**2. Role of oxidative stress in pathogenesis of Parkinson's disease (PD)**

PD is the second most common neurodegenerative disorder, characterised by the degeneration of dopaminergic neurons in the brain's substantia nigra pars compacta [31]. PD affects around 1–2 percent of the population over the age of 65, and the prevalence rises to 4% in people over the age of 85 [32]. Overabundance of ROS or other free radicals has been linked to the pathological mechanism underlying dopaminergic neuron degeneration. Mitochondrial dysfunction or inflammation may both cause excessive ROS production [10]. The proper role of redox-sensitive signalling proteins in neuron cells, as well as neuronal survival, is dependent on maintaining

redox homeostasis [33]. Mitochondria in neurons and glia are the main sources of ROS in the brain [10]. The production of these free radicals is exacerbated in PD due to neuroinflammation, dopamine degradation, mitochondrial dysfunction, ageing, GSH depletion, and high levels of iron or Ca2+ [10].

Consequently, when people with PD are exposed to environmental factors including pesticides, neurotoxins, and dopamine, ROS deposition may be exacerbated [34]. This is supported by a strong link between pesticide exposure and an increased risk of Parkinson's disease [34]. ROS have been shown to contribute significantly to dopaminergic neuronal loss [10]. Other research has indicated that the loss of dopaminergic neurons is linked to the existence of neuromelanin, since highly pigmented neurons are more vulnerable to damage [35]. The formation of neuromelanin appears to be related to dopamine auto-oxidation, a process induced by ROS overproduction [35].

Neurodegeneration produces reactive oxygen species (ROS), which can destroy key cellular proteins and disrupt lipid membranes, leading in oxidative stress. Mitochondrial dysfunction increases free radical generation in the respiratory chain [10]. Parkinson's disease has been linked to deficiencies in mitochondrial complex I in particular. Certainly, a significant portion of the unfavourable neuronal apoptosis seen in Parkinson's disease is due to a complex I deficiency [36]. A mutation in the PTEN-induced putative kinase 1 gene is associated to this impairment (PINK1). PINK1 is a protein found in all human tissues that plays a key role in keeping mitochondrial membrane potential and preventing oxidative stress [36]. The PINK1 mutation is linked to the onset of Parkinson's disease [36]. Mutations of leucine-rich repeat kinase 2 (LRRK2), parkin, alpha-synuclein, and DJ-1 have all been linked to the pathogenesis of Parkinson's disease. These mutations may impair mitochondrial function, resulting in an increase in reactive oxygen species (ROS) production and oxidative stress vulnerability. Mutant parkin may play key roles in the development of autosomal recessive PD due to its involvement in lowering ROS and limiting the production of neurotoxic proteins produced by ubiquitination [36]. Additionally, alpha synuclein aggregation has been demonstrated to disrupt mitochondrial complex I activities, causing ATP production impairment and mitochondrial malfunction [37]. Proteasomal dysfunction which is exacerbated by dopamine-derived ROS, has been linked to neurodegeneration in Parkinson's disease [37].

Currently, there is no effective cure for the treatment of Parkinson's disease, however, deeper insights into the role of ROS in the disease pathogenesis (initiation and progression) should lead to more effective treatments for PD symptoms. Many neuroprotective approaches have been discovered to minimise mitochondrial oxidative stress in dopaminergic neurons. Free radicals damage has been proven to be reduced by antioxidants [38]. GSH, ascorbic acid and tocopherol are essential antioxidants that the antioxidant lipoic acid can recycle. Secretion of GSH which enhance reduction of lipid peroxide is one of the mechanisms by which lipoic acid offered beneficial effects against oxidative damage in oxidative stress-induced mitochondrial dysfunction [39]. In an animal study, it was discovered that treatment with lipoic acid enhanced motor coordination and ATP efficiency resulting in neuroprotection [40]. Furthermore, treatment of lipoic acid in a rotenone rats' model of parkinsonian rats showed enhanced motor performance and marked reduction in neuronal lipid peroxide in the brain [40]. Neuroprotective ability of phytochemicals and antioxidant substances including polyphenols, Ginko biloba, docosahexaenoic acid (DHA), tocopherol, ascorbic acid, and coenzyme Q10, and have all been studied in animal experiments with remarkable findings [41–46]. However, no convincing evidence of their neuroprotective benefits has been found in human [47]. Failures of such

antioxidant medications should provide future recommendations for treating PD patients with combination therapies aimed at limiting ROS production in the brain and improving mitochondrial function [48].
