Role of Homocysteine in the Ischemic Stroke and Development of Ischemic Tolerance

Someplace in all these big words is some useful information to be acted upon, which will never occur.  You put an RFP out to researchers, pay for it with foundation grants and write the results up in a stroke protocol available in a public database.  
http://journal.frontiersin.org/article/10.3389/fnins.2016.00538/full?

Ján Lehotský^1*, Barbara Tothová¹, Maria Kovalská^1,2, Dušan Dobrota¹, Anna Beňová¹, Dagmar Kalenská¹ and Peter Kaplán¹

• ¹Institute of Medical Biochemistry and BioMed, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
• ²Institute of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia

Homocysteine (Hcy) is a toxic, sulfur-containing intermediate of methionine metabolism. Hyperhomocysteinemia (hHcy), as a consequence of impaired Hcy metabolism or defects in crucial co-factors that participate in its recycling, is assumed as an independent human stroke risk factor. Neural cells are sensitive to prolonged hHcy treatment, because Hcy cannot be metabolized either by the transsulfuration pathway or by the folate/vitamin B12 independent remethylation pathway. Its detrimental effect after ischemia-induced damage includes accumulation of reactive oxygen species (ROS) and posttranslational modifications of proteins via homocysteinylation and thiolation. Ischemic preconditioning (IPC) is an adaptive response of the CNS to sub-lethal ischemia, which elevates tissues tolerance to subsequent ischemia. The main focus of this review is on the recent data on homocysteine metabolism and mechanisms of its neurotoxicity. In this context, the review documents an increased oxidative stress and functional modification of enzymes involved in redox balance in experimentally induced hyperhomocysteinemia. It also gives an interpretation whether hyperhomocysteinemia alone or in combination with IPC affects the ischemia-induced neurodegenerative changes as well as intracellular signaling. Studies document that hHcy alone significantly increased Fluoro-Jade C- and TUNEL-positive cell neurodegeneration in the rat hippocampus as well as in the cortex. IPC, even if combined with hHcy, could still preserve the neuronal tissue from the lethal ischemic effects. This review also describes the changes in the mitogen-activated protein kinase (MAPK) protein pathways following ischemic injury and IPC. These studies provide evidence for the interplay and tight integration between ERK and p38 MAPK signaling mechanisms in response to the hHcy and also in association of hHcy with ischemia/IPC challenge in the rat brain. Further investigations of the protective factors leading to ischemic tolerance and recognition of the co-morbid risk factors would result in development of new avenues for exploration of novel therapeutics against ischemia and stroke.

Introduction

Many experimental and clinical studies provide evidence that co-morbid disorders are potential risk factors for development of vascular disorders in humans including stroke (Lehotský et al., 2009a; Kwon et al., 2014). At present, there are several known factors elevating the risk of ischemic stroke which include transient ischemic attack (TIA), arterial diseases, atrial fibrillation, improper diet and/or obesity and physical inactivity (Dirnagl et al., 2009). As it has been verified by many studies, even mild hyperhomocysteinemia (hHcy) may increase the risk for clinical manifestations of stroke, probably due to the pleiotropic biochemical properties of homocysteine (Hcy) and its impact on venous and arterial atherosclerotic modifications (Refsum et al., 1998; Steele et al., 2013; Kwon et al., 2014; Petras et al., 2014; Williams et al., 2014). In fact, Hcy suppresses NO production by endothelial cells and platelets and increases generation of reactive oxygen species (ROS) by the release of arachidonic acid from the platelets. It also inhibits glutathione peroxidase and thus stimulates proliferation of endothelial cells (see Petras et al., 2014, for review). In addition, Hcy has been shown to inhibit methyltransferases, to suppress DNA repair and to facilitate apoptosis when accumulated inside the cells. Autooxidation of Hcy metabolites results in H₂0₂ accumulation (Boldyrev et al., 2013) and challlenging neurons to Hcy metabolites for longer period leads to necrotic cell death (Ziemińska et al., 2003). Clinical studies suggest that elevated homocysteine level frequently parallels progressive aging as well as neurodegenerative and acute disorders of the CNS, e.g., Alzheimer's disease or Parkinson's disease (Dionisio et al., 2010). Designing appropriate animal models relevant to the clinical conditions of human stroke is an important step for studying the disease ethiology. Until now, only sparse studies have been developed to explore the mutual effect of HCy and ischemic preconditioning (IPC) in animal models of ischemic stroke.

In this paper we summarize current overview on homocysteine conversion steps in the organism and present the genetic and metabolic causes of hyperhomocysteinemia-related neurotoxicity. Based on the results from our laboratory, we also document, in this context, that mutual effect of experimental hyperhomocysteinemia (hHCy) and ischemic insult with or without pre-ischemic challenge can have different outcomes on the extent of neuronal degeneration as well as on the intracellular signaling pathways leading to the preconditioning phenomenon.

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