Monoterpenoid Epoxidiol Ameliorates the Pathological Phenotypes of the Rotenone-Induced Parkinson’s Disease Model by Alleviating Mitochondrial Dysfunction

Abstract

Parkinson’s disease is the second most common neurodegenerative disease. Unfortunately, there is still no definitive disease-modifying therapy. In our work, the antiparkinsonian potential of trans-epoxide (1S,2S,3R,4S,6R)-1-methyl-4-(prop-1-en-2-yl)-7-oxabicyclo [4.1.0]heptan-2,3-diol (E-diol) was analyzed in a rotenone-induced neurotoxicity model using in vitro, in vivo and ex vivo approaches. It was conducted as part of the study of the mitoprotective properties of the compound. E-diol has been shown to have cytoprotective properties in the SH-SY5Y cell line exposed to rotenone, which is associated with its ability to prevent the loss of mitochondrial membrane potential and restore the oxygen consumption rate after inhibition of the complex I function. Under the conditions of rotenone modeling of Parkinson’s disease in vivo, treatment with E-diol led to the leveling of both motor and non-motor disorders. The post-mortem analysis of brain samples from these animals demonstrated the ability of E-diol to prevent the loss of dopaminergic neurons. Moreover, that substance restored functioning of the mitochondrial respiratory chain complexes and significantly reduced the production of reactive oxygen species, preventing oxidative damage. Thus, E-diol can be considered as a new potential agent for the treatment of Parkinson’s disease.

Chemical composition and studying the possible neuroprotective effect of iridoids-rich fraction from Pentas lanceolata leaves using rotenone model of Parkinson’s disease in mice

“…Stressful environment results in free radicals' production which interacts with oxygen molecules on membrane lipids to produce peroxy radicals, which are accountable for lipid peroxidation represented by MDA (Rizk et al, 2018;Aziz et al, 2022). Our research reveals that rotenone-treated mice showed elevated MDA levels, as reported by others (Mohammad et al, 2023;Aleksandrova et al, 2023) whereas such enhancement is restored to normal using L-dopa and the iridoids-rich fraction isolated from Pentas lanceolata (PIRF) leaves as results in decrease in MDA level.…”

“…The enzyme acetylcholine esterase (AChE) is the key enzyme in the hydrolysis of the neurotransmitter acetylcholine and is also the target of most of the clinically used agents for the treatment of PD (Wang et al, 2020). AChE level in brain homogenates of different treated groups was represented in Figure (9). Rotenone treatment had decreased the AchE level by 40.5%.…”

Neuroprotective Effects and Cognitive Enhancement of Allomargaritarine in 5xFAD Alzheimer's Disease Mice Model

“…The activity of electron transport chain complexes was assessed in preparation of the mitochondrial p2 fraction of the brain (10 µg/well) using the Agilent Seahorse XF96e Analyzer (Seahorse Bioscience, USA) to measure the rate of oxygen uptake triggered by modulators as described early [32]. For this purpose, the activators of the electron transport chain complex Iglutamate/malate, the inhibitor of the complex I -rotenone (2 µM), the substrate of the difficult IIpotassium succinate (2 µM), the inhibitor of the complex III -antimycin A, and the substrates of the complex IV -0.5 µM ascorbate/tetramethyl-p-phenylenediamine (TMPD) were used.…”

3-N-butylphthalide attenuates neuroinflammation in rotenone-induced Parkinson’s disease models via the cGAS-STING pathway

“… 13 , 14 In neurons, rotenone inhibits respiratory chain complex I in the mitochondria and subsequently induces the production of reactive oxygen species (ROS) and mitochondrial dysfunction, leading to progressive damage of dopaminergic neurons. 14 , 15 Pathological changes induced by rotenone are not limited to dopaminergic neuron deterioration, 16 – 18 but also include overactivation of microglia adjacent to the neurons. Sherer et al revealed that rotenone can activate microglia in rodent PD models before the anatomical pathology results in dopaminergic neurons loss.…”