Abstract
Progressive degeneration of neurons and aggravation of dopaminergic neurons in the substantia nigra pars compacta results in the loss of dopamine in the brain of Parkinson’s disease (PD) patients. Numerous therapies, exhibiting transient efficacy have been developed; however, they are mostly accompanied by side effects and limited reliability, therefore instigating the need to develop novel optimistic treatment targets. Significant therapeutic targets have been identified, namely: chaperones, protein Abelson, glucocerebrosidase-1, calcium, neuromelanin, ubiquitin-proteasome system, neuroinflammation, mitochondrial dysfunction, and the kynurenine pathway (KP). The role of KP and its metabolites and enzymes in PD, namely quinolinic acid (QUIN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranillic acid (3-HAA), kunurenine-3-monooxygenase (KMO), etc. has been reported. The neurotoxic QUIN, N-methyl-D-aspartate (NMDA) receptor agonist, and neuroprotective KYNA—which antagonizes QUIN actions—primarily justify the Janus-faced role of KP in PD. Moreover, KP has been reported to play a biomarker role in PD detection. Therefore, the authors detail the neurotoxic, neuroprotective, and immunomodulatory neuroactive components, alongside the upstream and downstream metabolic pathways of KP, forming a basis for a therapeutic paradigm of the disease while recognizing KP as a potential biomarker in PD, thus facilitating the development of a suitable target in PD management.
Highlights
The greatest obstacle associated with neurodegenerative disorders is that they are incurable, and the deterioration is progressive with time and age
The downstream kynurenine pathway (KP) metabolite, 3-hydroxyanthranillic acid (3-HAA), promotes auto-oxidation, resulting in production of super-reactive oxygen species, which is substantially elevated by superoxide dismutase (SOD), but curbed by catalase [119]. These results indicate that neurotoxicity, mediated by 3-hydroxy anthranilic acid (3-HAA) and 3-HK, occurs by production of free radicals, which can be prevented by pharmacological upregulation of catalase activity
Despite the conventional therapeutic paradigm employed in Parkinson’s disease (PD), the results exhibit limited efficacy, lesser tolerance, elevated side effects, and progressive deterioration of the dopaminergic neurons, where the ratio of positive to negative effects keeps on decreasing
Summary
The greatest obstacle associated with neurodegenerative disorders is that they are incurable, and the deterioration is progressive with time and age. These pathologies vary in symptoms, pathological features, and drug candidates. The therapies available for the disease are associated with hindrances, such as inability to cross the blood–brain barrier (BBB), side effects, limited life span, etc., alongside primary challenges such as the development of sensitive and reliable of biomarkers for disease detection [6,7]. These can uncover the possibility of development of a novel therapeutic regime in PD, thereby giving an opportunity to researchers all over the world to investigate the possible involvement of KP metabolites and enzymes in PD progression and establish its significance as a potential target. The manuscript details the role of upstream and downstream KP metabolites in PD, followed by identifying KP as a biomarker in disease detection, and elaborating the therapeutic considerations related to it
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