Homocysteine and Gliotoxicity.

Homocysteine is a sulfur amino acid that does not occur in the diet, but it is an essential intermediate in normal mammalian metabolism of methionine. Hyperhomocysteinemia results from dietary intakes of Met, folate, and vitamin B12 and lifestyle or from the deficiency of specific enzymes, leading to tissue accumulation of this amino acid and/or its metabolites. Severe hyperhomocysteinemic patients can present neurological symptoms and structural brain abnormalities, of which the pathogenesis is poorly understood. Moreover, a possible link between homocysteine (mild hyperhomocysteinemia) and neurodegenerative/neuropsychiatric disorders has been suggested. In recent years, increasing evidence has emerged suggesting that astrocyte dysfunction is involved in the neurotoxicity of homocysteine and possibly associated with the physiopathology of hyperhomocysteinemia. This review addresses some of the findings obtained from in vivo and in vitro experimental models, indicating high homocysteine levels as an important neurotoxin determinant of the neuropathophysiology of brain damage. Recent data show that this amino acid impairs glutamate uptake, redox/mitochondrial homeostasis, inflammatory response, and cell signaling pathways. Therefore, the discussion of this review focuses on homocysteine-induced gliotoxicity, and its impacts in the brain functions. Through understanding the Hcy-induced gliotoxicity, novel preventive/therapeutic strategies might emerge for these diseases.

Chronic mild Hyperhomocysteinemia impairs energy metabolism, promotes DNA damage and induces a Nrf2 response to oxidative stress in rats brain.

Homocysteine (HCY) has been linked to oxidative stress and varied metabolic changes that are dependent on its concentration and affected tissues. In the present study we evaluate parameters of energy metabolism [succinate dehydrogenase (SDH), complex II and IV (cytochrome c oxidase), and ATP levels] and oxidative stress [DCFH oxidation, nitrite levels, antioxidant enzymes and lipid, protein and DNA damages, as well as nuclear factor erythroid 2-related (Nrf2) protein abundance] in amygdala and prefrontal cortex of HCY-treated rats. Wistar male rats were treated with a subcutaneous injection of HCY (0.03 µmol/g of body weight) from the 30th to 60th post-natal day, twice a day, to induce mild hyperhomocysteinemia (HHCY). The rats were euthanatized without anesthesia at 12 h after the last injection, and amygdala and prefrontal cortex were dissected for biochemical analyses. In the amygdala, mild HHCY increased activities of SDH and complex II and decreased complex IV and ATP level, as well as increased antioxidant enzymes activities (glutathione peroxidase and superoxide dismutase), nitrite levels, DNA damage, and Nrf 2 protein abundance. In the prefrontal cortex, mild HHCY did not alter energy metabolism, but increased glutathione peroxidase, catalase and DNA damage. Other analyzed parameters were not altered by HCY-treatment. Our findings suggested that chronic mild HHCY changes each brain structure, particularly and specifically. These changes may be associated with the mechanisms by which chronic mild HHCY has been linked to the risk factor of fear, mood disorders and depression, as well as in neurodegenerative diseases.

Chronic Mild Hyperhomocysteinemia Alters Inflammatory and Oxidative/Nitrative Status and Causes Protein/DNA Damage, as well as Ultrastructural Changes in Cerebral Cortex: Is Acetylsalicylic Acid Neuroprotective?

Homocysteine is a sulfur-containing amino acid derived from methionine metabolism. When plasma homocysteine levels exceed 10-15 µM, there is a condition known as hyperhomocysteinemia, which occur as a result of an inborn error of methionine metabolism or by non-genetic causes. Mild hyperhomocysteinemia is considered a risk factor for development of neurodegenerative diseases. The objective of the present study was to evaluate whether acetylsalicylic acid has neuroprotective role on the effect of homocysteine on inflammatory, oxidative/nitrative stress, and morphological parameters in cerebral cortex of rats subjected to chronic mild hyperhomocysteinemia. Wistar male rats received homocysteine (0.03 µmol/g of body weight) by subcutaneous injections twice a day and acetylsalicylic acid (25 mg/Kg of body weight) by intraperitoneal injections once a day from the 30th to the 60th postpartum day. Control rats received vehicle solution in the same volume. Results showed that rats subjected to chronic mild hyperhomocysteinemia significantly increased IL-1ß, IL-6, and acetylcholinesterase activity and reduced nitrite levels. Homocysteine decreased catalase activity and immunocontent and superoxide dismutase activity, caused protein and DNA damage, and altered neurons ultrastructure. Acetylsalicylic acid totally prevented the effect of homocysteine on acetylcholinesterase activity and catalase activity and immunocontent, as well as the ultrastructural changes, and partially prevented alterations on IL-1ß levels, superoxide dismutase activity, sulfhydryl content, and comet assay. Acetylsalicylic acid per se increased DNA damage index. In summary, our findings showed that chronic chemically induced model of mild hyperhomocysteinemia altered some parameters and acetylsalicylic acid administration seemed to be neuroprotective, at least in part, on neurotoxicity of homocysteine.

Structural changes of fibrinogen molecule mediated by the N-homocysteinylation reaction.

Homocysteine and its cyclic ester homocysteine thiolactone (HTL) have been involved in the detrimental consequences associated to hyperhomocysteinemia, an independent risk factor for vascular diseases. HTL reacts with protein lysine residues in a process named N-homocysteinylation. The aim of our study was to evaluate the in vitro effects of HTL on the fibrinogen through electrophoretic methods. Fibrinogen was incubated with HTL at different molar ratios and structural changes of the protein were assessed by polyacrylamide gel electrophoresis (PAGE), capillary zone electrophoresis (CZE) and capillary isoelectric focusing (CIEF). Ellman´s reaction, CZE and proton nuclear magnetic resonance (1H NMR) were used to evaluate HTL hydrolyisis. On denaturing PAGE numerous bands were observed, being the three lower bands identical to those obtained by treatment with 2-mercaptoethanol. This effect was also detected by CZE. The results show a reducing action of HTL on the fibrinogen molecule, probably attributed to the sulfhydryl groups generated by N-homocysteinylation and/or by the ones present in the homocysteine molecule yielded by HTL hydrolysis. In order to distinguish between these two options, HTL stability was evaluated at different pH and incubation times. The results showed minimum HTL hydrolysis in our experimental conditions. We postulate that the reducing effect observed would be mainly associated to the new sulfhydryl groups generated by the N-homocysteinylation process. Moreover, a displacement of the HTL-treated fibrinogen isoforms towards more acidic pH values was detected. The structural changes of N-homocysteinylated fibrinogen could be involved in the pathological consequences of hyperhomocysteinemia.

Creatine supplementation prevents hyperhomocysteinemia, oxidative stress and cancer-induced cachexia progression in Walker-256 tumor-bearing rats.

The purpose of this study was to investigate (1) the impact of tumor growth on homocysteine (Hcy) metabolism, liver oxidative stress and cancer cachexia and, (2) the potential benefits of creatine supplementation in Walker-256 tumor-bearing rats. Three experiments were conducted. First, rats were killed on days 5 (D5), 10 (D10) and 14 (D14) after tumor implantation. In experiment 2, rats were randomly assigned to three groups designated as control (C), tumor-bearing (T) and tumor-bearing supplemented with creatine (TCr). A life span experiment was conducted as the third experiment. Creatine was supplied in drinking water for 21 days (8 g/L) in all cases. Tumor implantation consisted of a suspension of Walker-256 cells (8.0 × 10(7) cells in 0.5 mL of PBS). The progressive increase (P < 0.05) in tumor mass coincided with a progressively lower body weight and higher hepatic oxidative stress; plasma Hcy concentration was 80 % higher (P < 0.05) by 10 days of tumor implantation. Impaired Hcy metabolism was evidenced by decreased hepatic betaine-homocysteine methyltransferase (Bhmt), glycine N-methyltransferase (Gnmt) and cystathionine beta synthase (CBS) gene expression. In contrast, creatine supplementation promoted a 28 % reduction of tumor weight (P < 0.05). Plasma Hcy (C 6.1 ± 0.6, T 10.3 ± 1.5, TCr 6.3 ± 0.9, µmol/L) and hepatic oxidative stress were lower in the TCr group compared to T. Creatine supplementation was unable to decrease Hcy concentration and to increase SAM/SAH ratio in tumor tissue. These data suggest that creatine effects on hepatic impaired Hcy metabolism promoted by tumor cell inoculation are responsible to decrease plasma Hcy in tumor-bearing rats. In conclusion, Walker-256 tumor growth is associated with progressive hyperhomocysteinemia, body weight loss and liver oxidative stress in rats. Creatine supplementation, however, prevented these tumor-associated perturbations.

Ethanol extract of Brazilian propolis ameliorates cognitive dysfunction and suppressed protein aggregations caused by hyperhomocysteinemia.

Homocysteine (Hcy) has been proposed to be a risk factor for cognitive dysfunction. We investigated the effects and the underlying mechanisms of action of propolis, which has antioxidant activity on Hcy-induced oxidative stress in vitro and in vivo. For the in vitro assays, neuroblastoma SH-SY5Y and glioblastoma U-251MG cells were cultured with Hcy and various concentrations of propolis. Cell death and reactive oxygen species production were significantly suppressed by propolis in dose-dependent manner, compared with Hcy alone. For the in vivo assays, mice were fed a propolis-containing diet and Hcy thiolactone in water. Cognitive function was evaluated using the Morris water maze test. Propolis suppressed cognitive dysfunction caused by hyperhomocysteinemia. Accumulation of aggregated protein in brain was accelerated in hyperhomocysteinemia, and the accumulation was suppressed by propolis. Hyperhomocysteinemia, however, did not enhance the oxidative stress in brain. In vitro amyloid formation assay showed that Hcy accelerated lysozyme aggregation and propolis inhibited the aggregation.

Homocysteine induces blood vessel global hypomethylation mediated by LOX-1.

Homocysteine (Hcy) is an independent risk factor of atherosclerosis through its involvement with the methionine cycle. In this study, we aimed to determine the blood vessel global methylation rate in Hcy-induced atherosclerosis in apolipoprotein-E-deficient (ApoE-/-) mice, and to explore the possible mechanism of this change in endothelial cells. ApoE-/- mice were divided into a hyperlipidemia (HLP) group, a hyperhomocysteinemia (HHcy) group, and an HHcy + folate + vitamin B12 (HHcy+FA+VB) group. Wild-type C57BL/6J mice were prepared as controls. Total Hcy, lipids, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) contents in serum were measured with an automatic biochemistry analyzer and high-performance liquid chromatography. Methylation of B1 repetitive elements in blood vessels was tested using nested methylation-specific-polymerase chain reaction (nMS-PCR). Endothelial cells (ECs) were pretreated with Hcy or by adding FA and VB. Lectin-like oxidized LDL receptor-1 (LOX-1) expressions were determined by quantitative PCR, Western blot, and nMS-PCR. The HHcy group displayed severe HLP and HHcy. SAM and SAH contents were also elevated in the HHcy group compared with other groups. Methylation of B1 repetitive elements was significantly increased in the HHcy group (0.5050 ± 0.0182) compared to the HLP (0.5158 ± 0.0163) and control (0.5589 ± 0.0236) groups. mRNA and protein expressions of LOX-1 increased (0.2877 ± 0.0341, 0.6090 ± 0.0547), whereas methylation expression decreased (0.5527 ± 0.0148) after 100 µM Hcy stimulation in ECs. In conclusion, Hcy-induced atherosclerosis was closely associated with induced hypomethylation status in the blood vessel, and this process was partially mediated by LOX-1 DNA methylation.

Homocysteine induces energy imbalance in rat skeletal muscle: is creatine a protector?

Homocystinuria is a neurometabolic disease caused by a severe deficiency of cystathionine beta-synthase activity, resulting in severe hyperhomocysteinemia. Affected patients present several symptoms including a variable degree of motor dysfunction. In this study, we investigated the effect of chronic hyperhomocysteinemia on the cell viability of the mitochondrion, as well as on some parameters of energy metabolism, such as glucose oxidation and activities of pyruvate kinase, citrate synthase, isocitrate dehydrogenase, malate dehydrogenase, respiratory chain complexes and creatine kinase in gastrocnemius rat skeletal muscle. We also evaluated the effect of creatine on biochemical alterations elicited by hyperhomocysteinemia. Wistar rats received daily subcutaneous injections of homocysteine (0.3-0.6 µmol/g body weight) and/or creatine (50 mg/kg body weight) from the 6th to the 28th days of age. The animals were decapitated 12 h after the last injection. Homocysteine decreased the cell viability of the mitochondrion and the activities of pyruvate kinase and creatine kinase. Succinate dehydrogenase was increased other evaluated parameters were not changed by this amino acid. Creatine, when combined with homocysteine, prevented or caused a synergistic effect on some changes provoked by this amino acid. Creatine per se or creatine plus homocysteine altered glucose oxidation. These findings provide insights into the mechanisms by which homocysteine exerts its effects on skeletal muscle function, more studies are needed to elucidate them. Although creatine prevents some alterations caused by homocysteine, it should be used with caution, mainly in healthy individuals because it could change the homeostasis of normal physiological functions.

Mild hyperhomocysteinemia alters extracellular adenine metabolism in rat brain.

Since homocysteine (Hcy) is considered a risk factor to cerebral diseases and adenine nucleotides are important molecules to brain normal function, in the present study we investigated the effect of chronic mild hyperhomocysteinemia on ectonucleotidase activities and expression in rat cerebral cortex. The levels of ATP, ADP, AMP and adenosine (Ado) in cerebrospinal fluid (CSF) of adult rats also were evaluated by high-performance liquid chromatography. For the chronic chemically induced mild hyperhomocysteinemia, Hcy (0.03 µmol/g of body weight) was administered subcutaneously from the 30th to the 60th day of life. Control rats received saline solution in the same volumes. Results showed that Hcy significantly decreased nucleotide hydrolysis in the synaptosomal fraction and increased E-NTPDase1 and ecto-5'-nucleotidase transcripts in rat cerebral cortex. ATP levels were significantly increased, while Ado decreased in CSF of Hcy-treated rats. These findings suggest that the unbalance in ATP and Ado levels may be, at last in part, involved in the cerebral toxicity of mild hyperhomocysteinemia.

Chronic mild hyperhomocysteinemia alters ectonucleotidase activities and gene expression of ecto-5'-nucleotidase/CD73 in rat lymphocytes.

Since mild hyperhomocysteinemia is a risk factor for cardiovascular and cerebral diseases and extracellular nucleotides/nucleosides, which are controlled by the enzymatic action of ectonucleotidases, can induce an immune response, in the present study, we investigated the effect of chronic mild hyperhomocysteinemia on ectonucleotidase activities and expression in lymphocytes from mesenteric lymph nodes and serum of adult rats. For the chronic chemically induced mild hyperhomocysteinemia, Hcy (0.03 µmol/g of body weight) or saline (control) were administered subcutaneously from the 30th to the 60th day of life. Results showed that homocysteine significantly decreased ATP, ADP, and AMP hydrolysis in lymphocytes of adult rats. E-NTPDases transcriptions were not affected, while the ecto-5'-nucleotidase transcription was significantly decreased in mesenteric lymph nodes of hyperhomocysteinemic rats. ATP, ADP, and AMP hydrolysis were not affected by homocysteine in rat serum. Our findings suggest that Hcy in levels similar to considered risk factor to development of vascular diseases modulates the ectonucleotidases, which could lead to a pro-inflammatory status.

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and high plasma homocysteine in chronic hepatitis C (CHC) infected patients from the Northeast of Brazil.

BACKGROUND/AIM: Hyperhomocysteinemia due to Methylenetetrahydrofolate Reductase (MTHFR) gene, in particular the C677T (Ala222Val) polymorphism were recently associated to steatosis and fibrosis. We analyzed the frequency of MTHFR gene in a cross-sectional study of patients affected by Chronic Hepatitis C (CHC) from Northeast of Brazil. METHOD: One hundred seven-four untreated patients with CHC were genotyped for the C677T MTHFR. Genomic DNA was extracted from peripheral blood cells and the C677T MTHFR polymorphism was identified by PCR-RFLP. The homocysteine (Hcy) levels were determined by chemiluminescence method. All patients were negative for markers of Wilson's disease, hemochromatosis and autoimmune diseases and have current and past daily alcohol intake less than 100 g/week. RESULTS: Among subjects infected with CHC genotype non-1 the frequency of MTHFR genotypes TT was 9.8% versus 4.4% genotype 1 (p = 0.01). Nevertheless, association was found between the MTHFR genotype TT × CT/CC polymorphism and the degree of steatosis and fibrosis in both hepatitis C genotype (p < 0.05). A significant difference was found on plasma Hcy levels in patients with steatosis regardless of HCV genotype (p = 0.03). CONCLUSION: Our results indicate that plasma Hcy levels is highly prevalent in subjects with chronic hepatits C with steatosis regardless of HCV genotype and vitamin deficiency. The presence of genotype TT of MTHFR C677T polymorphism was more common in CHC genotype non-1 infected patient regardless of histopathological classification and genotype TT+CT frequencies were significant in the presence of fibrosis grade 1+2 and of steatosis in CHC infected patients from the northeast of Brazil regardless of HCV genotype. The genetic susceptibility of MTHFR C677T polymorphism should be confirmed in a large population.

Chronic hyperhomocysteinemia induces oxidative damage in the rat lung.

Tissue accumulation of homocysteine occurs in classical homocystinuria, a metabolic disease characterized biochemically by cystathionine ß-synthase deficiency. Vascular manifestations such as myocardial infarction, cerebral thrombosis, hepatic steatosis, and pulmonary embolism are common in this disease and poorly understood. In this study, we investigated the effect of chronic hyperhomocysteinemia on some parameters of oxidative stress (thiobarbituric acid-reactive substances, protein carbonyl content, 2',7'-dichlorofluorescein fluorescence assay, and total radical-trapping antioxidant potent) and activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) in the rat lung. Reduced glutathione content and glucose 6-phosphate dehydrogenase activity, as well as nitrite levels, were also evaluated. Wistar rats received daily subcutaneous injections of Hcy (0.3-0.6 µmol/g body weight) from the 6th to the 28th days-of-age and the control group received saline. One and 12 h after the last injection, rats were killed and the lungs collected. Hyperhomocysteinemia increased lipid peroxidation and oxidative damage to protein, and disrupted antioxidant defenses (enzymatic and non-enzymatic) in the lung of rats, characterizing a reliable oxidative stress. In contrast, this amino acid did not alter nitrite levels. Our findings showed a consistent profile of oxidative stress in the lung of rats, elicited by homocysteine, which could explain, at least in part, the mechanisms involved in the lung damage that is present in some homocystinuric patients.

Homocysteine induces cytoskeletal remodeling and production of reactive oxygen species in cultured cortical astrocytes.

Homocysteine (Hcy) is an excitatory amino acid which markedly enhances the vulnerability of neuronal cells to excitotoxicity and oxidative injury. Patients with severe hyperhomocysteinemia exhibit a wide range of clinical manifestations including neurological abnormalities such as mental retardation, cerebral atrophy, and seizures. In this study we treated cortical astrocytes and neurons in culture with 10 and 100 µM Hcy and after 24h exposure cytoskeletal remodeling was analyzed by immunocytochemistry. We observed dramatically altered actin cytoskeleton in astrocytes exposed to 100 µM Hcy, with concomitant change of morphology to fusiform and/or flattened cells with retracted cytoplasm. Moreover, we observed disruption of the glial fibrillary acidic protein (GFAP) meshwork, supporting misregulation of actin cytoskeleton. Induction of reactive oxygen species (ROS) in astrocytes showed fluctuating levels along 24h exposure to both Hcy concentrations. Actin remodeling induced by 100 µM Hcy was prevented by the antioxidants folate (5 µM) or trolox (80 µM). Unlike astrocyte cytoskeleton, results evidence little susceptibility of neuron cytoskeleton until 24h of treatment, since immunocytochemical analysis showed that 10 and 100 µM Hcy-treated neurons presented unaltered neurite arborization. Moreover, alterations in astrocyte and neuron viability were not observed along the 24h of exposure to Hcy. Neuron/astrocyte co-cultures evidence an anchorage dependence for neuronal survival over long exposure to Hcy. Taken together, these findings indicate, that the cytoskeleton of cortical astrocytes, but not of neurons in culture, is a target to Hcy and such effects are mediated by redox signaling. Astrocytes were able to respond to Hcy (100 µM) reorganizing their cytoskeleton, surviving, and protecting neurons from Hcy damage. Moreover our results suggest a protective role for astrocytes remodeling the cytoskelon, and probably generating signals that would assure neuronal survival in response to the damage induced by Hcy.

Increased inflammatory markers in brain and blood of rats subjected to acute homocysteine administration.

Hyperhomocysteinemia plays an etiologic role in the pathogenesis of disorders, including homocystinuria and neurodegenerative and cardiovascular diseases. In the present study, we studied the effect of acute administration of homocysteine, similar to that found in homocystinuria, on parameters of inflammation such as cytokines (TNF-alpha, IL-1beta and IL-6), chemokine CCL2 (MCP-1), nitrite and acute phase-proteins (C-reactive protein and alpha(1)-Acid glycoprotein) levels in brain and blood of rats. In addition, a differential count of blood leukocytes was performed. Wistar rats, aged 29 days, received a single subcutaneous injection of saline (control) or homocysteine (0.6 micromol/g body weight). Fifteen minutes, 1 h, 6 h or 12 h after the injection, the rats were sacrificed and serum, hippocampus and cerebral cortex were used. Results showed that homocysteine significantly increased proinflammatory cytokines (TNF-alpha, IL-1beta and IL-6) and chemokine CCL2 (MCP-1) in serum, hippocampus and cerebral cortex. Nitrite levels also increased in hippocampus and cerebral cortex at 15 min, 1 h and 6 h, but not 12 h after homocysteine administration. Acute phase-protein levels were not altered by homocysteine. The percentage of neutrophils and monocytes significantly increased in blood at 15 min and 1 h, but not at 6 h and 12 h after acute hyperhomocysteinemia, when compared to the control group. Our results showed that acute administration of homocysteine increased inflammatory parameters, suggesting that inflammation might be associated, at least in part, with the neuronal and cardiovascular dysfunctions observed in homocystinuric patients.

Ischemic stroke subtypes and thrombophilia in young and elderly Brazilian stroke patients admitted to a rehabilitation hospital.

BACKGROUND AND PURPOSE: We sought to examine ischemic stroke subtypes and prevalence of thrombophilia in Brazilian stroke patients. METHOD: A total of 130 consecutive young and 200 elderly stroke patients were studied. RESULTS: Prevalence of thrombophilia was, respectively: protein S deficiency (11.5% versus 5.5%), protein C deficiency (0.76% versus 1%), resistance to activated protein C (2.3% versus 3.5%), mutation in V Leiden factor (1.5% versus 2%), antithrombin III deficiency (0% versus 0%), lupus anticoagulant (0% versus 0.5%), anticardiolipin antibodies (3% versus 10%; P=0.01), hyperhomocysteinemia (31.5% versus 53.5%; P=0.0001), mutation of the MTHFR gene in homocigosis (10% versus 5%), and heterocigosis (27.6% versus 41.9%; P=0.01). CONCLUSIONS: Prothrombotic conditions were more frequent in stroke of undetermined cause.

Mild hyperhomocysteinemia promotes renal hemodynamic dysfunction without histopathologic changes in adult rats.

BACKGROUND: Hyperhomocysteinemia is able to promote glomerular damage and generate tubulointerstitial lesions. These findings were reported in rats with unilateral nephrectomy or in weanling rats with normal function, two experimental models that are exposed to other concomitant vascular risk factors. The aim of this work is to study whether mild hyperhomocisteinemia per se can induce renal histopathologic changes in adults rats with normal renal function at either 10 or 44 weeks of hyperhomocysteinemia. METHODS: Two months old male Wistar rats (N= 52) were randomly allocated to either a normal control (N= 26) or hyperhomocysteinemic (N= 26) group. Control and hyperhomocysteinemic groups had free access to either tap water or homocysteine thiolactone 50 mg/kg/day, during 10 or 44 weeks. Plasma homocysteine levels were determined by a high-performance liquid chromatography (HPLC) method. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were calculated from inulin and sodium para-aminohippurate (PAH) clearance determinations. Structural renal changes were investigated in kidneys fixed by perfusion. Histopathologic and morphometric analysis were carried out by standard methods. RESULTS: Plasma total homocysteine levels were 53% (10 weeks) and 56% (44 weeks) higher in hyperhomocysteinemic group compared to the control group. GFR and RPF were significantly lower in hyperhomocysteinemic than in control group. The histopathologic and morphometric studies did not show any differences between the control and hyperhomocysteinemic rats at 10 or 44 weeks. CONCLUSION: The present results show that mild hyperhomocysteinemia is able to induce renal functional and biochemical alterations in male adult rats that are not associated with renal histopathologic changes.

Hiperhomocisteinemia y preeclampsia: una combinación con grave riesgo vascular. Revisión bibliográfica y presentación de caso clínico / Hyperhomocysteinemia and preeclampsia: a combination with acute vascular risk

Dos tercios de los episodios de enfermedad vascular pueden atribuirse a factores de riesgo vasculares, ambientales y hereditarios. Un factor de riesgo independiente sería el aumento de homocisteína. Hoy se cuestiona si la hiperhomocisteinemia es causa de aterosclerosis y si su disminución reduce el riesgo de enfermedad cardiovascular. La prevalencia de hiperhomocisteinemia ha sido estimada en un 5 por ciento de la población general y en un rango de 13-47 por ciento en pacientes con enfermedad arteriosclerótica. Aunque la homocisteinuria fue descripta en 1962 los reportes en el mundo coinciden en que el diagnóstico es muchas veces erróneo o tardío. ¿Por qué el diagnóstico de la homocisteinuria es problemático?. En primer lugar la homocisteinuria es una patología rara y otros diagnósticos son considerados antes. Secundariamente hay problemas técnicos para la medición de la concentración de aminoácidos sulfuros en los fluidos. La ausencia de tratamiento de esta patología conduce al riesgo de: enfermedad coronaria, enfermedad cerebrovascular y tromboembolismo. Fue hallado que altos niveles de homocisteína en circulación materna o fetal se asocia con enfermedad vascular placentaria con el riesgo de preeclampsia en la madre y/o retardo del crecimiento intrauterino (RCIU) en el feto. Se encontró niveles más altos de homocisteína en embarazos complicados por preeclampsia. Los resultados apoyan que la hiperhomocisteinemia puede ser un marcador de riesgo para enfermedad vascular placentaria y preeclampsia materna. El interés de esta presentación es estimar si la relación entre preeclampsia e hiperhomocisteinemia constituye un factor predictor de riesgo vascular materno y/o fetal. (AU)