Central and Systemic Responses to Methionine-Induced Hyperhomocysteinemia in Mice

Abstract

Hyperhomocysteinemia has been considered a risk factor for neuropsychiatric disorders, but the mechanisms involved in this process have not been completely elucidated. The aim of this study was to analyze the influence of hyperhomocysteinemia induction by methionine supplementation considering different levels and periods of exposure in mice. For this purpose, methionine supplementation at concentrations of 0.5 and 1% were administered in water to increase homocysteinemia in male C57BL/6 mice, and was maintained for 3 time periods (2, 4 and 6 months of treatment). The results from one-carbon metabolism parameters, brain-derived neurotrophic factor (BDNF) concentrations and behavioral evaluation were compared. The 0.5% supplementation was efficient in increasing plasma homocysteine levels after 2 and 6 months. The 1% supplementation, increased plasma homocysteine after 2, 4 and 6 months. Little influence was observed in cysteine and glutathione concentrations. Frontal cortex BDNF levels showed a lack of treatment influence in all periods; only the expected decrease due to increasing age was observed. Moreover, the only behavioral alteration observed using a novel object recognition task was that which was expected with increasing age. We found that responses to hyperhomocysteinemia varied based on how it was reached, and the length of toxicity. Moreover, hyperhomocysteinemia can affect the normal pattern of one carbon metabolism during age increase in mice. These findings allow the establishment of a reliable animal model for studies in this field.

Hydrogen sulfide attenuates homocysteine‐induced cognitive deficits and neurochemical alterations by improving endogenous hydrogen sulfide levels

“…These results are consistent with the previous reports suggesting elevated Hcy levels in brain tissues following Hcy administration . A similar increase in Hcy levels was observed in cerebral cortex of animals following methionine‐induced HHcy . Hcy and H 2 S are both intermediates in methionine metabolism exerting opposite effects on neuronal cell viability .…”

Palm tocotrienol-rich fraction inhibits methionine-induced cystathionine β-synthase in rat liver

“…In vitro studies demonstrated that addition of pro-oxidants to liver cell line increased conversion of homocysteine to cystathionine [29] and later to glutathione [42]. However, few studies have reported that glutathione content was unaltered in rats after methionine load [1,4]. The augmented hepatic oxidative stress measured as TBARS observed in the methioninefed group might also contribute to the activation of the transsulphuration pathway in our study.…”

Large Neutral Amino Acid Supplementation Exerts Its Effect through Three Synergistic Mechanisms: Proof of Principle in Phenylketonuria Mice

“…Brain methionine concentrations were even significantly increased by 5.5-fold in PKU mice on LNAA supplementation compared to normal chow, corresponding with the similarly strong increases in blood. Although the cerebral and systemic effects and possible toxicity due to these strongly elevated methionine concentrations are not fully understood [ 36 ], at least these results warrant against indiscriminate supplementation of methionine in PKU. Also, brain histidine concentrations in PKU mice were even further increased on LNAA supplementation.…”