Nitric Oxide Donors as Neuroprotective Agents after an Ischemic Stroke-Related Inflammatory Reaction

Abstract

Cerebral ischemia initiates a cascade of detrimental events including glutamate-associated excitotoxicity, intracellular calcium accumulation, formation of Reactive oxygen species (ROS), membrane lipid degradation, and DNA damage, which lead to the disruption of cellular homeostasis and structural damage of ischemic brain tissue. Cerebral ischemia also triggers acute inflammation, which exacerbates primary brain damage. Therefore, reducing oxidative stress (OS) and downregulating the inflammatory response are options that merit consideration as potential therapeutic targets for ischemic stroke. Consequently, agents capable of modulating both elements will constitute promising therapeutic solutions because clinically effective neuroprotectants have not yet been discovered and no specific therapy for stroke is available to date. Because of their ability to modulate both oxidative stress and the inflammatory response, much attention has been focused on the role of nitric oxide donors (NOD) as neuroprotective agents in the pathophysiology of cerebral ischemia-reperfusion injury. Given their short therapeutic window, NOD appears to be appropriate for use during neurosurgical procedures involving transient arterial occlusions, or in very early treatment of acute ischemic stroke, and also possibly as complementary treatment for neurodegenerative diseases such as Parkinson or Alzheimer, where oxidative stress is an important promoter of damage. In the present paper, we focus on the role of NOD as possible neuroprotective therapeutic agents for ischemia/reperfusion treatment.

Ischemia/reperfusion-induced upregulation of TIGAR in brain is mediated by SP1 and modulated by ROS and hormones involved in glucose metabolism

“…Ischemia/reperfusion insult promotes the release of large amounts of hormones from cells, including adrenaline (Kanda and Watanabe, 2007), glucagon (Thorens, 2011) and glucocorticoid, such as hydrocortisone (Kainuma et al, 2009), all of which can raise the blood glucose levels or influence glucose metabolism (Costa et al, 2007;Godinez-Rubi et al, 2013). We thus investigated if these hormones would regulate the expression of TIGAR during reperfusion.…”

Participation of NO-synthase in Control of Nitric Oxide Level in Rat Hippocampus after Modelling of Ischaemic and Haemorrhagic Insult

“…It has been shown that the use of inhibitors of NOS L-NNA and L-NAME does not reduce the size (volume) of infarction in a model of focal cerebral ischaemia in the rat (Dawson et al 1992, Sancesario et al 1994 and, on the contrary, increases the focal ischaemic stroke (Yamamoto et al 1992). NO donors are used as neuroprotective agents at ischaemic injury (Evgenov et al 2006, Godínez-Rubí et al 2013. Based on the time course of ischaemia-induced changes in NO levels and NOS regulation in the brain and cerebral blood vessels, several strategies have been suggested to manipulate the NO system for the treatment of strokes (Bolaños and Almeida 1999).…”

“…The problem of cerebral ischaemia is most acute in the world (Donnan et al 2008, Lambertsen et al 2012, Godínez-Rubí et al 2013. Accumulating experience of observations shows that the ischaemic injury and inflammation account for the pathogenic progression of the stroke (Yilmaz andGranger 2008, Yang et al 2011).…”

“…NO, synthesised by constitutive isoforms of NO-synthases (NOS), provides an adequate blood supply to the brain regions, affects the activity of neurons and regulates cell metabolism (Forstermann and Sessa 2011). On the other hand, there is no doubt that the role of the NO system in the pathogenesis of a number of diseases associated with vascular disorders is defining , Terpolilli et al 2012, Godínez-Rubí et al 2013. Previously, by the methods of EPR spectroscopy, our team has evaluated the effect of ischaemic stroke on the intensity of NO production in the tissues of the brain, heart and liver of rats in vivo (Andrianov et al 2016).…”

Nitric oxide plays a dual role in the oxidative injury of cultured rat microglia but not astroglia

“…Several lines of evidence suggest that NO enhances oxidative damage evoked by hydrogen peroxide (H 2 O 2 ) in vascular and rat hepatoma cells (Ioannidis and de Groot, 1993;Zhou et al, 2013); however, NO is protective against ROS-mediated cell death, as evidenced by NO-mediated suppression of heart hypoxia/reoxygenation or liver ischemia-reperfusion injury (Korge et al, 2008;Kuo et al, 2013). In neurons, NO can be either protective or detrimental to ROS toxicity, which depends on several critical factors, including the source (e.g., neuronal, glial or endothelial NOS), concentration and oxidation-reduction status of NO, the type, time length and severity of the ROS insult, and the use of experimental animal species/cell types (Mohanakumar et al, 1998;Wei et al, 2000;Calabrese et al, 2007;Allen et al, 2009;Godinez-Rubi et al, 2013). Nevertheless, to our knowledge, the effects of NO on oxidative toxicity in glial cells remain unclear.…”