Mechanisms involved in the ischemic tolerance in brain: effect of the homocysteine

Abstract

Hyperhomocysteinemia (hHCy) is recognized as a co-morbid risk factor of human stroke. It also aggravates the ischemia-induced injury by increased production of reactive oxygen species, and by the homocysteinylation and thiolation of functional proteins. Ischemic preconditioning represents adaptation of the CNS to sub-lethal ischemia, resulting in increased brain tolerance to subsequent ischemia. We present here an overview of recent data on the homocysteine (Hcy) metabolism and on the genetic and metabolic causes of hHCy-related neuropathologies in humans. In this context, the review documents for an increased oxidative stress and for the functional modifications of enzymes involved in the redox balance in experimentally induced hHCy. Hcy metabolism leads also to the redox imbalance and increased oxidative stress resulting in elevated lipoperoxidation and protein oxidation, the products known to be included in the neuronal degeneration. Additionally, we examine the effect of the experimental hHCy in combination with ischemic insult, and/or with the preischemic challenge on the extent of neuronal degeneration as well as the intracellular signaling and the regulation of DNA methylation. The review also highlights that identification of the effects of co-morbid factors in the mechanisms of ischemic tolerance mechanisms would lead to improved therapeutics, especially the brain tissue.

Fig. 1

Pathways and the mechanisms of Hcy toxicity leading to the stroke. SAM-S-adenosyl methionine, SAH-S-adenosyl Hcy, hHCy hyperhomocysteinemia. Increased dietary intake of methionine and deficiency of vitamine B₆, B₁₂, and folate leads in the predisposed individual to hHCy. Prolonged elevated level of Hcy initiates complex processes which include oxidative stress, protein homocysteinylation, and Ca²⁺ dysregulation. These events in parallel with epigenetic changes can finalize to apoptosis and blood–brain dysregulation manifested as stroke

Fig. 2

Overview of the Hcy metabolism and the role of dietary vitamins. Dietary methionine acts as a methyl donor via conversion of S-adenosyl methionine (SAM) to S-adenosyl Hcy (SAH). SAH by release of Adenosine produces Hcy. Methionine is directly converted to Hcy in the presence of methyl tetrahydrofolic acid (methyl THF) and vitamine B₆. Conversion of Hcy to cysteine requires vitamine B₆

Fig. 3

Mechanisms leading to the Hcy neurotoxicity and the protection induced by IPC in hyperhomocysteinemic conditions. (+): increased number of cells (activity), (−): decreased number of cells (activity). Hcy induced neurotoxicity includes dysregulation in redox balance, lipo- and protein oxidation and Ca²⁺ pump dysfunction which is detected in sensitive cells by increased Fluoro-Jade B staining and TUNEL analysis. IPC suppresses oxidative dysregulation which leads to lower Fluoro-Jade B and TUNEL positivities in sensitive cells