NOX Inhibitors - A Promising Avenue for Ischemic Stroke

Lots of big words used to confuse exactly what was discovered and what followup is needed to prove it works or not. But followup will never occur since we have NO leadership and NO stroke strategy.
https://enjournal.org/DOIx.php?id=10.5607/en.2017.26.4.195
Exp Neurobiol. 2017 Aug;26(4):195-205. English.
Published online Aug 25, 2017.  https://doi.org/10.5607/en.2017.26.4.195
Copyright © Experimental Neurobiology 2017.

Jong Youl Kim,1 Joohyun Park,1,2 Jong Eun Lee,1,2 and Midori A. Yenari3

1Department of Anatomy, Yensei University College of Medicine, Seoul 03722, Korea.

2BK21 Plus Project for Medical Sciences and Brain Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea.

3Department of Neurology, University of California, San Francisco, and San Francisco Veterans Affairs Medical Center, San Francisco, California 94121, USA.

To whom correspondence should be addressed. Jong Eun Lee, TEL: 82-2-2228-1646, FAX: 82-2-365-0700, Email: jelee@yuhs.ac To whom correspondence should be addressed. Midori A. Yenari, TEL: 1-415 750-2011, FAX: 1-415 750-2273, Email: yenari@alum.mit.edu

Received July 27, 2017; Revised August 09, 2017; Accepted August 09, 2017.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Go to: Abstract

NADPH-oxidase (NOX) mediated superoxide originally found on leukocytes, but now recognized in several types of cells in the brain. It has been shown to play an important role in the progression of stroke and related cerebrovascular disease. NOX is a multisubunit complex consisting of 2 membrane-associated and 4 cytosolic subunits. NOX activation occurs when cytosolic subunits translocate to the membrane, leading to transport electrons to oxygen, thus producing superoxide. Superoxide produced by NOX is thought to function in long-term potentiation and intercellular signaling, but excessive production is damaging and has been implicated to play an important role in the progression of ischemic brain. Thus, inhibition of NOX activity may prove to be a promising treatment for ischemic brain as well as an adjunctive agent to prevent its secondary complications. There is mounting evidence that NOX inhibition in the ischemic brain is neuroprotective, and targeting NOX in circulating immune cells will also improve outcome. This review will focus on therapeutic effects of NOX assembly inhibitors in brain ischemia and stroke. However, the lack of specificity and toxicities of existing inhibitors are clear hurdles that will need to be overcome before this class of compounds could be translated clinically.

Keywords: ischemic stroke; NADPH oxidase; superoxide; NOX inhibition

Go to: INTRODUCTION

Stroke is caused by occlusion of or hemorrhage from a blood vessel supplying the brain. It is a cause of long-term disability and ranks as the third frequent cause of death following heart disease and cancer, yet despite high prevalence, the number of approved therapies remains low [1, 2]. The major therapeutic strategy for treatment of acute ischemic stroke is rapid recanalization, either by pharmacological means through thrombolytic agents, or mechanical thrombectomy [3]. However, the time window for intervention limits these therapies to a small number of patients, and their inappropriate use can actually worsen outcome.
Stroke, via occlusion of cerebral artery(ies) brings on energy depletion and subsequent death of cells in the vascular territory. Currently, understanding of the pathophysiology of ischemic stroke indicates that the mechanism of neuronal injury can be characterized according to infarct progression over time. The acute stage appears within minutes up to a few hours after ischemic stroke onset, during which ionic homeostasis is disrupted by the decrease in cerebral blood flow. This phenomenon leads to increased intracellular calcium concentrations and stimulation of glutamate release, producing excitotoxicity and a spreading depression throughout the ischemic region [4, 5, 6]. Water enters the intracellular space due to osmotic gradients, causing cells swell, and the resulting vasogenic edema can give rise to intracranial pressure, vascular compression and herniation [5]. Furthermore, the generation of reactive oxygen species (ROS) can destroy membranes, mitochondria and DNA, leading to proteins misfolding and enzyme dysfunction. These factors are exacerbated in the event of reperfusion takes place. In the second-subacute phase occurs a few hours to a few days after ischemia. An inflammatory and cell death (apoptosis and necrosis) response develops as a result of the stimulatory influences of the acute phase [4, 5, 7]. In additional to these responses, high intracellular calcium concentrations built up during the acute phase lead to the overactivation of several proteolytic enzyme systems.
Recent studies have focused on the role of superoxide generating systems in immune cells and their consequences on reperfusion injury (RI), or that injury which results when the occluded vessel is reopened. Of the various systems by which cells can generate reactive oxygen species (ROS), the topic of this review will focus on superoxide produced by activation of the NADPH oxidase (NOX). Superoxide is soluble in solution and can combine with other ROS to form more toxic molecules after experimental ischemic stroke [8]. The importance of NOX in production of ROS and subsequent neuronal cell death has been the subject of somewhat recent investigations. Several other enzymes found throughout the cell are involved in ROS generation, including xanthine oxidase, lipoxygenase, cylcoocxygenases (COX) and substrate coupled nitric oxide synthetase, but none of these can produce the large amount of ROS observed in nonphagocytic cells in both normal and pathological conditions [9]. In the last decade, study into the NOX enzyme has made a major new turn with discovery of a large number of NOX homologs which may allow for a more targeted therapeutic approach. At present, no specific treatments exist for NOX induced ROS in central nervous system (CNS) diseases and most of these diseases have very few therapeutic options at all. This will be discussed in more detail in this review.

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