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Myrcene Salvages Rotenone-Induced Loss of Dopaminergic Neurons by Inhibiting Oxidative Stress, Inflammation, Apoptosis, and Autophagy
Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in motor deficits. The exact etiology of PD is currently unknown; however, the pathological hallmarks of PD include excessive production of reactive oxygen species, enhanced...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9863310/ https://www.ncbi.nlm.nih.gov/pubmed/36677744 http://dx.doi.org/10.3390/molecules28020685 |
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author | Azimullah, Sheikh Jayaraj, Richard L. Meeran, Mohamed Fizur. Nagoor Jalal, Fakhreya Y. Adem, Abdu Ojha, Shreesh Beiram, Rami |
author_facet | Azimullah, Sheikh Jayaraj, Richard L. Meeran, Mohamed Fizur. Nagoor Jalal, Fakhreya Y. Adem, Abdu Ojha, Shreesh Beiram, Rami |
author_sort | Azimullah, Sheikh |
collection | PubMed |
description | Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in motor deficits. The exact etiology of PD is currently unknown; however, the pathological hallmarks of PD include excessive production of reactive oxygen species, enhanced neuroinflammation, and overproduction of α-synuclein. Under normal physiological conditions, aggregated α-synuclein is degraded via the autophagy lysosomal pathway. However, impairment of the autophagy lysosomal pathway results in α-synuclein accumulation, thereby facilitating the pathogenesis of PD. Current medications only manage the symptoms, but are unable to delay, prevent, or cure the disease. Collectively, oxidative stress, inflammation, apoptosis, and autophagy play crucial roles in PD; therefore, there is an enormous interest in exploring novel bioactive agents of natural origin for their protective roles in PD. The present study evaluated the role of myrcene, a monoterpene, in preventing the loss of dopaminergic neurons in a rotenone (ROT)-induced rodent model of PD, and elucidated the underlying mechanisms. Myrcene was administered at a dose of 50 mg/kg, 30 min prior to the intraperitoneal injections of ROT (2.5 mg/kg). Administration of ROT caused a considerable loss of dopaminergic neurons, subsequent to a significant reduction in the antioxidant defense systems, increased lipid peroxidation, and activation of microglia and astrocytes, along with the production of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and matrix metalloproteinase-9. Rotenone also resulted in impairment of the autophagy lysosomal pathway, as evidenced by increased expression of LC3, p62, and beclin-1 with decreased expression in the phosphorylation of mTOR protein. Collectively, these factors result in the loss of dopaminergic neurons. However, myrcene treatment has been observed to restore antioxidant defenses and attenuate the increase in concentrations of lipid peroxidation products, pro-inflammatory cytokines, diminished microglia, and astrocyte activation. Myrcene treatment also enhanced the phosphorylation of mTOR, reinstated neuronal homeostasis, restored autophagy-lysosomal degradation, and prevented the increased expression of α-synuclein following the rescue of dopaminergic neurons. Taken together, our study clearly revealed the mitigating effect of myrcene on dopaminergic neuronal loss, attributed to its potent antioxidant, anti-inflammatory, and anti-apoptotic properties, and favorable modulation of autophagic flux. This study suggests that myrcene may be a potential candidate for therapeutic benefits in PD. |
format | Online Article Text |
id | pubmed-9863310 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-98633102023-01-22 Myrcene Salvages Rotenone-Induced Loss of Dopaminergic Neurons by Inhibiting Oxidative Stress, Inflammation, Apoptosis, and Autophagy Azimullah, Sheikh Jayaraj, Richard L. Meeran, Mohamed Fizur. Nagoor Jalal, Fakhreya Y. Adem, Abdu Ojha, Shreesh Beiram, Rami Molecules Article Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in motor deficits. The exact etiology of PD is currently unknown; however, the pathological hallmarks of PD include excessive production of reactive oxygen species, enhanced neuroinflammation, and overproduction of α-synuclein. Under normal physiological conditions, aggregated α-synuclein is degraded via the autophagy lysosomal pathway. However, impairment of the autophagy lysosomal pathway results in α-synuclein accumulation, thereby facilitating the pathogenesis of PD. Current medications only manage the symptoms, but are unable to delay, prevent, or cure the disease. Collectively, oxidative stress, inflammation, apoptosis, and autophagy play crucial roles in PD; therefore, there is an enormous interest in exploring novel bioactive agents of natural origin for their protective roles in PD. The present study evaluated the role of myrcene, a monoterpene, in preventing the loss of dopaminergic neurons in a rotenone (ROT)-induced rodent model of PD, and elucidated the underlying mechanisms. Myrcene was administered at a dose of 50 mg/kg, 30 min prior to the intraperitoneal injections of ROT (2.5 mg/kg). Administration of ROT caused a considerable loss of dopaminergic neurons, subsequent to a significant reduction in the antioxidant defense systems, increased lipid peroxidation, and activation of microglia and astrocytes, along with the production of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and matrix metalloproteinase-9. Rotenone also resulted in impairment of the autophagy lysosomal pathway, as evidenced by increased expression of LC3, p62, and beclin-1 with decreased expression in the phosphorylation of mTOR protein. Collectively, these factors result in the loss of dopaminergic neurons. However, myrcene treatment has been observed to restore antioxidant defenses and attenuate the increase in concentrations of lipid peroxidation products, pro-inflammatory cytokines, diminished microglia, and astrocyte activation. Myrcene treatment also enhanced the phosphorylation of mTOR, reinstated neuronal homeostasis, restored autophagy-lysosomal degradation, and prevented the increased expression of α-synuclein following the rescue of dopaminergic neurons. Taken together, our study clearly revealed the mitigating effect of myrcene on dopaminergic neuronal loss, attributed to its potent antioxidant, anti-inflammatory, and anti-apoptotic properties, and favorable modulation of autophagic flux. This study suggests that myrcene may be a potential candidate for therapeutic benefits in PD. MDPI 2023-01-10 /pmc/articles/PMC9863310/ /pubmed/36677744 http://dx.doi.org/10.3390/molecules28020685 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Azimullah, Sheikh Jayaraj, Richard L. Meeran, Mohamed Fizur. Nagoor Jalal, Fakhreya Y. Adem, Abdu Ojha, Shreesh Beiram, Rami Myrcene Salvages Rotenone-Induced Loss of Dopaminergic Neurons by Inhibiting Oxidative Stress, Inflammation, Apoptosis, and Autophagy |
title | Myrcene Salvages Rotenone-Induced Loss of Dopaminergic Neurons by Inhibiting Oxidative Stress, Inflammation, Apoptosis, and Autophagy |
title_full | Myrcene Salvages Rotenone-Induced Loss of Dopaminergic Neurons by Inhibiting Oxidative Stress, Inflammation, Apoptosis, and Autophagy |
title_fullStr | Myrcene Salvages Rotenone-Induced Loss of Dopaminergic Neurons by Inhibiting Oxidative Stress, Inflammation, Apoptosis, and Autophagy |
title_full_unstemmed | Myrcene Salvages Rotenone-Induced Loss of Dopaminergic Neurons by Inhibiting Oxidative Stress, Inflammation, Apoptosis, and Autophagy |
title_short | Myrcene Salvages Rotenone-Induced Loss of Dopaminergic Neurons by Inhibiting Oxidative Stress, Inflammation, Apoptosis, and Autophagy |
title_sort | myrcene salvages rotenone-induced loss of dopaminergic neurons by inhibiting oxidative stress, inflammation, apoptosis, and autophagy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9863310/ https://www.ncbi.nlm.nih.gov/pubmed/36677744 http://dx.doi.org/10.3390/molecules28020685 |
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