Administration Of L-methionine Research Articles

Improvement in renal function of Hyperhomocysteinemic rats by panax ginseng

Hyperhomocysteinemia is a condition characterized by elevated levels of homocysteine in the blood, which has been linked to various cardiovascular and renal complications, including impaired renal function. , a widely used medicinal herb, has been shown to possess antioxidant, anti-inflammatory, and vasoprotective properties. However, its potential role in improving renal function in hyperhomocysteinemic conditions remains largely unexplored. Hyperhomocysteinemia is a metabolic disorder characterized by elevated levels of homocysteine in the blood, which is associated with impaired renal function. This study aimed to investigate the potential therapeutic effects of Panax Ginseng on renal function in hyperhomocysteinemic rats. Male Wistar rats There were five animals per group. Group 1 functioned as the control group, receiving a typical meal (chow feed) and unlimited water. L-methionine (1.7 g/kg/day, p.o.) was given to group 2 Hyperhomocysteinemia (HHCY Control) once daily. A modest dosage of Panax ginseng (50 mg/kg body weight) and L-methionine (1.7 g/kg/day, p.o.) was administered orally to the third group (test drug 1). The fourth group (test drug 2) got the same combination of L-methionine (1.7 g/kg/day, p.o.) and Panax ginseng (high dosage, 100 mg/kg body weight). In addition, the second, third, and fourth groups of rats received intraperitoneal doxorubicin injections at a dosage of 5 mg/kg after 1 hour of L-methionine administration at intervals of 15 days in order to produce Hyperhomocysteinemia-mediated nephrotoxicity. After 28 days of the trial, the animals were slaughtered, and the blood levels of homocysteine, creatinine, and urea were measured. We measured the amounts of urea, creatinine, and homocysteine in the serum. administration effectively improved renal function and attenuated histopathological changes in hyperhomocysteinemic rats. These findings suggest that Panax Ginseng may have a renoprotective effect in Hyperhomocysteinemia-induced renal dysfunction.

S-adenosyl-l-methionine antidepressant-like effects involve activation of 5-HT1A receptors

S-adenosyl-l-methionine (SAMe), a methyl donor, induces antidepressant effects in preclinical and clinical studies of depression. However, the mechanisms behind these effects have been poorly investigated. Since SAMe is involved in monoamine metabolism, this work aimed at 1) testing the effects induced by systemic treatment with SAMe in mice submitted to the forced swimming test (FST) and tail suspension test (TST); 2) investigating the involvement of serotonergic neurotransmission in the behavioral effects induced by SAMe. To do that, male Swiss mice received systemic injections (1 injection/day, 1 or 7 days) of imipramine (30 mg/kg), L-methionine (400, 800, 1600, and 3200 mg/kg), SAMe (10, 25, 50, 100, and 200 mg/kg), or vehicle (10 ml/kg) and were submitted to the FST or TST, 30 min after the last injection. The effect of SAMe (50 mg/kg) was further investigated in independent groups of male Swiss mice pretreated with p-chlorophenylalanine (PCPA, serotonin synthesis inhibitor, 150 mg/kg daily, 4 days) or with WAY100635 (5-HT1A receptor antagonist, 0.1 mg/kg, 1 injection). One independent group was submitted to the FST and euthanized immediately after for collection of brain samples for neurochemical analyses. Serotonin (5-HT) and noradrenaline (NA) levels were measured in the hippocampus (HPC) and prefrontal cortex (PFC). Furthermore, to investigate if the treatments used could induce any significant exploratory/motor effect which would interfere with the FST results, the animals were also submitted to the open field test (OFT). The administration of imipramine (30 mg/kg), L-methionine (400, 800, 1600, and 3200 mg/kg), and SAMe (10 and 50 mg/kg) reduced the immobility time in the FST, an effect blocked by pretreatment with PCPA and WAY100635. None of the treatments increased the locomotion in the OFT. In conclusion, our results suggest that the antidepressant-like effects induced by SAMe treatment are dependent on serotonin synthesis and 5-HT1A receptor activation.

Sitagliptin Attenuates the Cognitive Deficits in L-Methionine-Induced Vascular Dementia in Rats.

Vascular dementia (VaD) is the second most prevalent type of dementia characterized by progressive cognitive deficits and is a major risk factor for the development of Alzheimer's disease and other neurodegenerative disorders. This study is aimed at determining the potential neuroprotective effect of sitagliptin (STG) on cognitive deficits in L-methionine-induced VaD in rats and the possible underlying mechanisms. 30 adult male Wistar albino rats were divided equally (n = 10) into three groups: control, VaD, and VaD + STG groups. The cognitive performance of the animals was conducted by open field, elevated plus maze, Y-maze, novel object recognition, and Morris water maze tests. Serum homocysteine, TNF-α, IL-6, IL-10, total cholesterol, and triglycerides levels were assessed together with hippocampal MDA, SOD, and BDNF. Histopathological and immunohistochemical assessments of the thoracic aorta and hippocampus (CA1 region) were also performed. Chronic L-methionine administration impaired memory and learning and induced anxiety. On the other hand, STG protected against cognitive deficits through improving oxidative stress biomarkers, inflammatory mediators, lipid profiles, and hippocampus level of BDNF as well as decreasing caspase-3 and GFAP and increasing Ki-67 immunoreactions in the hippocampus. Also, STG improved the endothelial dysfunction via upregulation of aortic eNOS immunoreaction. STG improved the cognitive deficits of L-methionine-induced VaD by its antioxidant, anti-inflammatory, antiapoptotic, and neurotrophic effects. These findings suggest that STG may be a promising future agent for protection against VaD.

Morphofunctional changes in the rat's liver of different ages after L-methionine administration

Background: Literature data on the effect of methionine on functional activity and, especially, on morphological changes in the liver parenchyma in animals of different ages are sporadic, and research results are often ambiguous.
 Aim: The purpose of this work was to study and compare the morphofunctional changes in the liver of rats of different ages on prolonged administration of L-methionine.
 Material and Methods: The experiment was performed on 48 male Wistar rats of 3 and 15 months of age. Animals of the experimental group received L-methionine at a dose of 250 mg/kg body weight in addition to the standard diet, daily for 21 days. Histological preparations were prepared from liver tissue by a standard technique. Morphometry was performed on digital images using the computer program «Image J». Succinate dehydrogenase activity and protein concentration were determined in the suspension of hepatocyte mitochondria.
 Results: It was revealed that 21-day administration of L-methionine to rats led to hypertrophy of the hepatocyte nucleus, an increase in the nuclear-cytoplasmic ratio, the number of binuclear hepatocytes, and the nucleolus in the cell nucleus. The relative area of ​​the sinusoids network increased by 50% in 3-month-old animals. This indicated a better blood filling of the liver parenchyma. The increase in succinate dehydrogenase activity and protein concentration was revealed in the suspension of hepatocyte mitochondria of the experimental rats. This indicated an increase in the mitochondria energy potential and protein-synthetic activity.
 Conclusions: The administration of prophylactic doses of methionine to healthy rats leads to the appearance of pronounced morphological and functional signs of increased activity of hepatocytes. The severity of this effect has a distinct age-dependent character. In young rats, it is more pronounced than in mature rats. The results of the study are important for practical medicine when using methionine for therapeutic and prophylactic purposes.

The Protective Effects of Pioglitazone Against Cognitive Impairment Caused by L-methionine Administration in a Rat Model.

Accumulating evidence indicates that elevated levels of methionine are associated with cognitive decline, including loss of memory. The exact mechanisms behind this observation are not completely understood but could be related to an increase in oxidative stress markers in hippocampal tissues. The above increase in oxidative stress could be directly caused by an increase in the blood levels of methionine (hypermethioninemia) or one of its metabolites, such as homocysteine. Pioglitazone is a drug primarily used for the treatment of type 2 diabetes mellitus. Several reports showed that using pioglitazone protects against cognitive decline observed in Alzheimer's disease. Pioglitazone has antioxidant properties independent of its hypoglycemic effects. Taken together, we hypothesized that pioglitazone protects against memory loss triggered by elevated levels of methionine through lowering oxidative stress in the hippocampus. To test this hypothesis, we used chronic administration of L-methionine in a rat model. Spatial learning and memory were evaluated in the model using a radial arm water maze (RAWM). The levels of several markers related to oxidative stress were measured in hippocampal tissues recovered from experimental rats. Current results showed that administration of L-methionine was associated with a significant loss of short- and long-term memory and an increase in blood homocysteine levels. The above memory changes were associated with an increase in lipid peroxidation and a decrease in the activity of catalase and glutathione peroxidase antioxidant enzymes in the hippocampus. The combined treatment of pioglitazone with L-methionine protected rat model from memory loss. It also prevented changes observed in lipid peroxidation and changes in the activity of catalase and glutathione peroxidase enzymes. Current findings indicate that pioglitazone is a viable therapeutic option that protects against cognitive changes observed upon administration of L-methionine.

Effects of Sargassum wightii Methanolic Extract on L-Methionine Induced Experimental Vascular Dementia like Syndrome in Albino Wistar Rats

Sargassum wightii is brown seaweeds with high nutritive value with natural bioactive compounds having diverse therapeutic activity. In recent years, research on Sargassum wightii has gain much interest in neuropharmacological field. Basing on neuroprotective effect of Sargassum wightii against Parkinson’s disease animal models, the possible protective effect on dementia is hypothesised. Addressing this question the present study was designed to investigate the effect of S. wightii on L-methionine induced vascular dementia like syndrome in male wistar albino rats. Vascular dementia was induced by oral administration of L-methionine (1.7 g/kg) per body weight for 4weeks S. wightii was given from day1 to day32. The neurobehavioral assessment was performed by Morris water maze test for learning and memory ability and blood sample was collected for serum nitrite and homocysteine analysis. The whole brain content was subjected to a series of biochemical analysis that included brain cholinesterase, malondialdehyde, reduced glutathione and histopathological examination. L-methionine impaired learning and memory, increased serum homocysteine and decreased serum nitrite level significantly (p<0.001). It also increased brain thiobarbituric acid reactive substances, reduced glutathione and increased acetylcholinesterase activity significantly (p<0.001). Sargassum wightii at 200mg/kg and 400mg/kg body weight reversed the L-methionine induced learning and memory deficits (p<0.01) and (p<0.001) respectively. The L-methionine induced biochemical alterations in serum and brain as well as histopathological aberration in cortex and hippocampus were restored by Sargassum wightii (p<0.01). This study concluded that Sargassum wightii ameliorated L-methionine induced vascular dementia like syndrome and provided a new concept in anti-dementia therapy as a neuroprotectants.

Role of GABRD Gene Methylation in the Nucleus Accumbens in Heroin-Seeking Behavior in Rats.

Epigenetic modifications such as DNA methylation play important roles in regulating gene expression and may mediate neuroplasticity and lead to drug-induced aberrant behaviors. Although several brain regions and neurobiological mechanisms have been suggested to be involved in these processes, there is remarkably little known about the effects of DNA methylation on heroin-seeking behavior. Using a Sprague-Dawley rat model, we show that heroin self-administration resulted in gamma-aminobutyric acid type A receptor subunit delta (GABRD) gene hypomethylation, which was associated with transcriptional upregulation of GABRD in the nucleus accumbens (NAc). Systemic l-methionine (MET) administration significantly strengthened the reinstatement of heroin-seeking behavior induced by heroin priming, whereas intra-NAc injections of the DNA methyltransferase (DNMT) inhibitor 5-aza-2′-deoxycytidine (5-Aza-dC) had the opposite effect on heroin-seeking. Meanwhile, 5-Aza-dC treatment decreased DNA methylation and upregulated the expression of GABRD in the NAc, whereas MET had the opposite effect. Our results also reveal that 5-Aza-dC might alter the methylation landscape of the GABRD gene by directly repressing DNMT1 and DNMT3A expression. Furthermore, reinstatement of heroin-seeking behavior was significantly inhibited by directly overexpressing GABRD and remarkably reinforced by GABRD gene silencing in the NAc. Collectively, these results suggest that targeting the GABRD gene and its methylation might represent a novel pharmacological strategy for treating heroin addiction and relapse.

Methionine Supplementation Abolishes Nicotine-Induced Place Preference in Zebrafish: a Behavioral and Molecular Analysis.

In zebrafish, nicotine is known to regulate sensitivity to psychostimulants via epigenetic mechanisms. Little however is known about the regulation of addictive-like behavior by DNA methylation processes. To evaluate the influence of DNA methylation on nicotine-induced conditioned place preference (CPP), zebrafish were exposed to methyl supplementation through oral L-methionine (Met) administration. Met was found to reduce dramatically nicotine-induced CPP as well as behaviors associated with drug reward. The reduction was associated with the upregulation of DNA methyltransferases (DNMT1 and 3) as well as with the downregulation of methyl-cytosine dioxygenase-1 (TET1) and of nicotinic receptor subunits. Met also increased the expression of histone methyltransferases in nicotine-induced CPP groups. It reversed the nicotine-induced reduction in the methylation at α7 and NMDAR1 gene promoters. Treatment with the DNMT inhibitor 5-aza-2'-deoxycytidine (AZA) was found to reverse the effects of Met in structures of the reward pathway. Interestingly, Met did not modify the amount of the phospho-form of CREB (pCREB), a key factor establishing nicotine conditioning, whereas AZA increased pCREB levels. Our data suggest that nicotine-seeking behavior is partially dependent on DNA methylation occurring probably at specific gene loci, such as α7 and NMDAR1 receptor gene promoters. Overall, they suggest that Met should be considered as a potential therapeutic drug to treat nicotine addiction.

Edaravone protects from memory impairment induced by chronic L-methionine administration.

Hyperhomocysteinemia is a well-known cause of cognitive impairment and neurodegeneration. Increased oxidative stress in the brain has a major possible role in hyperhomocysteinemia-induced pathogenesis. Edaravone is a potent free radical scavenger that has a neuroprotective effect against memory impairment in several experimental models. The current study investigated the possible protective effect of edaravone in L-methionine-induced vascular dementia in a rat model. L-methionine was given (1.7mg/kg/day) through oral gavage, while edaravone was given (6mg/kg/day) intraperitoneally. The administration of methionine and edaravone started concomitantly and continued for a total of 9weeks. Spatial learning and memory were assessed using the radial arm water maze (RAWM). Changes in the oxidative stress-related biomarkers in the hippocampus were assessed using enzymatic assays. Chronic L-methionine administration resulted in short-term and long-term memory impairment, whereas edaravone prevented such effect. Furthermore, edaravone ameliorated L-methionine induced decrease in the activity of the antioxidant enzymes catalase and glutathione peroxidase as well as the ratio of reduced glutathione to oxidized glutathione (GSH/GSSG ratio). Edaravone also prevented increase in the oxidized glutathione (GSSG) secondary to chronic L-methionine administration. In conclusion, the current study suggests that memory impairment and oxidative stress secondary to chronic L-methionine administration can be prevented by edaravone, probably via enhancing antioxidant mechanisms in the hippocampus.

Neurotrophic factors and inflammatory cytokines in the mother-placenta-fetus system in experimental hyperhomocysteinemia

An essential aspect of metabolic imbalance of L-homocysteine and its accumulation in blood (hyperhomocysteinemia) is its aggravating effect in pregnancy. However, little is known about the effects of maternal increased L-homocysteine levels on brain development of fetuses. In the development of the fetus, accompanied by changes in metabolism in the placenta, an important role belongs to neurotrophic factors and apoptosis. This study investigated the effects of chronic L-methionine administration on some parameters of inflammation and on neurotrophic factor levels in the brain of embryos, as well as in the placenta and serum of pregnant rats. The observed disturbances can be resulted from both a direct impact of L-homocysteine and its metabolites on the fetal CNS, and hyperhomocysteinemia-caused changes in normal state of the placenta.

Neuroprotective effects of zafirlukast, piracetam and their combination on L-Methionine-induced vascular dementia in rats.

Vascular dementia is considered a vascular cognitive impairment disease caused by neuronal degeneration in the brain. Several studies have supported the hypothesis that oxidative stress and endothelial dysfunction are the main pathogenic factors in vascular dementia. This current study aims to determine the possible neuroprotective effects of zafirlukast, piracetam and the combination of piracetam and zafirlukast on L-methionine-induced vascular dementia in rats. Male Wistar albino rats were divided into five groups. Group I was the normal control, and group II received L-methionine (1700mg/kg, P.O.) for 32days. The remaining groups received zafirlukast (20mg/kg, P.O.), piracetam (600mg/kg, P.O.) or their combination (zafirlukast 20mg/kg+piracetam 600mg/kg, P.O.) for 32days after L-methionine administration. Afterwards, the cognitive and memory performances of the rats were investigated using the novel object recognition (NOR) test; rats were then sacrificed for histopathological and biochemical analyses. L-methionine-induced vascular dementia altered rats' behaviours and the brain contents of different neurotransmitters and acetylcholinesterase activity while increasing levels of oxidative stress and causing notable histopathological alterations in brain tissues. The treatment of vascular dementia with zafirlukast and the combination improved neurochemical, behavioural and histological alterations to a comparable level to those of piracetam. Thus, zafirlukast, piracetam and the combination of both drugs can be considered as potential therapeutic strategies for the treatment of vascular dementia induced by L-methionine. To the best of our knowledge, this study is the first to explore the neuroprotective effects of zafirlukast and piracetam on L-methionine-induced vascular dementia.

Optogenetic inhibition of medial prefrontal cortex projections to the nucleus accumbens core and methyl supplementation via L-Methionine attenuates cocaine-primed reinstatement.

DNA methylation has been identified as a powerful and activity-dependent regulator of changes in the brain that may underlie neuroadaptations in response to various types of stimuli, including exposure to drugs of abuse. Indeed, the medial prefrontal cortex (mPFC) projections to the nucleus accumbens (NAc) are critically important for reinstated cocaine-seeking in a rodent model of cocaine relapse. This circuitry undergoes several epigenetic modifications following cocaine exposure, including changes in DNA methylation that are associated with drug-seeking behavior. We have previously shown that methyl supplementation via L-Methionine (MET) administration attenuates cocaine-seeking behavior and reverses expression and methylation patterns of the immediate early gene c-fos, suggesting that MET may act by altering the excitability of this circuitry during cocaine reinstatement. In the current study, male rats were microinjected with an adeno-associated virus overexpressing halorhodopsin in the mPFC, optical fibers were surgically implanted into the NAc, and the rats were given injections of MET daily. Rats underwent acquisition of cocaine self-administration (0.75 mg/kg/infusion, 2-h sessions) followed by extinction training in the absence of drug-paired cues. Two reinstatement tests were conducted: cue-induced reinstatement without optogenetic manipulations and cocaine-primed reinstatement with optogenetic inhibition of mPFC-to-NAc projections. There were no group differences before the cocaine-primed reinstatement session, and all groups showed robust cue-induced reinstatement. Both rats treated with MET and rats that received mPFC-to-NAc inhibition showed an abolishment of cocaine-primed reinstatement, suggesting that systemic methyl supplementation may act through this critical circuity.

Caffeine Prevents Memory Impairment Induced by Hyperhomocysteinemia.

L-Methionine chronic administration leads to impairment of memory. This impairment is due to the increase in the body oxidative stress, which damages neurons and prevents their firing. On the other hand, caffeine has antioxidant and neuroprotective effects that could prevent impairment of memory induced by L-methionine chronic administration. In the current study, this hypothesis was evaluated. L-methionine (1.7g/kg/day) was orally administered to animals for 4weeks and caffeine (0.3g/L) treatment was added to the drinking water. The radial arm water maze (RAWM) was used to test spatial learning and memory. Antioxidant biomarkers were assessed in the hippocampus tissues using biochemical assay methods. Chronic L-methionine administration induced (short- and long-) term memory impairment (P < 0.05), while caffeine treatment prevented such effect. Additionally, L-methionine treatment reduced catalase and glutathione peroxidase (GPx") enzymatic activities, and reduced glutathione (GSH) to oxidized glutathione (GSSG) ratio. These effects were normalized by caffeine treatment. Activity of superoxide dismutase (SOD) was unchanged by either L-methionine or caffeine treatments. In conclusion, L-methionine induces impairment of memory, and caffeine treatment prevented this impairment probably through affecting hippocampus antioxidant mechanisms.

Possible role of endothelin receptor against hyperhomocysteinemia and β-amyloid induced AD type of vascular dementia in rats.

Vascular dementia (VaD) is considered as the second commonest form of dementia after Alzheimer's disease (AD). The study was designed to investigate the effect of endothelin receptor against β-amyloid induced AD type of vascular dementia. This disease was induced by combine administration of single ICV (intracerebroventricle) infusion of β-amyloid (Aβ) once and chronic oral administration of l-Methionine for 21 days. Bosentan (dual endothelin receptor antagonist) was administered for 21 days. Behavioral alterations were observed during different time interval of the study. Animals were killed immediately following the last behavior session. Oxidative parameters, acetylcholinesterase activity, neuro-inflammatory markers, amyloid beta levels were determined in hippocampus and cortex while serum homocysteine, serum nitrite carotid artery superoxide anion level were also determined. Endothelial function was measured on isolated carotid artery using myograph instrument. Aβ+l-Methionine showed more significant development of cognitive and vascular endothelial deficits, manifested in terms of increase in serum homocysteine level, endothelial dysfunction, impairment of learning and memory, enhanced brain acetylcholinesterase activity, marked mito-oxidative damage in rats. We have observed that l-Methionine and combination of Aβ+l-Methionine significantly enhanced Aβ level both in cortex as well as hippocampus. Treatment of bosentan attenuated Aβ+l-Methionine induced impairment of learning and memory, enhanced Aβ level, mitochondrial and endothelial dysfunction. The results of present study concluded that bosentan offers protection against β-amyloid-induced vascular dementia in rats. Endothelin receptor may be considered as a potential pharmacological target for the management of AD type of vascular dementia.

Hesperidin, a citrus flavonoid, protects against l-methionine-induced hyperhomocysteinemia by abrogation of oxidative stress, endothelial dysfunction and neurotoxicity in Wistar rats

Context: Hesperidin (HSP), a flavanoglycone found in citrus fruits, has antioxidant, anti-inflammatory and neuroprotective properties.Objective: This study evaluates the protective effect of HSP on l-methionine-induced hyperhomocysteinemia (HHcy) in rats.Materials and methods: Male Wistar rats were randomly divided into seven groups as DMSO, l-methionine, HSP (25, 50 and 100 mg/kg), HSP-per se (100 mg/kg) and donepezil (0.1 mg/kg). HHcy was induced by oral administration of l-methionine (1.7 g/kg) for 32 days. From the 14th day of study HSP (25, 50 and 100 mg/kg) and donepezil was administered orally to l-methionine-treated rats. Cognitive impairment induced by HHcy was determined using the Morris water maze (MWM) and Y-maze on video tracking system (28th–32nd day). Different biomarkers of HHcy in serum and brain and vascular reactivity were evaluated and histopathology (thoracic aorta and brain) was done.Results: HSP (100 mg/kg) treatment in l-methionine-treated rats exhibited significant (p < 0.001) dose-dependent activity and reduced behavioural deficits, brain acetylcholinesterase (25.99 ± 2.36 versus 10.73 ± 1.26 μmoles/mg), brain lipid peroxidation (15.25 ± 1.65 versus 6.18 ± 0.74 nM/mg), serum homocysteine (Hcy) (22.37 ± 0.30 versus 11.01 ± 1.01 μg/mL) and serum cholesterol (182.7 ± 2.15 versus 101.5 ± 2.76 mg/dL) and increased brain antioxidant levels. HSP significantly (p < 0.001) reduced endothelial dysfunction (ED) by abolishing the effect of l-methionine on acetylcholine-induced endothelial-dependent relaxation and increased serum nitrite and vascular nitric oxide bioavailability along with the restoration of histological aberrations.Conclusion: HSP exerts a protective effect on HHcy by abrogating oxidative stress, ED and neurotoxicity.

DNA methylation regulates gabrb2 mRNA expression: developmental variations and disruptions in l-methionine-induced zebrafish with schizophrenia-like symptoms.

Single nucleotide polymorphisms (SNPs) in the human type A gamma-aminobutyric acid (GABA) receptor β2 subunit gene (GABRB2) have been associated with schizophrenia and quantitatively correlated with mRNA expression in the postmortem brain tissue of patients with schizophrenia. l-Methionine (MET) administration has been reported to cause a recrudescence of psychotic symptoms in patients with schizophrenia, and similar symptoms have been generated in MET-induced mice. In this study, a zebrafish animal model was used to evaluate the relationship between the gabrb2 mRNA expression and its promoter DNA methylation in developmental and MET-induced schizophrenia-like zebrafish. The results indicated developmental increases in global DNA methylation and decreases in gabrb2 promoter methylation in zebrafish. A significant increase in gabrb2 mRNA levels was observed after GABA was synthesized. Additionally, the MET-triggered schizophrenia-like symptoms in adult zebrafish, involving social withdrawal and cognitive dysfunction analyzed with social interaction and T-maze behavioral tests, were accompanied by significantly increased DNA methylation levels in the global genome and the gabrb2 promoter. Furthermore, the significant correlation between gabrb2 mRNA expression and gabrb2 promoter methylation observed in the developmental stages became non-significant in MET-triggered adult zebrafish. These findings demonstrate that gabrb2 mRNA expression is associated with DNA methylation varies by developmental stage and show that these epigenetic association mechanisms are disrupted in MET-triggered adult zebrafish with schizophrenia-like symptoms. In conclusion, these results provide plausible epigenetic evidence of the GABAA receptor β2 subunit involvement in the schizophrenia-like behaviors and demonstrate the potential use of zebrafish models in neuropsychiatric research.

Effects of fisetin on hyperhomocysteinemia-induced experimental endothelial dysfunction and vascular dementia.

This study was designed to investigate the effects of fisetin (FST) on hyperhomocysteinemia (HHcy)-induced experimental endothelial dysfunction (ED) and vascular dementia (VaD) in rats. Wistar rats were randomly divided into 8 groups: control, vehicle control, l-methionine, FST (5, 10, and 25 mg/kg, p.o.), FST-per se (25 mg/kg, p.o.), and donepezil (0.1 mg/kg, p.o.). l-Methionine administration (1.7 g/kg, p.o.) for 32 days induced HHcy. ED and VaD induced by HHcy were determined by vascular reactivity measurements, behavioral analysis using Morris water maze and Y-maze, along with a biochemical and histological evaluation of thoracic aorta and brain tissues. Administration of l-methionine developed behavioral deficits; triggered brain lipid peroxidation (LPO); compromised brain acetylcholinesterase activity (AChE); and reduced the levels of brain superoxide dismutase (SOD), brain catalase (CAT), brain reduced glutathione (GSH), and serum nitrite; and increased serum homocysteine and cholesterol levels. These effects were accompanied by decreased vascular NO bioavailability, marked intimal thickening of the aorta, and multiple necrotic foci in brain cortex. HHcy-induced alterations in the activities of SOD, CAT, GSH, AChE, LPO, behavioral deficits, ED, and histological aberrations were significantly attenuated by treatment with fisetin in a dose-dependent manner. Collectively, our results indicate that fisetin exerts endothelial and neuroprotective effects against HHcy-induced ED and VaD.

Effect of L-Methionine on the Risk of Phosphate Stone Formation

To determine the physiological effects following administration of the sulfur-containing amino acid L-methionine on urinary risk factors for calcium oxalate and phosphate stone formation under controlled, standardized conditions. Twelve healthy subjects were studied while consuming a standardized diet for 6 days. Day 5 was considered as control day. On day 6 (test day), participants received 1500 mg L-methionine at 9 AM. On the control and test days, 24-hour fractional urine collections were obtained. After single-dose administration of L-methionine, 24-hour fractional urinary pH decreased to values between 5.98 and 6.32. Urinary sulfate excretion, a direct marker for the metabolism of L-methionine, and ammonium excretion, which reflects the increase in net acid production, increased significantly after L-methionine administration. Urinary calcium excretion did not differ between control and test day (5.55 vs 5.45 mmol/24 hours; P = .754). The relative supersaturation of brushite and struvite decreased significantly by 25% (P = .010) and 34% (P = .049), respectively, whereas the risk of calcium oxalate stone formation was not affected by application of L-methionine (P = .477). The present findings show that L-methionine effectively decreases urinary pH and the risk of struvite and calcium phosphate stone formation in healthy subjects. Hypercalciuria is not expected to occur at physiological doses of L-methionine.

Low-dose L-methionine-associated Changes in Behavioural Indices in Young Rats

Objective: The study objectives were to investigate the effects of L-methionine (at low doses) on open-field novelty-induced behaviours, anxiety-related behaviours, working-memory and brain S-adenosyl-methionine (SAMe) levels in young rats. This was with a view to determine whether administration of low doses of L-methionine can significantly alter behavioural parameters, working-memory and brain SAMe levels, or not. Methodology: Wistar rats (40-45 g each) were given distilled water or L-methionine (5 and 10 mg/kg body weight) orally for 21 days. Behaviours were assessed after the first and last dose of L-methionine. Results: In the open field, significant increases in horizontal locomotion and rearing were seen after the first dose, while repeated administration led to their suppression. Suppression of grooming behaviour was observed at both times of assessment. Working-memory in the radial-arm maze was significantly reduced following repeated administration; while the elevated plus-maze test revealed anxiolytic responses following both acute and repeated administration. Patterns of changes in horizontal locomotion in the y-maze and radial-arm maze were similar to that of the open-field. There was no significant difference in brain levels of SAMe at end of study. Conclusion: The study demonstrated an association between low dose L-methionine administration and behavioural changes in young rats. It therefore brings to light, the behavioural changes that may occur due to addition of low doses of L-methionine to the diet.

Nebivolol to attenuate the effects of hyper-homocysteinaemia in rats

ObjectiveThis study investigated the prophylactic effect of nebivolol against hyper-homocysteinaemia (hHcy) induced oxidative stress in brain, heart, liver and kidney tissues and histomorphometric changes in the thoracic aorta. MethodsTwenty-four adult male Wistar rats were divided into a control, nebivolol, hHcy and nebivolol + hHcy group. hHcy was induced by oral administration of l-methionine (1 g/kg/day) for 28 days. 10 mg/kg/day nebivolol was administered orally for 28 days. Malondialdehyde (MDA) and glutathione (GSH) levels and catalase (CAT) and superoxide dismutase (SOD) activities in the tissues were determined. The total cross-sectional area (TCSA), luminal cross-sectional area (LCSA) and intima-media thickness (IMT) were measured in the thoracic aorta. ResultsHomocysteine (Hcy) levels were lower in the nebivolol + hHcy group than in the hHcy group. Nebivolol treatment significantly decreased high MDA levels in the brain, heart and liver tissues. The level of GSH was higher in the brain, heart and kidney tissues of the nebivolol + hHcy group (P < 0.001). The activity of CAT increased only in the kidney tissue of the nebivolol + hHcy group (P < 0.01), and the activity of SOD was significantly increased in all the tissues in this group. Increased TCSA and IMT in the nebivolol + hHcy group were significantly decreased after nebivolol administration. The LCSA was significantly higher in the hHcy group than the control group, probably due to outward vascular remodelling. ConclusionNebivolol treatment may be useful in different clinical scenarios where hHcy affects physiopathological pathways.