Chemically induced model of hypermethioninemia in rats

Stefanello, Francieli Moro; Matté, Cristiane; Scherer, Emilene B. S.; Wannmacher, Clóvis Milton Duval; Wajner, Moaçir; Wyse, Ângela T. S.

doi:10.1016/j.jneumeth.2006.07.029

Cited by 31 publications

(26 citation statements)

References 25 publications

(21 reference statements)

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“…That is in agreement with our previous work demonstrating that body and brain weight were not altered by Met treatment [12]. Figure 1 shows that chronic administration of Met did not affect the spatial memory acquisition phase.…”

Section: Resultssupporting

confidence: 93%

“…Animals exposed to Met treatment presented no differences in physical growth and brain weight when compared to the control group, suggesting that Met did not cause malnutrition in the rats [12]. By using this model, in the present study we investigated the effect of chronic hypermethioninemia on spatial navigation tasks in the Morris water maze.…”

Section: Discussionmentioning

confidence: 98%

“…Animal models are useful to better understand the pathophysiology of diseases. In this context, we have recently developed in our laboratory a chemically experimental model of hypermethioninemia [12], in which we produced high levels of Met in blood of rats similar to those found in some pathological conditions such as methionine adenosyltransferase deficiency, homocystinuria and glycine N-methyltransferase deficiency [2,13]. We cannot discard the increase of Met metabolites in the plasma of rats subjected to this model, such as S-adenosylmethionine, homocysteine and S-adenosylhomocysteine, perhaps cystathionine and sarcosine.…”

Section: Discussionmentioning

confidence: 99%

“…Animals received 1.34 lmol Met/g body weight during the first 8 days of treatment, 2.01 lmol Met/g body weight from day 14th to 20th and 2.68 lmol Met/g body weight from day 21st to 28th. The doses of Met administered were dependent on animal age, which were determined by following pharmacokinetic parameters, apparent volume of distribution, plasmatic halftime and plasmatic clearance after Met injection [12]. Rats subjected to this treatment achieved plasma Met levels (around to 2 mmol/L) similar to those found in hypermethioninemic patients with some inherited pathological conditions [2,13].…”

Section: Methionine Administration Proceduresmentioning

confidence: 99%

“…As for the acute treatment, 29-day-old rats received one single subcutaneous injection of Met correspondent to 2.68 lmol/g of body weight and control rats received an equivalent volume of saline [12]. The animals were killed 1, 3 or 12 h after injection and the cerebral cortex was dissected and prepared as described above.…”

Section: Methionine Administration Proceduresmentioning

confidence: 99%

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Hypermethioninemia Increases Cerebral Acetylcholinesterase Activity and Impairs Memory in Rats

et al. 2007

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In the present study we investigated the effect of chronic hypermethioninemia on rat performance in the Morris water maze task, as well as on acetylcholinesterase (AChE) activity in rat cerebral cortex. For chronic treatment, rats received subcutaneous injections of methionine (1.34-2.68 micromol/g of body weight), twice a day, from the 6th to the 28th day of age; control rats received the same volume of saline solution. Groups of rats were killed 3 h, 12 h or 30 days after the last injection of methionine to AChE assay and another group was left to recover until the 60th day of life to assess the effect of early methionine administration on reference and working spatial memory of rats. AChE activity was also determined after behavioral task. Results showed that chronic treatment with methionine did not alter reference memory when compared to saline-treated animals. In the working memory task, we observed a significant days effect with significant differences between control and methionine-treated animals. Chronic hypermethioninemia significantly increased AChE activity at 3 h, 12 h or 30 days after the last injection of methionine, as well as before or after behavioral test. The effect of acute hypermethioninemia on AChE was also evaluated. For acute treatment, 29-day-old rats received one single injection of methionine (2.68 micromol/g of body weight) or saline and were killed 1, 3 or 12 h later. Results showed that acute administration of methionine did not alter cerebral cortex AChE activity. Our findings suggest that chronic experimental hypermethioninemia caused cognitive dysfunction and an increase of AChE activity that might be related, at least in part, to the neurological problems presented by hypermethioninemic patients.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Methionine Administration Proceduresmentioning

confidence: 99%

Section: Methionine Administration Proceduresmentioning

confidence: 99%

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Hypermethioninemia Increases Cerebral Acetylcholinesterase Activity and Impairs Memory in Rats

et al. 2007

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Methionine increases BDNF DNA methylation and improves memory in epilepsy

Parrish

Buckingham

Mascia

et al. 2015

Ann Clin Transl Neurol

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ObjectiveTemporal lobe epilepsy (TLE) patients exhibit signs of memory impairments even when seizures are pharmacologically controlled. Surprisingly, the underlying molecular mechanisms involved in TLE-associated memory impairments remain elusive. Memory consolidation requires epigenetic transcriptional regulation of genes in the hippocampus; therefore, we aimed to determine how epigenetic DNA methylation mechanisms affect learning-induced transcription of memory-permissive genes in the epileptic hippocampus.MethodsUsing the kainate rodent model of TLE and focusing on the brain-derived neurotrophic factor (Bdnf) gene as a candidate of DNA methylation-mediated transcription, we analyzed DNA methylation levels in epileptic rats following learning. After detection of aberrant DNA methylation at the Bdnf gene, we investigated functional effects of altered DNA methylation on hippocampus-dependent memory formation in our TLE rodent model.ResultsWe found that behaviorally driven BdnfDNA methylation was associated with hippocampus-dependent memory deficits. Bisulfite sequencing revealed that decreased BdnfDNA methylation levels strongly correlated with abnormally high levels of BdnfmRNA in the epileptic hippocampus during memory consolidation. Methyl supplementation via methionine (Met) increased BdnfDNA methylation and reduced BdnfmRNA levels in the epileptic hippocampus during memory consolidation. Met administration reduced interictal spike activity, increased theta rhythm power, and reversed memory deficits in epileptic animals. The rescue effect of Met treatment on learning-induced BdnfDNA methylation, Bdnf gene expression, and hippocampus-dependent memory, were attenuated by DNA methyltransferase blockade.InterpretationOur findings suggest that manipulation of DNA methylation in the epileptic hippocampus should be considered as a viable treatment option to ameliorate memory impairments associated with TLE.

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High levels of methionine and methionine sulfoxide: Impact on adenine nucleotide hydrolysis and redox status in platelets and serum of young rats

Soares

Mattos

Ávila

et al. 2018

J of Cellular Biochemistry

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We investigated acute and chronic effects administration of methionine (Met) and/or methionine sulfoxide (MetO) on ectonucleotidases and oxidative stress in platelets and serum of young rats. Wistar rats were divided into four groups: control, Met, MetO, and Met + MetO. In acute treatment, the animals received a single subcutaneous injection of amino acid(s) and were euthanized after 1 and 3 hours. In chronic protocol, Met and/or MetO were administered twice a day with an 8-hour interval from the 6th to the 28th day of life. Nucleoside triphosphate phosphohydrolase and 5'-nucleotidase activities were reduced in platelets and serum by Met, MetO, and Met + MetO after 3 hours and 21 days. Adenosine deaminase activity reduced in platelets at 3 hours after MetO and Met + MetO administration and increased after 21 days in animals treated with Met + MetO. Superoxide dismutase and catalase activities decreased in platelets in MetO and Met + MetO groups after 3 hours, while reactive oxygen species (ROS) levels increased in same groups. Catalase activity in platelets decreased in all experimental groups after chronic treatment. Met, MetO, and Met + MetO administration increased plasmatic ROS levels in acute and chronic protocols; glutathione S-transferase activity increased by MetO and Met + MetO administration at 3 hours, and ascorbic acid decreased in all experimental groups in acute and chronic protocols. Thiobarbituric acid reactive substances increased, superoxide dismutase and catalase activities reduced in the Met and/or MetO groups at 3 hours and in chronic treatment. Our data demonstrated that Met and/or MetO induced changes in adenine nucleotide hydrolysis and redox status of platelets and serum, which can be associated with platelet dysfunction in hypermethioninemia.

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Chemically induced model of hypermethioninemia in rats

Cited by 31 publications

References 25 publications

Hypermethioninemia Increases Cerebral Acetylcholinesterase Activity and Impairs Memory in Rats

Hypermethioninemia Increases Cerebral Acetylcholinesterase Activity and Impairs Memory in Rats

Methionine increases BDNF DNA methylation and improves memory in epilepsy

High levels of methionine and methionine sulfoxide: Impact on adenine nucleotide hydrolysis and redox status in platelets and serum of young rats

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