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

Sushruta Koppula,Dong-Kug Choi,In Su Kim,Hemant Kumar

doi:10.1155/2012/823902

Abstract

Reactive oxygen species (ROSs) are emerging as important players in the etiology of neurodegenerative disorders including Parkinson's disease (PD). Out of several ROS-generating systems, the inflammatory enzymes nicotinamide adenine dinucleotide phosphate (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 management 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.

Highlights

Brain inflammation may contribute to a wide variety of neurodegenerative pathologies
LPS-induced extracellular reactive oxygen species (ROSs) production via the inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) cytosolic subunit p47phox translocation to the cell membrane. These findings strongly suggest that the protective effects of sinomenine are most likely mediated through the inhibition of microglial NADPH oxidase activity [70]
Studies of postmortem Parkinson’ disease (PD) brains and various cellular and animal models of PD in the last two decades strongly suggest that the neuroinflammation caused by oxidative stress is one of the major mechanisms in PD pathology

Summary

Introduction

Brain inflammation may contribute to a wide variety of neurodegenerative pathologies. Mediators of Inflammation (iNOS), myeloperoxidase, lipoxygenase, and cyclooxygenase (COX) These enzymes contribute to the pathogenesis of various neurodegenerative diseases including PD. Earlier studies postulated that NADPH oxidase and iNOS are not expressed in normal CNS conditions, but in PD patients and in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) intoxicated mice. Both are clearly expressed and activated in glial cells in the ventral midbrain. These two major inflammatory enzymes that produce ROS may have a pathogenic role in PD, because when they are lacking in mutant mice, they show less loss of dopaminergic neurons [13,14,15]. We summarize claims by recent patents for several agents as potential NADPH oxidase and iNOS inhibitors

Reactive Oxygen Species and PD

Role of NADPH-Oxidase-Derived ROS Signaling in PD

NADPH Oxidase Inhibitors and Experimental Models of PD

Role of iNOS-Derived ROS Signaling in PD

Inducible Nitric Oxide Synthase Inhibitors and Experimental Models of PD

Findings

Conclusion