Neurotoxic Effects of High Levels of Homocysteine

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Homocysteine is an endogenous amino acid derivative which damages the endothelial cells that line the inside of blood vessels and contributes to the pathogenesis of atherosclerosis and vascular dysfunction.

A high level of homocysteine in the blood (hyperhomocysteinemia) makes a person more prone to endothelial cell injury, which leads to inflammation in the blood vessels, which in turn may lead to atherogenesis, which can result in ischemic injury.

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Figure: Homocysteine Metabolic Pathways

The remethylation pathway requires vitamin B12, folate, and the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). In kidney and liver, homocysteine is also remethylated by the enzyme betaine homocysteine methyltransferase (BHMT), which transfers a methyl group to homocysteine via the demethylation of betaine to dimethylglycine (DMG). The transsulfuration pathway requires the enzyme cystathionine-synthase (CBS) and vitamin B6 (pyridoxal-5’-phosphate). Once formed from cystathionine, cysteine can be utilized in protein synthesis and glutathione (GSH) production. Figure taken from: www.nature.com/cdd/journal/v11/n1s/fig_tab/4401451f1.html

It is recommended that an optimal homocysteine level is <8µmol/L. One comprehensive review showed that every 2.5 µmol/L increase above this optimal level is associated with about a 20% increase in stroke risk. [1]

Elevated homocysteine levels is a result of a faulty and defective methylatio n process in the body the high levels of homocysteine in the bloodstream is not being remethylated When you have poor methylation your body’s levels of homocysteine will elevate.

A variety of extrinsic and intrinsic factors including stress, nutritional deficits, certain disease states, and genetics can contribute to insufficient methylation.

Homocysteine is metabolized through two pathways: remethylation and transsulfuration.

Remethylation requires folate and B12 coenzymes.

Transsulfuration requires pyridoxal-5’-phosphate, the B6 coenzyme.

Table: Neurotoxic Effects of High Levels of Homocysteine

Toxic Effects of Homocysteine

Anatomy/Condition

Effect

Notes/Reference(s)

Blood Flow

Homocysteine has been associated with reduced blood flow to the brain

[2]

Memory

Homocysteine can impair memory

[3]

Cognitive function

Homocysteine can result in poorer global cognitive function

[4]

Brain volume

Homocysteine results in smaller overall brain volume

[5]

Brain infarcts

Homocysteine is associated with increased silent brain infarcts (subclinical stroke-like blood vessel occlusions in the brain).

[6]

Dementia

Elevated homocysteine may cause dementia in the elderly

[7] [8]

Depression

Elevated Homocysteine may cause Depression

[9]

Neurons and mylein sheath

Homocysteine may kill Neurons and the Myelin Sheaths that surround Neurons.

[10]

Schizophrenia

Elevated Homocysteine levels may cause Schizophrenia

[11]

Aggressiveness

Elevated Homocysteine levels may cause Aggressiveness.

[12]

Astrocytes

Homocysteine may stimulate the death of Astrocytes.

[13]

References:


[1] Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002 Oct 23-30;288(16):2015-22.

[2] Kumar M et al. Homocysteine decreases blood flow to the brain due to vascular resistance in carotid artery. Neurochem Int. 2008 Dec;53(6-8):214-9.

[3] Matte C et al. Acute homocysteine administration impairs memory consolidation on inhibitory avoidance task and decreases hippocampal brain-derived neurotrophic factor immunocontent: prevention by folic acid treatment. Neuroscience. 2009 Nov 10;163(4):1039-45.

[4] Siuda J et al. From mild cognitive impairment to Alzheimer’s disease – influence of homocysteine, vitamin B12 and folate on cognition over time: results from one-year follow-up. Neurol Neurochir Pol. 2009 Jul-Aug;43(4):321-9.

[5] Seshadri S et al. Association of plasma total homocysteine levels with subclinical brain injury: cerebral volumes, white matter hyperintensity, and silent brain infarcts at volumetric magnetic resonance imaging in the Framingham Offspring Study. Arch Neurol. 2008 May;65(5):642-9.

[6] Seshadri S et al. Association of plasma total homocysteine levels with subclinical brain injury: cerebral volumes, white matter hyperintensity, and silent brain infarcts at volumetric magnetic resonance imaging in the Framingham Offspring Study. Arch Neurol. 2008 May;65(5):642-9.

[7] Leblhuber F., et al. Hyperhomocysteinemia in dementia. J Neural Transm. 107(12):1469-1474, 2000. Department of Gerontology, Landesnervenklinik Wagner Jauregg, Linz, Austria.

Kessler, H., et al. [Homocysteine and dementia.] Fortschr Neurol Psychiatr. 71(3):150-156, 2003.

[8] http://www.ncbi.nlm.nih.gov/pubmed/18843658?dopt=Citation

[9] Bjelland, I., et al. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 60(6):618-626, 2003. Department of Public Health and Primary Health Care, Locus for Homocysteine and Related Vitamins, University of Bergen, Norway. ingvar.bjelland@uib.no

[10] Firshein, R. The Nutraceutical Revolution. Riverhead Books via Penguin Putnam Inc., New York, USA. 1998:147.

[11] Haidemenos, A., et al. Plasma homocysteine, folate and B12 in chronic schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2007. 8th Psychiatric Department, Psychiatric Hospital of Attica, Athens, Greece.

[12] Stoney, et al. Plasma homocysteine concentrations are positively associated with hostility and anger. Life Sciences. 66(23):2267-2275, 2000.

[13] Maler, J. M., et al. Homocysteine induces cell death of rat astrocytes in vitro. Neurosci Lett. 347(2):85-88, 2003. Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany


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