Studies on homocysteine plasma levels in Alzheimer?s patients. Relevance for neurodegeneration

Agnati, Luigi F.; Genedani, Susanna; Rasio, G.; Galantucci, Maria; Saltini, Sabrina; Filaferro, Monica; Franco, Rafael; Mora, Francisco; Ferré, Sergi; Fuxé, Kjell

doi:10.1007/s00702-004-0154-7

Cited by 39 publications

(26 citation statements)

References 14 publications

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“…Amyloidosis is accelerated in a mouse model of Alzheimer;s disease (Tg2576 mice) when they are fed a HHcy diet (low folate, vitamin B 6 , and vitamin B 12 ) (185). Hcy is a major risk factor for dementia (4,8,26,49,102,111,141,165). Even mildly elevated Hcy (Ͼ14 mol/l) creates a twofold increase in the risk of dementia with a significant correlation between [Hcy] and cognitive impairment (47,141).…”

Section: Neurological and Neurovascular Disorders In Cbs Deficiencymentioning

confidence: 99%

“…Hcy has two fates in mammals: remethylation to methionine or transsulfuration to cysteine. The elevation of Hcy levels in plasma, hyperhomocysteinemia (HHcy), is an independent and graded risk factor for both cardiovascular (CVD) (61a, 166) and neurovascular (NVD) diseases (4,58,61,86,92,102,131,138,153,187). HHcy is caused by genetic deficiencies in the enzymes responsible for remethylation or transsulfuration of Hcy, nutritional deficiencies in vitamins serving as cofactors for these enzymes, and transient HHcy by dietary overload of methionine-rich foods (e.g., meats, dairy products, sesame seeds).…”

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confidence: 99%

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Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research

Beard

Bearden

2011

American Journal of Physiology-Heart and Circulatory Physiology

104

110

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Homocysteine (Hcy), a cardiovascular and neurovascular disease risk factor, is converted to hydrogen sulfide (H(2)S) through the transsulfuration pathway. H(2)S has attracted considerable attention in recent years for many positive effects on vascular health and homeostasis. Cystathionine β-synthase (CBS) is the first, and rate-limiting, enzyme in the transsulfuration pathway. Mutations in the CBS gene decrease enzymatic activity, which increases the plasma Hcy concentration, a condition called hyperhomocysteinemia (HHcy). Animal models of CBS deficiency have provided invaluable insights into the pathological effects of transsulfuration impairment and of both mild and severe HHcy. However, studies have also highlighted the complexity of HHcy and the need to explore the specific details of Hcy metabolism in addition to Hcy levels per se. There has been a relative paucity of work addressing the dysfunctional H(2)S production in CBS deficiency that may contribute to, or even create, HHcy-associated pathologies. Experiments using CBS knockout mice, both homozygous (-/-) and heterozygous (+/-), have provided 15 years of new knowledge and are the focus of this review. These murine models present the opportunity to study a specific mechanism for HHcy that matches one of the etiologies in many human patients. Therefore, the goal of this review was to integrate and highlight the critical information gained thus far from models of CBS deficiency and draw attention to critical gaps in knowledge, with particular emphasis on the modulation of H(2)S metabolism. We include findings from human and animal studies to identify important opportunities for future investigation that should be aimed at generating new basic and clinical understanding of the role of CBS and transsulfuration in cardiovascular and neurovascular disease.

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Section: Neurological and Neurovascular Disorders In Cbs Deficiencymentioning

confidence: 99%

mentioning

confidence: 99%

Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research

Beard

Bearden

2011

American Journal of Physiology-Heart and Circulatory Physiology

104

110

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“…It was in accordance with previous reports that the expression of apoptosis regulatory proteins, Bax and Bcl-2, would be altered by Hcy (15). It was also suggested that Hcy generates reactive oxygen species, which attacks the polyunsaturated fatty acids of neuronal cell membranes and induces lipid peroxidation in the hippocampus (16). Hcy is a non-protein amino acid, or thiol-containing amino, which is derived from methionine (17).…”

Section: Discussionmentioning

confidence: 99%

Morphine pre- and post-conditioning exacerbates apoptosis in rat hippocampus cells in a model of homocysteine-induced oxidative stress

2017

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Abstract. Recent investigations indicated that morphine has protective effects in different ischemia/reperfusion models and may protect against neuronal cell death, while other evidence showed that morphine induces apoptosis in neurons. Therefore, the current study was conducted to investigate preand post-conditioning effects of morphine on hippocampal cell apoptosis in a rat model of homocysteine (Hcy)-induced oxidative stress. In the present study, 0.5 µmol/µl Hcy was injected into bilateral intrahipocampal in the rat brain and morphine at a therapeutic dose of 10 mg/kg was injected intraperitoneally 5 days before and after Hcy injection in rats. The left and right rat hippocampus were removed for biochemical and histopathological analysis. In addition, hippocampal cell apoptosis was assayed by the TUNEL kit. Our results indicated that malondialdehyde (MDA) and superoxide anion (SOA) levels in the Hcy group were increased significantly compared to the control group (P<0.001). In addition, morphine pre-and post-treatment increased the MDA and SOA levels significantly in rat hippocampus compared with other groups (P<0.001). It was found that Hcy alone induced apoptosis in hippocampus cells and significantly increased the number of TUNEL-positive cells in rat hippocampus compared to the other group (P<0.001). Notably, our results indicated that pre-and post-treatment by morphine increased apoptosis in hippocampus cells compared with the other group (P<0.001). In conclusion, morphine neuroprotection and neurotoxicity needs to be further investigated to determine morphine side-effects in medical applications and to identify new targets for potential therapies.

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“…Hcy is a non-essential sulphur-containing amino acid, produced as a natural consequence of methionine metabolism, and its accumulation in the brains of aged individuals appears to be a strong independent risk factor for dementia and other neurodegenerative diseases [27][28][29]. Hcy treatment of cultured cortical neurons caused apoptosis in a dose-dependent manner (Fig.…”

Section: Resultsmentioning

confidence: 96%

Chk1 has an essential role in the survival of differentiated cortical neurons in the absence of DNA damage

Blain

2011

Apoptosis

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Neuronal death in the central nervous system contributes to the development of age-related neurodegeneration. The ATR/Chk1 pathway appears to function neuroprotectively to prevent DNA damage induced by cytotoxic agents. Here, we examine the function of Chk1 on cell viability of cortical neurons in the absence of additional DNA damaging stimuli. The Chk1-specific inhibitor, UCN-01, and the ATR inhibitor, Caffeine, cause neuronal apoptosis in differentiated neurons in the absence of additional treatment, whereas inhibition of ATM or Chk2, does not. UCN-01 treatment increased the detection of γ-H2AX phosphorylation, DNA strand breaks, and an activated p53-dependent DNA damage response (DDR), suggesting that Chk1 normally helps to maintain genomic stability. UCN-01 treatment also enhanced the apoptosis seen in neurons treated with DNA damaging agents, such as camptothecin (CPT). Our results indicate that Chk1 is essential for neuronal survival, and perturbation of this pathway increases a cell's sensitivity to naturally accumulating DNA damage.

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Studies on homocysteine plasma levels in Alzheimer?s patients. Relevance for neurodegeneration

Cited by 39 publications

References 14 publications

Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research

Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research

Morphine pre- and post-conditioning exacerbates apoptosis in rat hippocampus cells in a model of homocysteine-induced oxidative stress

Chk1 has an essential role in the survival of differentiated cortical neurons in the absence of DNA damage

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