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[Hyperhomocysteinemia: atherothrombosis and neurotoxicity].

Abstract

The positive correlation existing between hyperhomocyst(e)inemia [HH(e)] and vascular disease has firmly been established through data derived from numerous epidemiological and experimental observations. Clinical data corroborate that homocysteine (Hcy) is an independent risk factor for coronary, cerebral and peripheral arterial occlusive disease or peripheral venous thrombosis. Hcy is a sulfhydryl-containing amino acid that is formed by the demethylation of methionine. It is normally catalyzed to cystathionine by cystathionine beta-synthase a pyridoxal phosphate-dependent enzyme. Hcy is also remethylated to methionine by 5-methyltetrahydrofolate-Hcy methyltransferase (methionine synthase), a vitamin B12 dependent enzyme and by betaine-Hcy methyltransferase. Nutritional status such as vitamin B12, or vitamin B6, or folate deficiencies and genetic defects such as cystathionine beta-synthase or methylene-tetrahydrofolate reductase may contribute to increasing plasma homocysteine levels. The pathogenesis of Hcy-induced vascular damage may be multifactorial, including direct Hcy damage to the endothelium, stimulation of proliferation of smooth muscle cells, enhanced low-density lipoprotein peroxidation, increase of platelet aggregation, and effects on the coagulation system. Besides adverse effects on the endothelium and vessel wall, Hcy exert a toxic action on neuronal cells trough the stimulation of N-methyl-D-aspartate (NMDA) receptors. Under these conditions, neuronal damage derives from excessive calcium influx and reactive oxygen generation. This mechanism may contribute to the cognitive changes and markedly increased risk of cerebrovascular disease in children and young adults with homocystunuria. Moreover, during stroke, in hiperhomocysteinemic patients, disruption of the blood-brain barrier results in exposure of the brain to near plasma levels of Hcy. The brain is exposed to 15-50 microM H(e). Thus, the neurotoxicity of Hcy acting through the overstimulation of NMDA receptors could contribute to neuronal damage in homocystinuria and HH(e). Since HH(e) is associated with certain neurodegeneratives diseases, in the present review, the molecular mechanisms involved in neurotoxicity due to Hcy are discussed.

Authors+Show Affiliations

Departamento de Investigaciones Diagnósticas, Centro de Investigaciones Médicas Albert Einstein, Fundacion CIMAE, Buenos Aires, Argentina.

Pub Type(s)

English Abstract
Journal Article
Review

Language

spa

PubMed ID

10797837

Citation

Fridman, O. "[Hyperhomocysteinemia: Atherothrombosis and Neurotoxicity]." Acta Physiologica, Pharmacologica Et Therapeutica Latinoamericana : Organo De La Asociacion Latinoamericana De Ciencias Fisiologicas Y [de] La Asociacion Latinoamericana De Farmacologia, vol. 49, no. 1, 1999, pp. 21-30.
Fridman O. [Hyperhomocysteinemia: atherothrombosis and neurotoxicity]. Acta Physiol Pharmacol Ther Latinoam. 1999;49(1):21-30.
Fridman, O. (1999). [Hyperhomocysteinemia: atherothrombosis and neurotoxicity]. Acta Physiologica, Pharmacologica Et Therapeutica Latinoamericana : Organo De La Asociacion Latinoamericana De Ciencias Fisiologicas Y [de] La Asociacion Latinoamericana De Farmacologia, 49(1), pp. 21-30.
Fridman O. [Hyperhomocysteinemia: Atherothrombosis and Neurotoxicity]. Acta Physiol Pharmacol Ther Latinoam. 1999;49(1):21-30. PubMed PMID: 10797837.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - [Hyperhomocysteinemia: atherothrombosis and neurotoxicity]. A1 - Fridman,O, PY - 2000/5/8/pubmed PY - 2000/5/20/medline PY - 2000/5/8/entrez SP - 21 EP - 30 JF - Acta physiologica, pharmacologica et therapeutica latinoamericana : organo de la Asociacion Latinoamericana de Ciencias Fisiologicas y [de] la Asociacion Latinoamericana de Farmacologia JO - Acta Physiol Pharmacol Ther Latinoam VL - 49 IS - 1 N2 - The positive correlation existing between hyperhomocyst(e)inemia [HH(e)] and vascular disease has firmly been established through data derived from numerous epidemiological and experimental observations. Clinical data corroborate that homocysteine (Hcy) is an independent risk factor for coronary, cerebral and peripheral arterial occlusive disease or peripheral venous thrombosis. Hcy is a sulfhydryl-containing amino acid that is formed by the demethylation of methionine. It is normally catalyzed to cystathionine by cystathionine beta-synthase a pyridoxal phosphate-dependent enzyme. Hcy is also remethylated to methionine by 5-methyltetrahydrofolate-Hcy methyltransferase (methionine synthase), a vitamin B12 dependent enzyme and by betaine-Hcy methyltransferase. Nutritional status such as vitamin B12, or vitamin B6, or folate deficiencies and genetic defects such as cystathionine beta-synthase or methylene-tetrahydrofolate reductase may contribute to increasing plasma homocysteine levels. The pathogenesis of Hcy-induced vascular damage may be multifactorial, including direct Hcy damage to the endothelium, stimulation of proliferation of smooth muscle cells, enhanced low-density lipoprotein peroxidation, increase of platelet aggregation, and effects on the coagulation system. Besides adverse effects on the endothelium and vessel wall, Hcy exert a toxic action on neuronal cells trough the stimulation of N-methyl-D-aspartate (NMDA) receptors. Under these conditions, neuronal damage derives from excessive calcium influx and reactive oxygen generation. This mechanism may contribute to the cognitive changes and markedly increased risk of cerebrovascular disease in children and young adults with homocystunuria. Moreover, during stroke, in hiperhomocysteinemic patients, disruption of the blood-brain barrier results in exposure of the brain to near plasma levels of Hcy. The brain is exposed to 15-50 microM H(e). Thus, the neurotoxicity of Hcy acting through the overstimulation of NMDA receptors could contribute to neuronal damage in homocystinuria and HH(e). Since HH(e) is associated with certain neurodegeneratives diseases, in the present review, the molecular mechanisms involved in neurotoxicity due to Hcy are discussed. SN - 0327-6309 UR - https://www.unboundmedicine.com/medline/citation/10797837/[Hyperhomocysteinemia:_atherothrombosis_and_neurotoxicity]_ L2 - https://medlineplus.gov/vasculardiseases.html DB - PRIME DP - Unbound Medicine ER -