Implications for hyperhomocysteinemia: not homocysteine but its oxidized forms strongly inhibit neuronal network activity

Görtz, Philipp; Hoinkes, A.; Fleischer, Wiebke; Otto, F.; Schwahn, Bernd; Wendel, U.; Siebler, Mario

doi:10.1016/j.jns.2003.11.009

Cited by 52 publications

(28 citation statements)

References 31 publications

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“…Moreover, recent results demonstrated that the reduction in folate and vitamin B12 in culture medium produced an increase in pre-senilin 1 and beta-amyloid production (Fuso et al 2005). Several findings from in vitro models demonstrate that metabolites of Hcy, such as homocysteic acid, causes receptormediated elevation of intracellular Ca 2+ , leading to ROS production and cell death (Gortz et al 2004;Boldyrev et al 2005). Such signaling processes may also exist in circulating lymphocytes, considering that much attention has recently been focused on the existence of non-neural glutamate receptors in T-lymphocytes (Lombardi et al 2001;Pacheco et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Homocysteine induces DNA damage and alterations in proliferative capacity of T-lymphocytes: a model for immunosenescence?

et al. 2006

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Homocysteine (Hcy) appears to exert different effects on immune functions possibly contributing to age-related pathological states, including vascular diseases, immune dysfunction, and Alzheimer's disease. However, molecular mechanisms underlying Hcy toxicity need to be better characterized. Since T cells are a suitable model to address the possible role of replicative senescence during the in vivo aging, we investigated the effects of high Hcy concentrations on mitogen-activated lymphocytes, with regard to evaluation of DNA damage and cell cycle alterations. Cultured human peripheral blood lymphocytes were stimulated with mitogenic concanavalin A (5 microg/ml) for 48 h in the presence or absence of Hcy (1 mM). Both flow cytometric analysis and caspase-3 activity assay showed an increased rate of apoptosis in Hcy-treated lymphocyte cultures compared to controls. Further, Hcy exposure caused DNA fragmentation as evaluated by single cell gel electrophoresis showing the occurrence of comets. Cytokinesis-block micronucleus assay, performed after addition of cytochalasin B (5 microg/ml) and incubation up to 72 h, revealed a significantly higher frequency of micronucleated/binucleated cells in Hcy-treated cultures compared to controls (P < 0.001). Hcy also reduced cyclin B expression in comparison to control cultures, while cyclin D levels were not significantly affected. Cell cycle alterations, such as the inability of cells to enter into mitosis, could be related with DNA damage. These findings provided a link between perturbation of lymphocyte proliferation homeostasis and commitment towards apoptosis. Our results suggest the involvement of Hcy in the altered immune function associated with age and disease pathology.

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Section: Discussionmentioning

confidence: 99%

Homocysteine induces DNA damage and alterations in proliferative capacity of T-lymphocytes: a model for immunosenescence?

et al. 2006

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“…After that, abundant epidemiological evidence from more case studies involving over 2000 patients has been done to verify this relationship (Ueland et al, 1992 andStampfer andMalinow, 1995). Many investigators reported that patients with hyperhomocysteinemia have cerebrovascular disease and peripheral vascular disease (Boers et al, 1985); coronary artery disease (Clarke et al, 1991); atherosclerosis (Graham et al, 1997); vascular dementia and Alzheimer's disease (Refsum and Ueland, 1990;Diaz-Arrastia, 2000;Seshadri et al, 2002;Gortz et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Protective effects of Danshensu from the aqueous extract of Salvia miltiorrhiza (Danshen) against homocysteine-induced endothelial dysfunction

et al. 2004

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“…At physiological concentrations, the oxidised derivatives homocysteic acid and homocysteine sulphinic acid over-stimulate NMDA receptors (Gortz et al, 2004). By contrast memantine, an NMDA receptor antagonist (Lipton, 2005), has small but positive effects on outcome to treatment in combination with donepezil (Tariot et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

A randomised double‐blind placebo‐controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer's disease

Connelly

Prentice

Cousland

et al. 2007

Int J Geriat Psychiatry

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Implications for hyperhomocysteinemia: not homocysteine but its oxidized forms strongly inhibit neuronal network activity

Cited by 52 publications

References 31 publications

Homocysteine induces DNA damage and alterations in proliferative capacity of T-lymphocytes: a model for immunosenescence?

Homocysteine induces DNA damage and alterations in proliferative capacity of T-lymphocytes: a model for immunosenescence?

Protective effects of Danshensu from the aqueous extract of Salvia miltiorrhiza (Danshen) against homocysteine-induced endothelial dysfunction

A randomised double‐blind placebo‐controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer's disease

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