Reactive Oxygen Species and Inhibitors of Inflammatory Enzymes, NADPH Oxidase, and iNOS in Experimental Models of Parkinson's Disease

Department of Biotechnology, Research Institute of Inflammatory Diseases, Konkuk University, Chungju 380-701, Republic of Korea.
Mediators of Inflammation (Impact Factor: 3.24). 01/2012; 16. DOI: 10.1155/2012/823902
Source: PubMed


Reactive oxygen species (ROSs) are emerging as important players in the etiology of neurodegenerative disorders including Parkin-son's disease (PD). Out of several ROS-generating systems, the inflammatory enzymes nicotinamide adenine dinucleotide phos-phate (NADPH) oxidase and inducible nitric oxide synthase (iNOS) were believed to play major roles. Mounting evidence suggests that activation of NADPH oxidase and the expression of iNOS are directly linked to the generation of highly reactive ROS which affects various cellular components and preferentially damage midbrain dopaminergic neurons in PD. Therefore, appropriate man-agement or inhibition of ROS generated by these enzymes may represent a therapeutic target to reduce neuronal degeneration seen in PD. Here, we have summarized recently developed agents and patents claimed as inhibitors of NADPH oxidase and iNOS enzymes in experimental models of PD.

Download full-text


Available from: Sushruta Koppula
  • Source
    • "3.1. Cyclo(His-Pro) inhibits NO and presides over the Nrf2–NF-ÄB systems in LPS-activated BV-2 cells LPS is a common inflammogen that triggers a diverse array of microglial responses leading to the production of proinflammatory mediators (Cunningham, 2013; Meng and Lowell, 1997; Wen et al., 2007; Chung et al., 2010; Kim et al., 2000; Koppula et al., 2012). To determine whether and how cyclo(His-Pro) suppresses the glial NF-␬B pathway, we investigated the effects of the cyclic dipeptide on LPS-activated BV-2. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Many neurological and neurodegenerative diseases are associated with oxidative stress and glial inflammation, all related to endoplasmic reticulum stress. Cyclo(His-Pro) is an endogenous cyclic dipeptide that exerts cytoprotection by interfering with the Nrf2-NF-κB systems, the former presiding the antioxidant and the latter the pro-inflammatory cellular response. Here we investigated whether the cyclic dipeptide inhibits glial inflammation thus reducing the detrimental effect of inflammatory neurotoxins on neurons. We found that systemic administration of cyclo(His-Pro) exerts in vivo anti-inflammatory effects in the central nervous system by down-regulating hepatic and cerebral TNFα expression thereby counteracting LPS-induced gliosis. Mechanistic studies indicated that the cyclic dipeptide-mediated effects are achieved through the activation of Nrf2-driven antioxidant response and the inhibition of the pro-inflammatory NF-κB pathway. Moreover, by up-regulating Bip, cyclo(His-Pro) increases the ER stress sensitivity and triggers the unfolded protein response to alleviate the ER stress. These results unveil a novel potential therapeutic use of cyclo(His-Pro) against neuroinflammatory-related diseases and we might now consider its potential anti-inflammatory role in other neuropathological conditions.
    Full-text · Article · Mar 2014 · The international journal of biochemistry & cell biology
  • Source
    • "The induction of NOS produces high levels of NO and superoxide radicals for a prolonged period of time. These two ROS can either directly or indirectly promote neuronal death in PD [76] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroinflammation is a host-defense mechanism associated with restoration of normal structure and function of the brain and neutralization of an insult. Increasing neuropathological and biochemical evidence from the brains of individuals with Parkinson's disease (PD) provides strong evidence for activation of neuroinflammatory pathways. Microglia, the resident innate immune cells, may play a major role in the inflammatory process of the diseased brain of patients with PD. Although microglia forms the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly affect neurons by releasing various molecular mediators such as inflammatory cytokines (tumor necrosis factor- α , interleukin [IL]-6, and IL-1 β ), nitric oxide, prostaglandin E2, and reactive oxygen and nitrogen species. Moreover, recent studies have reported that activated microglia phagocytose not only damaged cell debris but also intact neighboring cells. This phenomenon further supports their active participation in self-enduring neuronal damage cycles. As the relationship between PD and neuroinflammation is being studied, there is a realization that both cellular and molecular mediators are most likely assisting pathological processes leading to disease progression. Here, we discuss mediators of neuroinflammation, which are known activators released from damaged parenchyma of the brain and result in neuronal degeneration in patients with PD.
    Full-text · Article · Jun 2013 · Mediators of Inflammation
  • Source
    • "There are many sources of oxidative stress in daily life, such as smoking [11], exercise [12] and radiation [13]. Reactive oxygen species (ROS) may induce many types of diseases, such as Parkinson's disease [14], cataracts [15], atherosclerosis [16], nephrotic syndromes [17], cancer [18], rheumatoid arthritis [19], ailments associated with ageing [20], stroke [21], and many others [22]. SOD detoxifies superoxide anion (O2−) to hydrogen peroxide (H2O2), and then catalase converts H2O2 into H2O and O2. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Low-dose irradiation induces various stimulating effects, especially activation of the biological defense system including antioxidative and immune functions. Oxidative stress induced by reactive oxygen species (ROS) can cause cell damage and death and can induce many types of diseases. This paper reviews new insights into inhibition of ROS-related diseases with low-dose irradiation or radon inhalation. X-irradiation (0.5 Gy) before or after carbon tetrachloride (CCl(4)) treatment inhibits hepatopathy in mice. X-irradiation (0.5 Gy) before ischemia-reperfusion injury or cold-induced brain injury also inhibits edema. These findings suggest that low-dose X-irradiation has antioxidative effects due to blocking the damage induced by free radicals or ROS. Moreover, radon inhalation increases superoxide dismutase activity in many organs and inhibits CCl(4)-induced hepatic and renal damage and streptozotocin-induced type I diabetes. These findings suggest that radon inhalation also has antioxidative effects. This antioxidative effect against CCl(4)-induced hepatopathy is comparable to treatment with ascorbic acid (vitamin C) at a dose of 500 mg/kg weight, or α-tocopherol (vitamin E) treatment at a dose of 300 mg/kg weight, and is due to activation of antioxidative functions. In addition, radon inhalation inhibits carrageenan-induced inflammatory paw edema, suggesting that radon inhalation has anti-inflammatory effects. Furthermore, radon inhalation inhibits formalin-induced inflammatory pain and chronic constriction injury-induced neuropathic pain, suggesting that radon inhalation relieves pain. Thus, low-dose irradiation very likely activates the defense systems in the body, and therefore, contributes to preventing or reducing ROS-related injuries, which are thought to involve peroxidation.
    Full-text · Article · Feb 2013 · Journal of Radiation Research
Show more