The expanding impact of methylglyoxal on behavior-related disorders.

Methylglyoxal (MGO) is a reactive dicarbonyl compound formed as a byproduct of glycolysis. MGO is a major cell-permeant precursor of advanced glycation end products (AGEs), since it readily reacts with basic phospholipids and nucleotides, as well as amino acid residues of proteins, such as arginine, cysteine, and lysine. The AGEs production induced by MGO are widely associated with several pathologies, including neurodegenerative diseases. However, the impact of MGO metabolism and AGEs formation in the central nervous system (particularly in neurons, astrocytes and oligodendrocytes) on behavior and psychiatric diseases is not fully understood. Here, we briefly present background information on the biological activity of MGO in the central nervous system. It was gathered the available information on the role of MGO metabolism at the physiological processes, as well as at the neurobiology of psychiatry diseases, especially pain-related experiences, anxiety, depression, and cognition impairment-associated diseases. To clarify the role of MGO on behavior and associated diseases, we reviewed primarily the main findings at preclinical studies focusing on genetic and pharmacological approaches. Since monoamine neurotransmitter systems are implicated as pivotal targets on the pathophysiology and treatment of psychiatry and cognitive-related diseases, we also reviewed how MGO affects these neurotransmission systems and the implications of this phenomenon for nociception and pain; learning and cognition; and mood. In summary, this review highlights the pivotal role of glyoxalase 1 (Glo1) and MGO levels in modulating behavioral phenotypes, as well as related cellular and molecular signaling. Conclusively, this review signals dopamine as a new neurochemical MGO target, as well as highlights how MGO metabolism can modulate the pathophysiology and treatment of pain, psychiatric and cognitive-related diseases.

Consulta de seguimento após inserção de dispositivo intrauterino de cobre (tcu 380a) pós-placentário / Consulta de seguimiento tras inserción de dispositivo intrauterino de cobre (tcu 380a) post placentario / Follow-up visit after post-placental copper intrauterine device insertion (tcu 380a)

RESUMO Objetivo: analisar a ocorrência de consultas de seguimento das mulheres usuárias de DIU de cobre (TCu 380A), inserido durante período pós-placentário (pós-parto e trans-cesárea), em um hospital público, da região Sul do Brasil. Método: coorte prospectiva com mulheres que inseriram o DIU no período pós-placentário e que responderam ao questionário referente à consulta de seguimento. A coleta ocorreu entre setembro/2020 e fevereiro/2021. Utilizou-se teste Qui-quadrado para análise, considerando-se valor de significância de 5% (p<0,05). Resultados: foram entrevistadas 285 mulheres, com média de idade de 28,5 anos e 10 de anos de estudo. Na amostra, 60,7% realizaram a consulta de seguimento com 29,8% no período adequado, 61,3% tiveram o exame ginecológico realizado e 78,1 % foram atendidas por médicos. As principais razões relatadas para a não ocorrência da consulta de seguimento foram indisponibilidade de consulta no período recomendado (38,2%) e orientação profissional para realização da consulta após ultrassonografia (26,3%). Conclusão: observou-se dificuldades na realização adequada da consulta de seguimento para grande parte da amostra. Os achados deste estudo sugerem a necessidade de ampliação do acesso aos serviços de saúde e capacitação das equipes de saúde para atendimento da consulta de seguimento após a inserção do DIU pós-placentário, baseada em protocolos definidos.

RESUMEN Objetivo: analizar la ocurrencia de consultas de seguimiento de las mujeres usuarias de DIU de cobre (TCu 380A), insertado durante período post placentario (postparto y transcesárea), en un hospital público, de la región Sur de Brasil. Método: cohorte prospectivo con mujeres que colocaron el DIU en el período post placentario y que respondieron al cuestionario referente a la consulta de seguimiento. La recolección tuvo lugar entre septiembre/2020 y febrero/2021. Se utilizó la prueba de chi-cuadrado para análisis, considerándose valor de significancia del 5% (p<0,05). Resultados: fueron entrevistadas 285 mujeres, con edad media de 28,5 años y 10 de años de estudio. En la muestra, 60,7% realizaron la consulta de seguimiento con 29,8% en el período adecuado, 61,3% tuvieron el examen ginecológico realizado y 78,1 % fueron atendidas por médicos. Las principales razones relatadas para la no ocurrencia de la consulta de seguimiento fueron indisponibilidad de consulta en el período recomendado (38,2%) y orientación profesional para realización de la consulta tras ultrasonografía (26,3%). Conclusión: se observaron dificultades en la realización adecuada de la consulta de seguimiento para gran parte de la muestra. Los hallazgos de este estudio sugieren la necesidad de ampliar el acceso a los servicios de salud y capacitación de los equipos de salud para atender la consulta de seguimiento después de la inserción del DIU post placentario, basada en protocolos definidos.

ABSTRACT Objective: to analyze the occurrence of follow-up visits of women using copper IUDs (TCu 380A) inserted during the post-placental period (postpartum and trans-cesarean), in a public hospital in Southern Brazil. Method: prospective cohort with women who had an IUD inserted in the post-placental period and who answered a survey regarding the follow-up visit. Collection took place between September 2020 and February 2021. The chi-square test was used for analysis, considering a significance value of 5% (p<0.05). Results: 285 women were interviewed, with an average age of 28.5 years and 10 years of study. In the sample, 60.7% had a follow-up visit, with 29.8% in the recommended period, 61.3% underwent a gynecological examination, and 78.1% were seen by physicians. The main reasons reported for non-occurrence of follow-up visit were unavailability to schedule an appointment in the recommended period (38.2%) and professionals advising to schedule the appointment after an ultrasonography (26.3%). Conclusion: difficulties in appropriately performing the follow-up visit were observed for a large part of the sample. The findings of this study suggest the need to expand access to health services and train health teams to provide follow-up visits after post-placental IUD insertion, based on defined protocols.

Methylglyoxal-Mediated Dopamine Depletion, Working Memory Deficit, and Depression-Like Behavior Are Prevented by a Dopamine/Noradrenaline Reuptake Inhibitor.

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.

Protective effects against memory impairment induced by methylglyoxal in mice co­treated with FPS­ZM1, an advanced glycation end products receptor antagonist.

Memory impairment is a feature of several diseases and detrimental as aging population have increased worldwide. Sustained advanced glycation end products (AGEs) receptor (RAGE) activation triggers the production of reactive oxygen species and inflammatory response, leading to neuronal dysfunction and neurodegenerative disorders. Methylglyoxal (MGO) is the most relevant and reactive glycating agent in vivo, leading to the formation of AGEs. Here, we investigated the role of RAGE on the memory impairment induced by MGO. Swiss female mice were treated for 11 days with MGO, FPS­ZM1 (a high­affinity RAGE antagonist), or the combination of both. Locomotor activity was not impaired by the treatments, as evaluated by the open field and spontaneous alternation test. MGO treatment impaired short­ and long­term spatial memory in the object location task, caused deficits on the short­term aversive memory in the step­down inhibitory avoidance task, and decreased working memory performance as evaluated by the Y­maze spontaneous alternation test. FPS­ZM1 treatment abolished deficits on the short­term aversive memory and working memory, but was unable to prevent the impairment in short­term or long­term spatial memory. Since the addition of RAGE antagonist in co­treatment with MGO protected mice from the aversive and working memory deficits, AGEs generated by the MGO treatment would be involved in the memory impairment due to RAGE activation. Therefore, further studies are required to establish the involvement of RAGE in the MGO­induced memory impairment. Nevertheless, our results suggested FPS­ZM1 treatment as a promising new therapeutic strategy to prevent cognitive dysfunction caused by dicarbonyl stress, further investigation is required to confirm our findings.

Fructose Intake Impairs Cortical Antioxidant Defenses Allied to Hyperlocomotion in Middle-Aged C57BL/6 Female Mice.

Recent evidence suggests that young rodents submitted to high fructose (FRU) diet develop metabolic, and cognitive dysfunctions. However, it remains unclear whether these detrimental effects of FRU intake can also be observed in middle-aged mice. Nine months-old C57BL/6 female mice were fed with water (Control) or 10% FRU in drinking water during 12 weeks. After that, metabolic, and neurochemical alterations were evaluated, focusing on neurotransmitters, and antioxidant defenses. Behavioral parameters related to motor activity, memory, anxiety, and depression were also evaluated. Mice consuming FRU diet displayed increased water, and caloric intake, resulting in weight gain, which was partially compensated due to decreased food pellet intake. FRU fed animals displayed increased plasma glucose, and cholesterol levels, which was not observed in overnight-fasted animals. Superoxide dismutase (SOD), and catalase (CAT) activities were markedly decreased in the prefrontal cortex of animals receiving FRU diet, while glutathione peroxidase (GPx) slightly increased. Liver (lower GPx), striatum (higher SOD and lower CAT), and hippocampus (no changes) were less impacted. No changes were observed in glutathione reductase, and thioredoxin reductase activities, two ancillary enzymes for peroxide detoxification. FRU intake did not alter serotonin, dopamine, and norepinephrine levels in the hippocampus, prefrontal cortex, and striatum. No significant alterations were observed in working, and short-term spatial memory; and in anxiety- and depressive-like behaviors in animals treated with FRU. Increased locomotor activity was observed in FRU-fed middle-aged mice, as evaluated in the open field, elevated plus-maze, Y maze, and object location tasks. Overall, these results demonstrate that high FRU consumption can disturb antioxidant defenses, and increase locomotor activity in middle-aged mice, open the opportunity for further studies to address the underlying mechanisms related to these findings.

Repeated Methylglyoxal Treatment Depletes Dopamine in the Prefrontal Cortex, and Causes Memory Impairment and Depressive-Like Behavior in Mice.

Methylglyoxal (MGO) is a highly reactive dicarbonyl molecule that promotes the formation of advanced glycation end products (AGEs), which are believed to play a key role in a number of pathologies, such as diabetes, Alzheimer's disease, and inflammation. Here, Swiss mice were treated with MGO by intraperitoneal injection to investigate its effects on motor activity, mood, and cognition. Acute MGO treatment heavily decreased locomotor activity in the open field test at higher doses (80-200 mg/kg), an effect not observed at lower doses (10-50 mg/kg). Several alterations were observed 4 h after a single MGO injection (10-50 mg/kg): (a) plasma MGO levels were increased, (b) memory was impaired (object location task), (c) anxiolytic behavior was observed in the open field and marble burying test, and (d) depressive-like behavior was evidenced as evaluated by the tail suspension test. Biochemical alterations in the glutathione and glyoxalase systems were not observed 4 h after MGO treatment. Mice were also treated daily with MGO at 0, 10, 25 and 50 mg/kg for 11 days. From the 5th to the 11th day, several behavioral end points were evaluated, resulting in: (a) absence of motor impairment as evaluated in the open field, horizontal bars and pole test, (b) depressive-like behavior observed in the tail suspension test, and (c) cognitive impairments detected on working, short- and long-term memory when mice were tested in the Y-maze spontaneous alternation, object location and recognition tests, and step-down inhibitory avoidance task. An interesting finding was a marked decrease in dopamine levels in the prefrontal cortex of mice treated with 50 mg/kg MGO for 11 days, along with a ~ 25% decrease in the Glo1 content. The MGO-induced dopamine depletion in the prefrontal cortex may be related to the observed memory deficits and depressive-like behavior, an interesting topic to be further studied as a potentially novel route for MGO toxicity.

Hydropower reservoirs: cytotoxic and genotoxic assessment using the Allium cepa root model.

Hydropower offers a reliable source of electricity in several countries, and Brazil supplies its energy needs almost entirely through hydropower plants. Nevertheless, hydropower plants comprise large buildings and water reservoirs and dams, resulting in huge ecological disruptions. Here, we analyzed the impact of four hydropower reservoirs construction in metals and pesticides incidence and the cytotoxic and genotoxic potential of sediment elutriate of rivers from southern Brazil. Our analyses have evidenced the elevated incidence of different metals (lead, iron, cadmium, and chrome) and pesticides (methyl parathion, atrazine, and 2,4-dichlorophenoxyacetic acid). We showed that Allium cepa exposed to sediment elutriates did not change the seed germination rate and mitotic index. However, roots from Allium cepa exposed to reservoirs sediment elutriates showed increased occurrence of chromosomal aberrations and nuclear abnormalities. Therefore, the results obtained in our study indicate that sediment from reservoirs present elevated concentration of metals and pesticides and a significant genotoxic potential. Taken together, our data support that hydropower reservoirs represent an environmental scenario that could impact surrounding wildlife and population.