Chronic Hyperhomocysteinemia provokes a memory defi- cit in rats in the Morris water maze task

Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
Behavioural Brain Research (Impact Factor: 3.03). 09/2004; 153(2):377-81. DOI: 10.1016/j.bbr.2003.12.013
Source: PubMed


Homocystinuria is an inherited metabolic disease biochemically characterized by tissue accumulation of homocysteine. Affected patients present mental retardation and other neurological symptoms whose mechanisms are still obscure. In the present study, we investigated the effect of chronic hyperhomocysteinemia on rat performance in the Morris water maze task. Chronic treatment was administered from the 6th to the 28th day of life by s.c. injection of homocysteine, twice a day at 8-h intervals; control rats received the same volume of saline solution. Animals were left to recover until the 60th day of life. Morris water maze tasks were then performed, in order to verify any effect of early homocysteine administration on reference and working memory of rats. Results showed that chronic treatment with homocysteine impaired memory of the platform location and that homocysteine treated animals presented fewer crossings to the place where the platform was located in training trials when compared to saline-treated animals (controls). In the working memory task, homocysteine treated animals also needed more time to find the platform. Our findings suggest that chronic experimental hyperhomocysteinemia causes cognitive dysfunction and that might be related to the neurological complications characteristic of homocystinuric patients.

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    • "These prior studies suggest that Hcy has multiple functions in the brain; this can likely explain its links to various psychiatric disorders, including schizophrenia and affective disorders. Animals exposed to Hcy exhibit compromised brain energy metabolism (Streck et al., 2003), altered long-term potentiation, disturbances of synaptic plasticity and cognitive impairment in terms of spatial learning (Algaidi et al., 2006) and memory deficits (Streck et al., 2004). Heterozygous and homozygous Mthfr knockout mice are also characterized by neurodevelopmental retardation and altered cerebellar morphology (Chen et al., 2001). "
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    ABSTRACT: Although homocysteine (Hcy) has been widely implicated in the etiology of various physical health impairments, especially cardiovascular diseases, overwhelming evidence indicates that Hcy is also involved in the pathophysiology of schizophrenia and affective disorders. There are several mechanisms linking Hcy to biological underpinnings of psychiatric disorders. It has been found that Hcy interacts with NMDA receptors, initiates oxidative stress, induces apoptosis, triggers mitochondrial dysfunction and leads to vascular damage. Elevated Hcy levels might also contribute to cognitive impairment that is widely observed among patients with affective disorders and schizophrenia. Supplementation of vitamins B and folic acid has been proved to be effective in lowering Hcy levels. There are also studies showing that this supplementation strategy might be beneficial for schizophrenia patients with respect to alleviating negative symptoms. However, there are no studies addressing the influence of add-on therapies with folate and vitamins B on cognitive performance of patients with schizophrenia and affective disorders. In this article, we provide an overview of Hcy metabolism in psychiatric disorders focusing on cognitive correlates and indicating future directions and perspectives.
    Frontiers in Behavioral Neuroscience 09/2014; 8. DOI:10.3389/fnbeh.2014.00343 · 3.27 Impact Factor
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    • "Moreover, hyperhomo-cysteinemia has been implicated in neuronal plasticity and neurodegenerative disorders in human study (5). The concentration of Hcy in the brain and cerebrospinal fluid is elevated in several neurological diseases in human and experimental animals (5, 15). Numerous studies have reported that homocysteine is elevated in Levodopa therapy for PD patients and suggested a substantial role of homocysteine in causing various neurotoxic effects (16). "
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    ABSTRACT: Parkinson's disease is a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of this cell death is unknown. Homocysteine (Hcy) is a non-protein amino acid. It is a homologue of the amino acid cysteine. The elevated levels of homocysteine in plasma have been associated with a number of disease states. Hcy (2 µmol / µl) was injected intracerebroventricular (i.c.v) in rats, five days later, the locomotor activity was measured with open field apparatus, Also apoptosis was investigated in substantia nigra cells by immunohistochemical analysis. Hcy could decrease locomotor activities significantly in rats as well as it could induce apoptosis in substantia nigra cells. These results suggest that Hcy is a neurotoxic metabolite and may induce cell death in some nuclei in the brain.
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    • "The group fed on 5% methionine showed an increase in time spent in the closed arms in the elevated plus maze, indicating a modification in emotional behaviour that involves structures as the amygdala and the ventral hippocampus. There is evidence that a prolonged exposition to high Hcy provoked a memory deficit in the Morris water maze task (Streck et al., 2004) and high levels of Hcy caused memory impairments (Reis et al., 2002). Moreover there is a correlation between high levels of plasma Hcy concentration and cognitive deficit assessed with the Mini-Mental State Examination (MMSE) in old depressed patients without vascular disease (Bell et al., 1992). "
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    ABSTRACT: Diets high in methionine lead to elevation of plasma homocysteine levels which are possibly linked to neurodegenerative diseases and oxidative stress. In the present study, we investigated the effects of methionine-enriched diet on antioxidant defences, on rat spontaneous behaviour and on the ability to sustain long-term potentiation in the dentate gyrus (DG). Sprague-Dawley rats were fed either a standard laboratory diet or a methionine enriched-diet (1% or 5% methionine in drinking water) for 8 weeks. After the 8 weeks, the animals were tested for spontaneous motor activity and habituation in an open field maze, for anxiety-like behaviour in an elevated plus maze and for the ability to sustain long-term potentiation (LTP) induced in the dentate gyrus under urethane anaesthesia. The brains were then removed and histochemically stained for superoxide dismutase (SOD) activity. Rats fed on 5% methionine significantly reduced total distance travelled during the open field test and exhibited no habituation with respect to the other two groups. Rats fed on 5% methionine also showed a significant increase of the anxiety level. Moreover, in this group, the ability to induce LTP in DG was impaired. SOD activity was significantly increased in the cerebral cortex of the rats fed on 1% and 5% methionine with respect to the control group. In conclusion, 5% methionine in drinking water led to evident impairment of locomotor skills and of synaptic plasticity. SOD activity in the cortex was increased in both the groups fed on 1% and 5% methionine, thus suggesting that metabolic adjustments, triggered by the methionine-enriched diet, are likely mediated by reactive oxygen species.
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