Mitochondrial Dysfunction and Parkinson’s Disease: Pathogenesis and Therapeutic Strategies

Vastegani, Sadegh Moradi; Nasrolahi, Ava; Ghaderi, Shahab; Belali, Rafie; Rashno, Masome; Farzaneh, Maryam; Khoshnam, Seyed Esmaeil

doi:10.1007/s11064-023-03904-0

Cited by 32 publications

(14 citation statements)

References 302 publications

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“…In PD brain, muscle, and platelets, there are systemic decreases in the activity of complex I of the mitochondrial electron transfer chain (ETC) (1)(2)(3)(4)(5). The discovery that MPP+ (1-methyl-4-phenyl-2,3-dihydropyridine), the active metabolite of the parkinsonism toxin Nmethyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), serves as a complex I inhibitor provides additional evidence for mitochondrial dysfunction in PD (3)(4)(5)14). Rotenone (ROT) is a neurotoxicant naturally present in tropical plants traditionally used as an herbicide and pesticide (8).…”

Section: Discussionmentioning

confidence: 99%

“…According to Vito et al, neurodegeneration and neurological impairments are caused due to multifactorial mechanisms such as chronic neuroinflammation, activation of brain immune cells i.e., microglia, altercating astroglia functioning in the brain (3)(4)(5)(6)(7)13,14). Aqueous leaf extract of WS is reported to exert anti-neuroinflammatory and neuroprotective effects by restricting the activation of pro-inflammatory cytokines by blocking the NF-B pathway and increased expression of MAP2 gene that helps in conditioning of activated microglia (dark coloured ameboid cells) to inactivated or normal microglia (light-coloured ramified cells) was demonstrated in a rat model (20).…”

Section: Discussionmentioning

confidence: 99%

“…arkinson's disease (PD) is a neurodegenerative disorder that selectively causes loss of dopaminergic neurons in the nigrostriatal area of the midbrain which results in a movement difficulty characterised by tremors, bradykinesia, and postural instability (1)(2)(3)(4)(5)(6). Lewy bodies and Lewy neurites are present due to PD pathology, and the nigrostriatal dopaminergic pathway is disturbed (2).…”

Section: Introductionmentioning

confidence: 99%

“…Several theories and medical management have been proposed for the understanding of the pathogenesis of PD (9)(10)(11)(12). This understanding has provided new approaches for novel treatments with few side effects for the underlying causes of motor dysfunction and cognitive impairments by slowing the disease's progression and neuronal loss (1)(2)(3)(4)(5)(6). The use of phytochemicals or phytoextracts, regenerative therapies, gene therapies, cell-based medicines, and drug repurposing with various indications have all gained attention as therapy methods (12).…”

Section: Introductionmentioning

confidence: 99%

“…Thirdly, it lends "biological plausibility" to the PD "pesticide-environmental exposure hypothesis". Fourth, it implies that mechanisms other than a bioenergetic (ATP) deficit must be at work as degeneration occurred at levels of complex I inhibition that had little to no influence on respiration (3)(4)(5).…”

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confidence: 99%

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Cytoprotective and anti-inflammatory effect of ethanolic extract of Withania somnifera root in combination with doxycycline in rotenone induced cytotoxicity in neuroblastoma cell lines

Epuri¹,

Prathap²,

Reddy³

et al. 2023

Biomedicine

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Introduction and Aim: Parkinson's disease (PD) is a neurodegenerative disorder that destroys dopaminergic neurons in the nigrostriatal area of the midbrain this results in a movement difficulty characterised by tremors, bradykinesia, and postural instability The present in vitro study is designed to assess the beneficial (cytoprotectant and anti-inflammatory) and cyto-toxicological effects of ethanolic Withania somnifera (Ashwagandha) root extract (EWSR) in presence of Rotenone (ROT) and other known neuroprotectants (Doxycycline and Ellagic acid). Materials and Methods: The nine groups used in the in vitro studies were normal control, positive control (Rotenone or Rot), W. somnifera root extract (EWSR), Doxycycline (Doxy), Ellagic acid (EA), ROT with EWSR, ROT with doxy, ROT with EA, ROT with EWSR-doxy, and ROT with EWSR-doxy-EA. The EWSR, doxy and EA treatment was started on the 24th hour following the rotenone administration and continued for the next 36 hours. After the 36th hour of protective therapy, quantification of pro-inflammatory cytokines (ELISA), cell viability or analyses of neuronal cell loss, cell cycle analysis and molecular analysis (RTPCR) was performed as a part of assessment. Results: Observations from the present in vitro studies clearly demonstrate the cytoprotective and anti-inflammatory properties of EWSR, and these beneficial or protective effects got enhanced when treated in combination with Doxy and EA indicating synergistic effect in the cells that were priorly treated with ROT, and later treated with EWSR, Doxy, and EA individually and in combination. Conclusion: The findings imply that EWSR reduces the in vitro effects of ROT by acting as an anti-inflammatory and cytoprotective agent.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Cytoprotective and anti-inflammatory effect of ethanolic extract of Withania somnifera root in combination with doxycycline in rotenone induced cytotoxicity in neuroblastoma cell lines

Epuri¹,

Prathap²,

Reddy³

et al. 2023

Biomedicine

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The role of mitochondrial dynamics in disease

Wang,

Dai,

et al. 2023

MedComm

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Mitochondria are multifaceted and dynamic organelles regulating various important cellular processes from signal transduction to determining cell fate. As dynamic properties of mitochondria, fusion and fission accompanied with mitophagy, undergo constant changes in number and morphology to sustain mitochondrial homeostasis in response to cell context changes. Thus, the dysregulation of mitochondrial dynamics and mitophagy is unsurprisingly related with various diseases, but the unclear underlying mechanism hinders their clinical application. In this review, we summarize the recent developments in the molecular mechanism of mitochondrial dynamics and mitophagy, particularly the different roles of key components in mitochondrial dynamics in different context. We also summarize the roles of mitochondrial dynamics and target treatment in diseases related to the cardiovascular system, nervous system, respiratory system, and tumor cell metabolism demanding high‐energy. In these diseases, it is common that excessive mitochondrial fission is dominant and accompanied by impaired fusion and mitophagy. But there have been many conflicting findings about them recently, which are specifically highlighted in this view. We look forward that these findings will help broaden our understanding of the roles of the mitochondrial dynamics in diseases and will be beneficial to the discovery of novel selective therapeutic targets.

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Regulation of mitophagy and mitochondrial function: Natural compounds as potential therapeutic strategies for Parkinson's disease

Liang,

Ma,

Zhong

et al. 2024

Phytotherapy Research

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Mitochondrial damage is associated with the development of Parkinson's disease (PD), indicating that mitochondrial‐targeted treatments could hold promise as disease‐modifying approaches for PD. Notably, natural compounds have demonstrated the ability to modulate mitochondrial‐related processes. In this review article, we discussed the possible neuroprotective mechanisms of natural compounds against PD in modulating mitophagy and mitochondrial function. A comprehensive literature search on natural compounds related to the treatment of PD by regulating mitophagy and mitochondrial function was conducted from PubMed, Web of Science and Chinese National Knowledge Infrastructure databases from their inception until April 2023. We summarize recent advancements in mitophagy's molecular mechanisms, including upstream and downstream processes, and its relationship with PD‐related genes or proteins. Importantly, we highlight how natural compounds can therapeutically regulate various mitochondrial processes through multiple targets and pathways to alleviate oxidative stress, neuroinflammation, Lewy's body aggregation and apoptosis, which are key contributors to PD pathogenesis. Unlike the single‐target strategy of modern medicine, natural compounds provide neuroprotection against PD by modulating various mitochondrial‐related processes, including ameliorating mitophagy by targeting the PINK1/parkin pathway, the NIX/BNIP3 pathway, and autophagosome formation (i.e., LC3 and p62). Given the prevalence of mitochondrial damage in various neurodegenerative diseases, exploring the exact mechanism of natural compounds on mitophagy and mitochondrial dysfunction could shed light on the development of highly effective disease‐modifying or adjuvant therapies targeting PD and other neurodegenerative disorders.

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Mitochondrial Dysfunction and Parkinson’s Disease: Pathogenesis and Therapeutic Strategies

Cited by 32 publications

References 302 publications

Cytoprotective and anti-inflammatory effect of ethanolic extract of Withania somnifera root in combination with doxycycline in rotenone induced cytotoxicity in neuroblastoma cell lines

Cytoprotective and anti-inflammatory effect of ethanolic extract of Withania somnifera root in combination with doxycycline in rotenone induced cytotoxicity in neuroblastoma cell lines

The role of mitochondrial dynamics in disease

Regulation of mitophagy and mitochondrial function: Natural compounds as potential therapeutic strategies for Parkinson's disease

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