Why Is Homocysteine Toxic for the Nervous and Immune Systems?

Abstract

Hyperhomocysteinemia is a risk factor for a number of neurodegenerative and cardiovascular diseases. We have shown that homocysteine induces excitotoxic effects in cells expressing glutamate receptors of the NMDA class. These receptors were found not only in neurons but also in immune-competent cells, neutrophils, red blood cells, cardiomyocytes, and osteoblasts. Activation of these cells by homocysteine results in an increase in cytoplasmic calcium ions, accumulation of reactive oxygen species, and activation of MAP kinase. An overload of immune-competent cells activates both necrotic and apoptotic cell death, whereas the neuropeptide carnosine (an antioxidant and immune modulator) protects cells against both processes. In a model of prenatal hyperhomocysteinemia in rats, we have found that carnosine protects animals against homocysteine toxicity with no change of the blood homocysteine levels. The efficiency of carnosine has also been demonstrated in clinical trials of chronic brain ischemia and Parkinson's disease.

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

“…Autooxidation of Hcy metabolites leads to the accumulation of strong oxidizing agent, H 2 O 2 . The necrotic death of neurons was induced after long term incubation of cells with Hcy metabolites [43]. Accumulation of the oxidized biomolecules modifies the biological functions of many cellular pathways.…”

“…In addition, Hcy acts an agonist for both groups of glutamate receptors, metabotropic (groups I and III) and ionotropic (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)) receptors, as well as for N -methyl- d -aspartate receptor (NMDA) [43]. Overstimulation of these receptors results in increased level of cytoplasmic calcium, higher production of free radicals and activation of caspases leading to apoptosis [19,43,46].…”

“…In addition, Hcy acts an agonist for both groups of glutamate receptors, metabotropic (groups I and III) and ionotropic (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)) receptors, as well as for N -methyl- d -aspartate receptor (NMDA) [43]. Overstimulation of these receptors results in increased level of cytoplasmic calcium, higher production of free radicals and activation of caspases leading to apoptosis [19,43,46]. Hcy mediated NMDA receptor induction of neuronal cells could lead to their death due to transient activation of extracellular signal-regulated kinases (ERKs), mitogen-activated protein kinase (MAPK) and p38 MAPK [47,48] that is different from downstream signaling pathways triggered by other NMDA receptor agonists.…”

A Human-Based Integrated Framework forAlzheimer’s Disease Research

“…The presence of high levels of both plasma and brain homocysteine (HCys) is correlated to AD and neurodegenerative disorders. Elevated HCys in brain microvessels may be implicated in the disruption of the blood-brain barrier [51] and induction of excitotoxicity in cells expressing glutamate receptors of the N-methyl-D-aspartate class [52]. Other biomarkers considered relevant to AD are: low levels of plasma uric acid [53,54], high levels of serum 3,4-dihydroxybutanoic acid (C 4 H 8 O 4 ), docosapentaenoic acid (C22:5) [55], and hexacosanoic acid (C26:0) [56], the presence of insulin resistance and high insulin-like growth factor expression [57][58][59], impaired glycemic levels [60], mitochondrial damage and increased mitochondrial O-linked N-acetylglucosamine transferase activity [61], the presence of a dyslipidemic profile [31,[62][63][64][65][66], deregulation of plasma orexin [67][68][69][70], and high levels of the secreted heparin-binding glycoprotein YKL-40 [71,72] (Table 2).…”

Carnosine and Related Peptides: Therapeutic Potential in Age-Related Disorders

“…Homocysteine activates cells expressing Nmethyl-D-aspartic acid (NMDA) receptors (e.g., neurons) and elicits Ca 2+ and ROS intracellular accumulation [97]. Carnosine significantly prevented the cells expressing NMDA receptors from excitotoxic damage mediated by NMDA and homocysteine [98], and it cannot be ruled out that this effect may be, at least in part, mediated by antioxidant and chelating ability of carnosine towards ROS and Ca 2+ . Other possible mechanisms for the biological activity of carnosine in PD may be acknowledged in the review performed by Hipkiss and coworkers (2013), which emphasizes the putative role of the MG in the pathogenesis of such disorder.…”