the inhibition of oxidative damage of dopamine neurons. We suggest that CEA contribute to improvement of movement and neuroprotection in PD through selective inhibition of mitochondrial respiration and ROS.

References: Panov, A., et al. Rotenone model of Parkinson disease: multiple brain mitochondria dysfunctions after short term systemic rotenone intoxication. The Journal of biological chemistry 280, 42026-42035 (2005).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/citrus-extract-a-protects-dopaminergic-neuron-by-modulating-mitochondrial-respiration-and-reactive-oxygen-species/