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Activation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure.

ABSTRACT: Methamphetamine (METH) is a highly addictive psychostimulant that causes long-lasting effects in the brain and increases the risk of developing neurodegenerative diseases. The cellular and molecular effects of METH in the brain are functionally linked to alterations in glutamate levels. Despite the well-documented effects of METH on glutamate neurotransmission, the underlying mechanism by which METH alters glutamate levels is not clearly understood. In this study, we report an essential role of proline biosynthesis in maintaining METH-induced glutamate homeostasis. We observed that acute METH exposure resulted in the induction of proline biosynthetic enzymes in both undifferentiated and differentiated neuronal cells. Proline level was also increased in these cells after METH exposure. Surprisingly, METH treatment did not increase glutamate levels nor caused neuronal excitotoxicity. However, METH exposure resulted in a significant upregulation of pyrroline-5-carboxylate synthase (P5CS), the key enzyme that catalyzes synthesis of proline from glutamate. Interestingly, depletion of P5CS by CRISPR/Cas9 resulted in a significant increase in glutamate levels upon METH exposure. METH exposure also increased glutamate levels in P5CS-deficient proline-auxotropic cells. Conversely, restoration of P5CS expression in P5CS-deficient cells abrogated the effect of METH on glutamate levels. Consistent with these findings, P5CS expression was significantly enhanced in the cortical brain region of mice administered with METH and in the slices of cortical brain tissues treated with METH. Collectively, these results uncover a key role of P5CS for the molecular effects of METH and highlight that excess glutamate can be sequestered for proline biosynthesis as a protective mechanism to maintain glutamate homeostasis during drug exposure.

SUBMITTER: Jones B

PROVIDER: S-EPMC7809342 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Recent evidence suggests that the effects of certain food additives may be synergistic or additive. Aspartame (ASP) and Monosodium Glutamate (MSG) are ubiquitous food additives with a common moiety: both contain acidic amino acids which can act as neurotransmitters, interacting with NMDA receptors concentrated in areas of the Central Nervous System regulating energy expenditure and conservation. MSG has been shown to promote a neuroendocrine dysfunction when large quantities are administered to mammals during the neonatal period. ASP is a low-calorie dipeptide sweetener found in a wide variety of diet beverages and foods. However, recent reports suggest that ASP may promote weight gain and hyperglycemia in a zebrafish nutritional model. METHODS:We investigated the effects of ASP, MSG or a combination of both on glucose and insulin homeostasis, weight change and adiposity, in C57BL/6?J mice chronically exposed to these food additives commencing in-utero, compared to an additive-free diet. Pearson correlation analysis was used to investigate the associations between body characteristics and variables in glucose and insulin homeostasis. RESULTS:ASP alone (50?mg/Kgbw/day) caused an increase in fasting blood glucose of 1.6-fold, together with reduced insulin sensitivity during an Insulin Tolerance Test (ITT) P?<?0.05. Conversely MSG alone decreased blood triglyceride and total cholesterol (T-CHOL) levels. The combination of MSG (120?mg/Kgbw/day) and ASP elevated body weight, and caused a further increase in fasting blood glucose of 2.3-fold compared to Controls (prediabetic levels); together with evidence of insulin resistance during the ITT (P?<?0.05). T-CHOL levels were reduced in both ASP-containing diets in both genders. Further analysis showed a strong correlation between body weight at 6?weeks, and body weight and fasting blood glucose levels at 17?weeks, suggesting that early body weight may be a predictor of glucose homeostasis in later life. CONCLUSIONS:Aspartame exposure may promote hyperglycemia and insulin intolerance. MSG may interact with aspartame to further impair glucose homeostasis. This is the first study to ascertain the hyperglycemic effects of chronic exposure to a combination of these commonly consumed food additives; however these observations are limited to a C57BL/6?J mouse model. Caution should be applied in extrapolating these findings to other species.

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Activation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure.

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