Potential Neuroprotective Treatment of Stroke: Targeting Excitotoxicity, Oxidative Stress, and Inflammation

We don't need potential we DEMAND actual.  WHEN THE HELL will you provide that? Maybe 50 years from now after you are the 1 in 4 per WHO that has a stroke?

Potential Neuroprotective Treatment of Stroke: Targeting Excitotoxicity, Oxidative Stress, and Inflammation

Qianwen Yang, Qianyi Huang, Zhiping Hu and Xiangqi Tang^*

• Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, China

Stroke is a major cause of death and adult disability. However, therapeutic options remain limited. Numerous pathways underlie acute responses of brain tissue to stroke. Early events following ischemic damage include reactive oxygen species (ROS)-mediated oxidative stress and glutamate-induced excitotoxicity, both of which contribute to rapid cell death within the infarct core. A subsequent cascade of inflammatory events escalates damage progression. This review explores potential neuroprotective strategies for targeting key steps in the cascade of ischemia–reperfusion (I/R) injury. NADPH oxidase (NOX) inhibitors and several drugs currently approved by the U.S. Food and Drug Administration including glucose-lowering agents, antibiotics, and immunomodulators, have shown promise in the treatment of stroke in both animal experiments and clinical trials. Ischemic conditioning, a phenomenon by which one or more cycles of a short period of sublethal ischemia to an organ or tissue protects against subsequent ischemic events in another organ, may be another potential neuroprotective strategy for the treatment of stroke by targeting key steps in the I/R injury cascade.

Introduction

Although stroke is a major cause of death and adult disability, therapeutic options remain limited. The development of new treatments including potential pharmaceutical agents is therefore of great importance. The acute responses of brain tissue to cerebral ischemia are complex. First, oxidative stress, which plays an essential role in the pathogenesis of cerebral ischemia–reperfusion (I/R) injury (Zalba et al., 2007; Carbone et al., 2015), is caused by increased reactive oxygen species (ROS) production and decreased activity levels of scavenger enzymes and protective antioxidants (De Silva and Miller, 2016; Grochowski et al., 2017). Second, glutamate, the most abundant excitatory neurotransmitter, acts as a potent neurotoxin under pathological conditions. Increased extracellular glutamate levels play an essential role in ischemia-mediated cytotoxicity through N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) ionotropic glutamate receptors (Chuang et al., 2011; Vaarmann et al., 2013; Khanna et al., 2015; Yoo et al., 2017). Third, minutes to hours after cerebral ischemia onset, a series of inflammatory events are triggered following the activation of resident cells including microglia. Several signals contribute to the two main activation phenotypes: classically activated (M1) and alternatively activated (M2) (Kim et al., 2015; Bonaventura et al., 2016; Fu and Yan, 2018). Microglia are sensitive to signaling through receptors such as toll-like receptors (TLRs) and peroxisome proliferator-activated receptor-γ (PPAR-γ) (Kim et al., 2015). Primary signals that upregulate inflammatory mediators include damage-associated molecular patterns (DAMPs) (Macrez et al., 2011; Bonaventura et al., 2016). Other signals are hyaluronan and pathogen-associated molecular patterns (PAMPs). Many DAMPs and PAMPS are sensed by TLRs (Macrez et al., 2011). The M1 phenotype promotes the release of inflammatory mediators such as nitric oxide and ROS. This leads to increased cell death and blood–brain barrier dysfunction, triggering the release of chemokines, activating matrix metalloproteinase (MMP)-9, and upregulating adhesion molecules. The M2 phenotype is activated by anti-inflammatory cytokines such as interleukin-4, which may inhibit inflammation and promote tissue repair and wound healing (Macrez et al., 2011; Kim et al., 2015; Bonaventura et al., 2016). The development of novel neuroprotective strategies to target key steps in this cascade may represent promising therapeutic options. Therefore, this review explores potential neuroprotective strategies for halting the cascade of I/R injury. These neuroprotective strategies include NADPH oxidase (NOX) inhibitors and drugs currently approved by the Food and Drug Administration to treat other diseases but show promise as new drugs for the treatment of stroke in animal experiments and clinical trials. Ischemic conditioning may be another neuroprotective strategy for stroke.

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