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The hippocampus of Ames dwarf mice exhibits enhanced antioxidative defenses following kainic acid-induced oxidative stress.

ABSTRACT: INTRODUCTION:The vulnerability of the hippocampus to the effects of aging has been found to be associated with a decline in growth hormone/insulin like growth factor-1 (GH/IGF-1), and an increase in oxidative stress. We have evidence that long-living GH-deficient Ames dwarf mice have enhanced antioxidant protection in the periphery but the protection in the central nervous system is less clear. MATERIAL AND METHODS:In the present study, we evaluated the antioxidative defense enzyme status in the hippocampus of Ames dwarf and wild type mice at 3, 12 and 24 months of age and examined the ability of each genotype to resist kainic acid-induced (KA) oxidative stress. An equiseizure concentration of KA was administered such that both genotypes responded with similar seizure scores and lipid peroxidation. RESULTS:We found that GH-sufficient wild type mice showed an increase in oxidative stress as indicated by the reduced ratio of glutathione: glutathione disulfide following KA injection while this ratio was maintained in GH-deficient Ames dwarf mice. In addition, glutathione peroxidase activity (GPx) as well as GPx1 mRNA expression was enhanced in KA-injected Ames dwarf mice but decreased in wild type mice. There was no induction of Nrf-2 (an oxidative stress-induced transcription factor) gene expression in Ames dwarf mice following KA further suggesting maintenance of antioxidant defense in GH-deficiency under oxidative stress conditions. DISCUSSION:Therefore, based on equiseizure administration of KA, Ames dwarf mice have an enhanced antioxidant defense capacity in the hippocampus similar to that observed in the periphery. This improved defense capability in the brain is likely due to increased GPx availability in Ames mice and may contribute to their enhanced longevity.

SUBMITTER: Sharma S

PROVIDER: S-EPMC6432800 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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The hippocampus of Ames dwarf mice exhibits enhanced antioxidative defenses following kainic acid-induced oxidative stress.

Sharma Sunita S Rakoczy Sharlene S Dahlheimer Kristine K Brown-Borg Holly H

Experimental gerontology 20100908 12

<h4>Introduction</h4>The vulnerability of the hippocampus to the effects of aging has been found to be associated with a decline in growth hormone/insulin like growth factor-1 (GH/IGF-1), and an increase in oxidative stress. We have evidence that long-living GH-deficient Ames dwarf mice have enhanced antioxidant protection in the periphery but the protection in the central nervous system is less clear.<h4>Material and methods</h4>In the present study, we evaluated the antioxidative defense enzym ...[more]

PMID: 20804841

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Project description:Long-lived Ames dwarf mice lack growth hormone, prolactin, and thyroid stimulating hormone. Additionally the dwarf mice have enzyme activities and levels that combat oxidative stress more efficiently than those of normal mice. We have shown that methionine metabolism in Ames mice is markedly different than in their wild type littermates. In our previous work we hypothesized that the flux of methionine to the transsulfuration pathway is enhanced in the dwarf mice. The current study was designed to determine whether the flux of methionine to the transsulfuration pathway is increased. We did this by injecting either l-[methyl-(3)H]-methionine or l-[(35)S]-methionine into dwarf or normal mice and then determined retained label (in form of S-adenosylmethionine) 45 min later. The amount of retained hepatic (3)H and (35)S label was significantly reduced in the dwarf mice; at 45 min the specific radioactivity of SAM (pCi/nmol SAM) was 56% lower (p < 0.05) for (3)H-label and 64% lower (p < 0.005) for (35)S-label in dwarf than wild type mice. Retention of (35)S was significantly lower in the brain (37%, p < .04) and kidney (47%, p < 0.02) of the dwarf compared to wild type mice; there was no statistical difference in retained (3)H-label in either brain or kidney. This suggests that both the methyl-moiety and the carbon chain of methionine are lost much faster in the dwarf compared to the wild type mouse, implying that both transmethylation in the liver and transsulfuration in the liver, brain, and kidney are increased in the dwarf mice. As further support, we determined by real-time RT PCR the expression of methionine metabolism genes in livers of mice. Compared to wild type, the Ames dwarf had increased expression of methionine adenosyltransferase 1a (2.3-fold, p = 0.013), glycine N-methyltransferase (3.8-fold, p = 0.023), betaine homocysteine methyltransferase (5.5-fold, p = 0.0006), S-adenosylhomocysteine hydrolase (3.8-fold, p = 0.0005), and cystathionase (2.6-fold; tended to be increased, p = 0.055). Methionine synthase expression was significantly decreased in dwarf compared to wild type (0.48-fold, p = 0.023). These results confirm that the flux of methionine to transsulfuration is enhanced in the Ames dwarf. This, along with data from previous studies support the hypothesis that altered methionine metabolism plays a significant role in the oxidative defense of the dwarf mouse and that the mechanism for the enhanced oxidative defense may be through altered GSH metabolism as a result of the distinctive methionine metabolism.

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The hippocampus of Ames dwarf mice exhibits enhanced antioxidative defenses following kainic acid-induced oxidative stress.

Publications

The hippocampus of Ames dwarf mice exhibits enhanced antioxidative defenses following kainic acid-induced oxidative stress.

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