Methylglyoxal-Mediated Dopamine Depletion, Working Memory Deficit, and Depression-Like Behavior Are Prevented by a Dopam
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Methylglyoxal-Mediated Dopamine Depletion, Working Memory Deficit, and Depression-Like Behavior Are Prevented by a Dopamine/Noradrenaline Reuptake Inhibitor Gudrian Ricardo Lopes de Almeida 1 & Jozimar Carlos Szczepanik 2 & Ingrid Selhorst 3 & Ariana Ern Schmitz 3 & Bárbara dos Santos 3 & Maurício Peña Cunha 1 & Isabella Aparecida Heinrich 2 & Gabriela Cristina de Paula 3 & Andreza Fabro De Bem 1,4 & Rodrigo Bainy Leal 1,2,3 & Alcir Luiz Dafre 1,2,3 Received: 27 April 2020 / Accepted: 22 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Methylglyoxal (MGO) is an endogenous toxin, mainly produced as a by-product of glycolysis that has been associated to aging, Alzheimer’s disease, and inflammation. Cell culture studies reported that MGO could impair the glyoxalase, thioredoxin, and glutathione systems. Thus, we investigated the effect of in vivo MGO administration on these systems, but no major changes were observed in the glyoxalase, thioredoxin, and glutathione systems, as evaluated in the prefrontal cortex and the hippocampus of mice. A previous study from our group indicated that MGO administration produced learning/memory deficits and depression-like behavior. Confirming these findings, the tail suspension test indicated that MGO treatment for 7 days leads to depression-like behavior in three different mice strains. MGO treatment for 12 days induced working memory impairment, as evaluated in the Y maze spontaneous alternation test, which was paralleled by low dopamine and serotonin levels in the cerebral cortex. Increased DARPP32 Thr75/Thr34 phosphorylation ratio was observed, suggesting a suppression of phosphatase 1 inhibition, which may be involved in behavioral responses to MGO. Co-treatment with a dopamine/noradrenaline reuptake inhibitor (bupropion, 10 mg/kg, p.o.) reversed the depression-like behavior and working memory impairment and restored the serotonin and dopamine levels in the cerebral cortex. Overall, the cerebral cortex monoaminergic system appears to be a preferential target of MGO toxicity, a new potential therapeutic target that remains to be addressed. Keywords Methylglyoxal . Mood disorder . Working memory . Dopamine . DARPP32
Abbreviations 5-HT Serotonin AGE Advanced glycation end products Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02146-3) contains supplementary material, which is available to authorized users. * Alcir Luiz Dafre [email protected] 1
Biochemistry Post-Graduation Program, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil
2
Neurosciences Post-Graduation Program, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil
3
Department of Biochemistry, Biological Sciences Center, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil
4
Department of Physiological Science, Institute for Biological Sciences, University of Brasília, Brasília, Brazil
AKR BUP Ctl DA DARPP32 D J 1 / PARK7 GCL Glo GR GSH HP MGO N
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