Antioxidant Therapeutics in Parkinson’s Disease: Current Challenges and Opportunities

Duarte-Jurado, Ana Patricia; Gopar-Cuevas, Yareth; Saucedo‐Cárdenas, Odila; Loera‐Arias, María de Jesús; Montes‐de‐Oca‐Luna, Roberto; García-García, Aracely; Rodríguez-Rocha, Humberto

doi:10.3390/antiox10030453

Cited by 45 publications

(25 citation statements)

References 165 publications

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“…Relevant to humans, there is no clinical evidence for L-DOPA being neurotoxic and detrimental to the progression of Parkinson’s disease symptoms 39 . In addition, antioxidant strategies have systematically failed to provide any therapeutic benefit in Parkinson’s disease clinical trials 40 . Even if NM synthesis per se was initially neuroprotective, its long-term accumulation until occupying most of the neuronal cytoplasm has deleterious consequences by physically interfering with intracellular communication 41–43 and impairing proteostasis 5,33 .…”

Section: Discussionmentioning

confidence: 99%

In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease

González-Sepúlveda

Compte

Cuadros

et al. 2022

Preprint

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Humans accumulate with age the dark-brown pigment neuromelanin inside specific neuronal groups. Neurons with the highest neuromelanin levels are particularly susceptible to degeneration in Parkinson's disease, especially dopaminergic neurons of the substantia nigra (SN), the loss of which leads to characteristic motor Parkinson's disease symptoms. In contrast to humans, neuromelanin does not appear spontaneously in most animals, including rodents, and Parkinson's disease is an exclusively human condition. Using humanized neuromelanin-producing rodents, we recently found that neuromelanin can trigger Parkinson's disease pathology when accumulated above a specific pathogenic threshold. Here, by taking advantage of this newly developed animal model, we assessed whether the intracellular buildup of neuromelanin that occurs with age can be slowed down in vivo to prevent or attenuate Parkinson's disease. Because neuromelanin derives from the oxidation of free cytosolic dopamine, we enhanced dopamine vesicular encapsulation in the SN of neuromelanin-producing rats by viral vector-mediated overexpression of vesicular monoamine transporter 2 (VMAT2). This strategy reduced the formation of potentially toxic oxidized dopamine species that can convert into neuromelanin and maintained intracellular neuromelanin levels below their pathogenic threshold. Decreased neuromelanin production was associated with an attenuation of Lewy body-like inclusion formation and a long-term preservation of dopamine homeostasis, nigrostriatal neuronal integrity and motor function in these animals. Our results demonstrate the feasibility and therapeutic potential of modulating age-dependent intracellular neuromelanin production in vivo, thereby opening an unexplored path for the treatment of Parkinson's disease and, in a broader sense, brain aging.

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Section: Discussionmentioning

confidence: 99%

In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease

González-Sepúlveda

Compte

Cuadros

et al. 2022

Preprint

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“…In addition to the age, which is the most important risk factor for neurodegenerative disease, genetic, epigenetic, environmental and lifestyle are initiation factors which play a role in the pathogenesis of PD [16,90,[103][104][105][106][107][108][109][110][111][112][113]. The preclinical studies, and diagnostic precision of PD are under extensive research, applying in vitro, in vivo, and in silico methodologies [114][115][116][117][118][119]. Until now, 21 PARK genes have been described in human genome as causative factors of the disease, furthermore, genetic variants of 26 loci have been shown to be important risk modifiers for PD.…”

Section: Damentioning

confidence: 99%

Single Nucleotide Polymorphisms of Indoleamine 2,3-Dioxygenase 1 Influenced the Age Onset of Parkinson's Disease

Török¹,

Maszlag-Török²,

Molnár³

et al. 2022

Front. Biosci. (Landmark Ed)

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Background: Earlier studies reported alterations of the kynurenine (KYN) pathway of tryptophan (TRP) metabolism in Parkinson's disease (PD). The first rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan dioxygenase were observed upregulated, resulting elevated KYN/TRP ratios in the serum and cerebrospinal fluid samples of patients with PD. More and more single nucleotide polymorphisms (SNPs) have been identified in a population of PD. However, little is known about the impact of genetic variations of the IDO on the pathogenesis of PD. Methods: SNP analysis of IDO1 was performed by allelic discrimination assay with fluorescently labelled TaqMan probes and a subgroup analysis was conducted according to the age of PD onset. The frame shifts variant rs34155785, intronic variant rs7820268, and promotor region variant rs9657182 SNPs of 105 PD patients without comorbidity were analyzed and compared to 129 healthy controls. Results: No significant correlation was found in three SNPs between PD patients and healthy controls. However, the subgroup analysis revealed that A alleles of rs7820268 SNP or rs9657182 SNP carriers contribute to later onset of PD than non-carriers. Conclusions: The study suggested that SNPs of IDO1 influenced the age onset of PD and genotyping of SNPs in certain alleles potentially serves as a risk biomarker of PD.

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“…N-acetylcysteine (NAC), a membrane-permeable cysteine precursor which functions as the rate-limiting substrate in GSH synthesis, is a potential therapeutic approach to target the GSH system, given that neurons cannot directly uptake GSH [80]. NAC has been found to ameliorate the decreased levels of GSH in the substantia nigra in a 6-OHDA hemi-parkinsonian rat model [81].…”

Section: Glutathionementioning

confidence: 99%

Evidence for Oxidative Pathways in the Pathogenesis of PD: Are Antioxidants Candidate Drugs to Ameliorate Disease Progression?

Leathem

Ortiz

Dennis

et al. 2022

IJMS

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Parkinson’s disease (PD) is a progressive neurodegenerative disorder that arises due to a complex and variable interplay between elements including age, genetic, and environmental risk factors that manifest as the loss of dopaminergic neurons. Contemporary treatments for PD do not prevent or reverse the extent of neurodegeneration that is characteristic of this disorder and accordingly, there is a strong need to develop new approaches which address the underlying disease process and provide benefit to patients with this debilitating disorder. Mitochondrial dysfunction, oxidative damage, and inflammation have been implicated as pathophysiological mechanisms underlying the selective loss of dopaminergic neurons seen in PD. However, results of studies aiming to inhibit these pathways have shown variable success, and outcomes from large-scale clinical trials are not available or report varying success for the interventions studied. Overall, the available data suggest that further development and testing of novel therapies are required to identify new potential therapies for combating PD. Herein, this review reports on the most recent development of antioxidant and anti-inflammatory approaches that have shown positive benefit in cell and animal models of disease with a focus on supplementation with natural product therapies and selected synthetic drugs.

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Antioxidant Therapeutics in Parkinson’s Disease: Current Challenges and Opportunities

Cited by 45 publications

References 165 publications

In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease

In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease

Single Nucleotide Polymorphisms of Indoleamine 2,3-Dioxygenase 1 Influenced the Age Onset of Parkinson's Disease

Evidence for Oxidative Pathways in the Pathogenesis of PD: Are Antioxidants Candidate Drugs to Ameliorate Disease Progression?

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