Hypermethioninemia induces memory deficits and morphological changes in hippocampus of young rats: implications on pathogenesis

Soares, Mayara Sandrielly Pereira; Mattos, Bruna da Silveira de; Souza, Anita Ávila de; Spohr, Luíza; Tavares, Rejane Giacomelli; Siebert, Cassiana; Moreira, Daniella de S; Wyse, Ângela T. S.; Carvalho, Fabiano B.; Rahmeier, Francine Luciano; Fernandes, Marilda da Cruz; Stefanello, Francieli Moro; Spanevello, Rosélia Maria

doi:10.1007/s00726-019-02814-2

Cited by 9 publications

(12 citation statements)

References 63 publications

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“…Remarkably, the neurodegenerative patterns worsen with the prolonged reperfusion times and the apparent diminishing in FJC+ cell at the 7th post-ischemic day is probably the result of the comprehensive neuronal disintegration, as we observed in our previous studies [ 20 , 21 , 22 , 23 , 24 ]. Our results are also consonant with the results of other laboratories [ 6 , 27 , 39 ], as well as clinical observations [ 6 , 40 , 41 ] and supports the idea that Met-enriched diet initiates hippocampal neurodegeneration which is aggravated after the global IRI ( Figure 4 ).…”

Section: Discussionsupporting

confidence: 93%

“…Most of the BBB damage usually occurs prior to 48 h post-stroke, as shown in the embolic ischemic model in rats [ 27 , 66 ]. It is known that hHcy can impair the endothelium’s capacity to regulate vascular tone by reduced bioavailability of NO, which leads to the endothelial dysfunction [ 6 , 68 ]. This could be one of the most important mechanisms by which hHcy exerts endothelial damage including also a greater sensitivity in cerebral microvessels [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…The impact of a high and moderate Met diet on different tissues has been discussed in many studies [ 1 , 2 , 3 ]. An elevated level of Met in plasma, hypermethioninemia (hMet), has been linked with memory deficits and morphological changes in the hippocampus of young rats [ 6 ]. Chronic hMet and its oxidative product, Met sulfoxide, induces cellular oxidative stress [ 7 , 8 ] in various organs and also contributes to the brain pathology [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

et al. 2020

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Hyperhomocysteinemia (hHcy) represents a strong risk factor for atherosclerosis-associated diseases, like stroke, dementia or Alzheimer’s disease. A methionine (Met)-rich diet leads to an elevated level of homocysteine in plasma and might cause pathological alterations across the brain. The hippocampus is being constantly studied for its selective vulnerability linked with neurodegeneration. This study explores metabolic and histo-morphological changes in the rat hippocampus after global ischemia in the hHcy conditions using a combination of proton magnetic resonance spectroscopy and magnetic resonance-volumetry as well as immunohistochemical analysis. After 4 weeks of a Met-enriched diet at a dose of 2 g/kg of animal weight/day, adult male Wistar rats underwent 4-vessel occlusion lasting for 15 min, followed by a reperfusion period varying from 3 to 7 days. Histo-morphological analyses showed that the subsequent ischemia-reperfusion insult (IRI) aggravates the extent of the sole hHcy-induced degeneration of the hippocampal neurons. Decreased volume in the grey matter, extensive changes in the metabolic ratio, deeper alterations in the number and morphology of neurons, astrocytes and their processes were demonstrated in the hippocampus 7 days post-ischemia in the hHcy animals. Our results suggest that the combination of the two risk factors (hHcy and IRI) endorses and exacerbates the rat hippocampal neurodegenerative processes.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

et al. 2020

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“…In addition, the CA3 and DG areas of the hippocampus participate in spatial learning and memory, which are important for the maintenance of hippocampal function. Furthermore, it has been demonstrated that HMD reduces the neurons number in the CA3 and DG [52,53], suggesting that these data help to understand the impact of HMD on changes in the nervous system. Although these effects are consistent with our results, they did not clarify the relationship between HMD-induced AD-like symptoms and 5-mC as in this work.…”

Section: Behavioural Neurologymentioning

confidence: 89%

High Methionine Diet-Induced Alzheimer’s Disease like Symptoms Are Accompanied by 5-Methylcytosine Elevated Levels in the Brain

Wei

Jiang

et al. 2021

Behavioural Neurology

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Background. Excessive or insufficient intake of methionine (Met) causes neuronal dysfunction, neurodegeneration, cerebrovascular dysfunction, vascular leakage, and short-term memory loss, which result in the occurrence of Alzheimer’s disease- (AD-) like symptoms. Objective. To determine the relationship between high methionine diets (HMD) induced AD-like symptoms and 5-methylcytosine (5-mC) level. Methods. C57BL/6J mice were randomly divided into two groups: the control group (Maintain diets) and the model group (2% HMD). Mice were fed with 2% HMD for 9 weeks. Animals were weighed and food intake was recorded weekly. Open field test, nesting ability test, Y maze test, new object recognition test, and Morris water maze test were used to detect the motor, learning, and memory ability. Hematoxylin-eosin (HE) staining was used to observe the damage of cells in hippocampus and cortex. Immunofluorescence (IF) staining was used to detect the expression and distribution of amyloid-β 1-40 (Aβ1-40), amyloid-β 1-42 (Aβ1-42), and 5-methylcytosine (5-mC) in hippocampus and cortex. Western blotting (WB) was used to determine the expression of Aβ and DNA methyltransferases- (DNMTs-) related proteins in the cortex. Enzyme-linked immunosorbent assay (ELISA) was performed to detect homocysteine (Hcy) level (ELISA). Results. Feeding of HMD decreased the body weight and food intake of mice. Behavioral testing revealed that HMD caused learning, memory, and motor ability impairment in the mice. HE staining results showed that HMD feeding caused damage of hippocampal and cortical neurons, along with disordered cell arrangement, and loss of neurons. Furthermore, HMD increased the contents of Aβ1-40, Aβ1-42, and 5-mC in the hippocampus and cortex. WB results showed that HMD increased the expression of Aβ production-related proteins, such as amyloid precursor protein (APP) and beta-secretase 1 (BACE1), and decreased the expression of Aβ metabolism-related protein in the cortex, including insulin-degrading enzyme (IDE) and neprilysin (NEP). Additionally, the decreased expression of DNA methyltransferase1 (DNMT1) was observed in HMD-treated mice, but there was no significant change of DNMT3a level. ELISA results showed that HMD increased the levels of Hcy in serum. Conclusion. Our result suggested that the HMD can cause neurotoxicity, leading to AD-like symptoms in mice, which may be related to 5-mC elevated.

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“…In addition, a study by Soares et al. (2020) showed that animals that received chronic administration of Met and/or MetO developed cognitive problems, which could be related to an increase in brain AChE (Soares et al., 2020).…”

Section: Discussionmentioning

confidence: 99%

Acute hypermethioninemia impairs redox homeostasis and acetylcholinesterase activity in the hippocampus, striatum, and cerebellum of young rats

Meine

Bona

Luduvico

et al. 2021

Intl J of Devlp Neuroscience

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Hypermethioninemia is characterized by high plasma concentrations of methionine (Met) and its metabolites, such as methionine sulfoxide (MetO), and neurological changes, such as cerebral edema and cognitive deficits. The aim of this study was to analyze the redox status and acetylcholinesterase (AChE) activity in the hippocampus, striatum, and cerebellum of young Wistar rats subjected to an acute hypermethioninemia protocol. The animals received, by subcutaneous injection, a single dose of Met (0.4 g/kg), MetO (0.1 g/kg), and Met + MetO, and 1 or 3 hr after administration, the animals were euthanatized for brain structure obtaining. In the hippocampus, an increase in lipid peroxidation and glutathione peroxidase (GPx) activity was observed at 1 hr in the MetO and Met + MetO groups, and a reduction in the superoxide dismutase activity was found in the Met + MetO group. Met and/or MetO induced a decrease in the thiol content and GPx activity and enhanced the lipid peroxidation at 3 hr. In the striatum, a reduction in the thiol content and GPx activity, an increase in lipid peroxidation, and AChE activity were induced by Met and/or MetO at 1 or 3 hr. Additionally, in the cerebellum, an increase in the AChE in the MetO and Met + MetO groups 1 hr after administration was observed. These data help to better understand the pathophysiological mechanisms that underlie the neurological changes found in hypermethioninemia patients.

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Hypermethioninemia induces memory deficits and morphological changes in hippocampus of young rats: implications on pathogenesis

Cited by 9 publications

References 63 publications

Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

High Methionine Diet-Induced Alzheimer’s Disease like Symptoms Are Accompanied by 5-Methylcytosine Elevated Levels in the Brain

Acute hypermethioninemia impairs redox homeostasis and acetylcholinesterase activity in the hippocampus, striatum, and cerebellum of young rats

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