Forebrain Ischemic Stroke and the Phenomenon of Ischemic Tolerance: Is Homocysteine Foe or Friend?

Hyperhomocysteinemia (hHCy) is a recognized comorbid risk factor of human brain stroke. We overview here the recent data on the homocysteine (Hcy) metabolism and on the genetic and metabolic causes of hHCy‐related neuropathologies. In context of our results which detected an increased oxidative stress in hyperhomocysteinemic rats, we discuss here the role of free radicals in this disorder. Brain ischemia‐reperfusion causes delayed neuronal death. Ischemic tolerance evoked by preconditioning (IPC) represents a phenomenon of central nervous system (CNS) adaptation to any subsequent ischemia. The paper describes changes in the mitogen‐activated protein kinases (MAPKs) protein pathways, and apoptotic markers were used to follow the degeneration process. Our studies provide evidence for the interplay and tight integration between extracellular signal‐regulated kinase (ERK) and p38 MAPKs signaling mechanisms in response to the hHCy and also in association with brain ischemia/IPC challenge. Recognition of the effects of risk factors in the ischemic tolerance would lead to improved therapeutics, especially the brain tissue

Histone Hyperacetylation as a Response to Global Brain Ischemia Associated with Hyperhomocysteinemia in Rats

Epigenetic regulations play an important role in both normal and pathological conditions of an organism, and are influenced by various exogenous and endogenous factors. Hyperhomocysteinemia (hHcy), as a risk factor for several pathological conditions affecting the central nervous system, is supposed to alter the epigenetic signature of the given tissue, which therefore worsens the subsequent damage. To investigate the effect of hHcy in combination with ischemia-reperfusion injury (IRI) and histone acetylation, we used the hHcy animal model of global forebrain ischemia in rats. Cresyl violet staining showed massive neural disintegration in the M1 (primary motor cortex) region as well as in the CA1 (cornu ammonis 1) area of the hippocampus induced by IRI. Neural loss was significantly higher in the group with induced hHcy. Moreover, immunohistochemistry and Western blot analysis of the brain cortex showed prominent changes in the acetylation of histones H3 and H4, at lysine 9 and 12, respectively, as a result of IRI and induced hHcy. It seems that the differences in histone acetylation patterns in the cortical region have a preferred role in pathological processes induced by IRI associated with hHcy and could be considered in therapeutic strategies