Dopaminemediated Oxidative Stress and Neuroinflammation in pd

PD is a progressive neurodegenerative disorder of nigrostriatal DA-ergic system. It is characterized by the loss of DA-ergic neurons in the substantia nigra pars compacta (SNpC) that control muscle movement [72], 50-70% loss of striatal dopamine, presence of Lewy bodies (intracytoplasmic protein aggregates mainly composed of a-synuclein in the midbrain [73], and mitochondrial complex I deficiency in the SNpc [74-76]. Although, molecular mechanism associated with the pathogenesis of PD is not fully understood. However, involvement of oxidative stress, inflammation, excitotoxicity, cytokine activation, mitochondrial dysfunction, and ubiquitin-proteasomal impairment has been suggested in PD [77-81]. In this review, I will emphasize the involvement of oxidative stress and neuroinflammation, because these processes have recently taken center stage for neurodegeneration in PD (Figure 6).

Figure 6. Possible ROS/RNS-mediated oxidative stress pathways implicating neurodegeneration of DA-ergic neurons in Parkinson disease: (1) mitochondrial dysfunction, (2) nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase), (3) increase in nitric oxide (NO) formation, (4) Ubiquitin-proteasome system (UPS) dysfunction. NADPH oxidase is comprised of cytoplasmic subunits (p47phox, p67phox, and p40phox) and upon phosphorylation by specific protein kinases, these subunits can form a complex and translocate to the plasma membrane to dock with the plasma membrane subunits (p91phox, p22phox, and Rac2). Catalysis of NADPH oxidase occurs in the p91phox subunit, and is initiated by transferring of electrons from molecular oxygen through redox coupling with NADPH, FAD, and heme, producing superoxide. diacylglycerol (DAG); nitric oxide synthase (NOS); (ONOO); (O2-); (InP3); (PtdIns-4,5-P2).

Figure 6. Possible ROS/RNS-mediated oxidative stress pathways implicating neurodegeneration of DA-ergic neurons in Parkinson disease: (1) mitochondrial dysfunction, (2) nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase), (3) increase in nitric oxide (NO) formation, (4) Ubiquitin-proteasome system (UPS) dysfunction. NADPH oxidase is comprised of cytoplasmic subunits (p47phox, p67phox, and p40phox) and upon phosphorylation by specific protein kinases, these subunits can form a complex and translocate to the plasma membrane to dock with the plasma membrane subunits (p91phox, p22phox, and Rac2). Catalysis of NADPH oxidase occurs in the p91phox subunit, and is initiated by transferring of electrons from molecular oxygen through redox coupling with NADPH, FAD, and heme, producing superoxide. diacylglycerol (DAG); nitric oxide synthase (NOS); (ONOO); (O2-); (InP3); (PtdIns-4,5-P2).

Oxidative stress is caused by a disturbance in the cellular prooxidant/antioxidant ratio. In this phenomenon, antioxidant mechanisms are overwhelmed by reactive oxygen species (ROS), which include (superoxide, hydroxyl, peroxyl, and hydroperoxyl radicals) and nonradical oxidizing agents, such as hydrogen peroxide, that can produce hydroxyl radicals [82]. Dopamine receptors are coupled with enzymes of phospholipid catabolism via G-proteins. These enzymes include phospholipase A2 (PLA2) and phospholipase C (PLC) (Figure 6). Activation of dopamine receptors leads to the stimulation of PLA2 and PLC, resulting in the production of arachidonic acid, AA (Figure 6). DA-ergic nigrostriatal neurons are also rich in glutamate receptors, which may contribute to excitotoxicity in PD [83]. Hyperstimulation of glutamate receptors results in extensive influx of Ca2+ that again activates PLA2, resulting in production of AA from neural membrane glycerophospholipids. Glutamate-mediated release of AA also involves participation of PLC/diacylglycerol lipase pathway (Figure 6). Enzymic oxidation of AA through cyclooxygenase results in the production of eicosanoids that promote inflammation. Non-enzymic oxidation of AA produces ROS that activates NF-kB, a key regulator of neuronal death (Figure 6). ROS interacts with p50 and p65 subunits of NF-kB and promotes the translocation of NF-kB from the cytoplasm to the nucleus [84]. In the nucleus, NF-kB promotes transcription of genes that encode number of proteins, including many enzymes (cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), superoxide dismutase (SOD), soluble phospholipase A2 (sPLA2), matrix metalloprotease (MMP), vascular cell adhesion molecule-1 (VCAM-1), and cytokines, such as TNF-a, IL-6, & IL-10. These mediators not only contribute to oxidative stress, but also induce neuroinflammation that may harm DA-ergic neurons.

In addition, different nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) isoforms are present in neurons and glial cells. NADPH oxidase is a complex that consists of two membrane-bound and three cytosolic components, plus rac 1 or rac 2 (Figure 6). Its activation involves the phosphorylation of one of the cytosolic components. In the presence of O2 and NADPH, this enzyme catalyzes the production of superoxide (O2"), implicating its role in altering synaptic plasticity [85]. In astrocytes and microglial cells, ROS are mainly produced by NADPH oxidase. Thus, mitochondrial dysfunction and NADPH oxidase produce ROS, which result in an imbalance in the cellular oxidative status (Figure 6). Similarly, activation of iNOS generates NO-, which reacts with O2" and generates peroxynitrite (ONOO-, a potent oxidant). ONOO--mediated protein nitration has been reported in PD [86]. ONOO- not only interacts with proteins and DNA but also reduces mitochondrial respiration, inhibits membrane pumps, and depletes cellular glutathione levels [87], contributing to death of DA-ergic neurons. The ubiquitin-proteasomal system (UPS) is responsible for homeostatic degradation of intact protein substrates as well as the elimination of damaged or misfolded proteins. ROS impair the UPS, which exacerbates protein aggregation, resulting in the formation of Lewy bodies (Figure 6). Collectively, ROS/RNS-mediated processes lead to oxidative and/or nitrosative damage to cellular proteins, lipids and DNA, implicating their major role in the neurodegeneration of dopaminergic neurons in PD.

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