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.

The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health

“…Accumulation of the oxidized biomolecules modifies the biological functions of many cellular pathways. Several mechanisms have been proposed for Hcy induced oxidative stress: (i) Hcy autoxidation; (ii) inhibition of the enzymatic activity of antioxidants in cells; (iii) disruption of extracellular superoxide dismutase from endothelial surfaces; (iv) activation of NADPH oxidases; and (v) nitric oxide synthase (NOS)-dependent generation of superoxide anion [44]. Moreover, reactive oxygen species and oxidative stress lead to the formation of nitrotyrosine, an indicator of nitric oxide and superoxide radical reaction, resulting in the formation of strong oxidant peroxynitrite.…”

“…Moreover, hHCy can often results in intracellular Ca 2+ mobilization and endoplasmic reticulum stress followed with the subsequent development of apoptotic events, remodeling of extracellular matrix in brain parenchyma and endothelial dysfunction [34,44,46]. In humans, the increased level of Ca 2+ damages mitochondria by collapsing the mitochondrial membrane potential and the production of ATP is suppressed.…”

“…Today, it is widely accepted that an elevated level of Hcy (more than 15 μM) is an independent risk factor for cardio and cerebrovascular diseases. Recent studies have demonstrated a strong correlation between elevated Hcy levels and neurological disorders, chronic kidney disease, osteoporosis, gastrointestinal disorders, cancer and congenital defects development [44,61,62,63,64]. …”

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

“…Homocysteine is converted in error editing reaction to homocysteine thiolactone. Conversion of homocysteine to cysteine requires vitamin B 6 (Kalani et al, 2013; Petras et al, 2014; Lehotsky et al, 2015). Adapted from Lehotsky et al (2015).…”

“…A prolonged elevated level of homocysteine initiates complex processes which include oxidative stress, protein homocysteinylation and Ca 2+ dysregulation. These events in parallel with epigenetic changes can culminate in apoptosis, neuronal death and blood-brain barrier dysregulation manifested as ischemic stroke (Kalani et al, 2013; Petras et al, 2014; Kovalska et al, 2015; Lehotsky et al, 2015; Škovierová et al, 2015). Adapted from Lehotsky et al (2015).…”