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.

Role of heme oxygenase-1 in the antidepressant-like effect of ursolic acid in the tail suspension test.

OBJECTIVES: This study investigated the involvement of heme oxygenase-1 (HO-1) in the antidepressant-like effects of ursolic acid (UA), a plant-derived compound with neuroprotective and antidepressant-like properties. METHODS: Mice received intracerebroventricular injections of zinc protoporphyrin IX (ZnPP) or cobalt protoporphyrin IX (CoPP) to inhibit or induce HO-1, respectively, together with effective (0.1 mg/kg, p.o.) or sub-effective (0.01 mg/kg, p.o.) doses of UA or fluoxetine (10 mg/kg, p.o.). Immobility time was assessed using the tail suspension test (TST) and the ambulatory behaviour with the open field test. HO-1 immunocontent was evaluated in mice hippocampus and prefrontal cortex. KEY FINDINGS: ZnPP prevented the anti-immobility effects of UA and fluoxetine. Combined treatment with a sub-effective dose of CoPP and UA synergistically exerted antidepressant-like effects in the TST. Acute administration of UA or CoPP, but not fluoxetine, increased the HO-1 immunocontent in the hippocampus. None of the treatments altered the HO-1 immunocontent in the prefrontal cortex. CONCLUSIONS: In conclusion, this work shows that increased hippocampal HO-1 content and activity mediate the antidepressant-like effect of UA in the TST.

Aerobic exercise ameliorates survival, clinical score, lung inflammation, DNA and protein damage in septic mice.

BACKGROUND AND OBJECTIVE: Sepsis is a potentially deadly organic dysfunction, and one of the main causes of mortality in intensive care units (ICU). Aerobic exercise (AE) is a preventive intervention in the establishment of inflammatory conditions, such as chronic lung diseases, but its effects on sepsis remain unclear. Therefore, this study aimed to evaluate the effects of AE on health condition, mortality, inflammation, and oxidative damage in an experimental model of pneumosepsis induced by Klebsiella pneumoniae (K.p). METHODS: Animals were randomly allocated to Control; Exercise (EXE); Pneumosepsis (PS) or Exercise + Pneumosepsis (EPS) groups. Exercised animals were submitted to treadmill exercise for 2 weeks, 30 min/day, prior to pneumosepsis induced by K.p tracheal instillation. RESULTS: PS produced a striking decrease in the health condition leading to massive death (85%). AE protected mice, as evidenced by better clinical scores and increased survival (70%). AE alleviated sickness behavior in EPS mice as evaluated in the open field test, and inflammation (nitrite + nitrate, TNF-α and IL-1ß levels) in broncoalveolar fluid. Catalase activity, oxidative damage to proteins and DNA was increased by sepsis and prevented by exercise. CONCLUSION: Overall, the beneficial effects of exercise in septic animals encompassed a markedly improved clinical score and decreased mortality, along with lower inflammation markers, less DNA and protein damage, as well as preserved antioxidant enzyme activity. Neural network risk analysis revealed exercise had a considerable effect on the overall health condition of septic mice.

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.

O Tratamento Medicamentoso Habitual é Suficiente para Manter o Controle da Frequência Cardíaca nos Pacientes com Insuficiência Cardíaca? / Is Current Drug Therapy for Heart Failure Sufficient to Control Heart Rate of Patients?

Resumo Fundamento Estudos revelam que pacientes com insuficiência cardíaca (IC) e frequência cardíaca (FC) <70 batimentos por minuto (bpm) evoluem melhor e têm menor morbimortalidade em comparação com FC >70. Entretanto, muitos pacientes com IC mantêm FC elevada. Objetivo Avaliar se os pacientes acompanhados em ambulatório de cardiologia têm sua FC controlada e como estava a prescrição dos medicamentos que reduzem a mortalidade na IC. Métodos Foram analisados de forma consecutiva pacientes que passaram em consulta e que já acompanhavam em ambulatório de cardiologia, idade > 18 anos e com diagnóstico de IC e fração de ejeção do ventrículo esquerdo (FEVE) <45%. Os pacientes em ritmo sinusal foram divididos em dois grupos: FC ≤70 bpm (G1) e FC >70 bpm (G2). Na análise estatística, foram utilizados os testes t de Student, Qui-quadrado. Foi considerado significante p <0,05. Utilizamos o programa Statistical Package for the Social Sciences (SPSS) para análise. Resultados Foram avaliados 212 pacientes de forma consecutiva. Destes, 41 (19,3%) apresentavam fibrilação atrial ou eram portadores de marca-passo e foram excluídos desta análise; assim, 171 pacientes foram analisados. Os pacientes em ritmo sinusal tinham idade média de 63,80 anos (±11,77), sendo 59,6% homens e FEVE média de 36,64% (±7,79). Com relação à etiologia, a isquêmica estava presente em 102 pacientes (59,65%), enquanto a cardiopatia chagásica em 17 pacientes (9,9%); 131 pacientes eram hipertensos (76,6%), enquanto 63 pacientes (36,84%) eram diabéticos. Quanto à FC, 101 pacientes apresentaram FC ≤70 bpm (59,06%) G1 e 70 pacientes (40,93%) FC >70 bpm (G2). A FC média no G1 foi de 61,53 bpm (±5,26) e no G2, 81,76 bpm (±9,52), p <0,001. A quase totalidade dos pacientes (98,8%) estava sendo tratada com carvedilol prescrito na dose média de 42,14 mg/dia (±18,55) no G1 versus 42,48 mg/dia (±21,14) no G2, p=0,911. A digoxina foi utilizada em 5,9% dos pacientes no G1 versus 8,5% no G2, p=0,510. A dose média de digoxina no G1 foi de 0,19 mg/dia (±0,06) e no G2 foi de 0,19 mg/dia (±0,06), p=0,999. A maioria dos pacientes (87,72%) utilizou o inibidor da enzima de conversão da angiotensina (IECA) ou bloqueador do receptor da angiotensina (BRA), e 56,72% utilizaram espironolactona. A dose média de enalapril foi de 28,86 mg/dia (±12,68) e de BRA foi de 87,80 mg/dia (±29,80). A maioria dos pacientes utilizou IECA ou BRA e com doses adequadas. Conclusão O estudo revelou que 40,93% dos pacientes estavam com FC acima de 70 bpm, apesar de o betabloqueador ter sido prescrito para praticamente todos os pacientes e em doses elevadas. Outras medidas precisam ser adotadas para manter a FC mais controlada nesse grupo de frequência mais elevada. (Arq Bras Cardiol. 2020; 115(6):1063-1069)

Abstract Background Studies have shown that heart failure (HF) patients with heart rate (HR) < 70 bpm have had a better clinical outcome and lower morbidity and mortality compared with those with HR > 70 bpm. However, many HF patients maintain an elevated HR. Objective To evaluate HR and the prescription of medications known to reduce mortality in HF patients attending an outpatient cardiology clinic. Methods We consecutively evaluated patients seen in an outpatient cardiology clinic, aged older than 18 years, with diagnosis of HF and left ventricular ejection fraction (LVEF) < 45%. Patients with sinus rhythm were divided into two groups - HR ≤ 70 bpm (G1) and HR > 70 bpm (G2). The Student's t-test and the chi-square test were used in the statistical analysis, and a p-value < 0.05 was considered statistically significant. The SPSS software was used for the analyses. Results A total of 212 consecutive patients were studied; 41 (19.3%) had atrial fibrillation or had a pacemaker implanted and were excluded from the analysis, yielding 171 patients. Mean age of patients was 63.80 ± 11.77 years, 59.6% were men, and mean LVEF 36.64±7.79%. The most prevalent HF etiology was ischemic (n=102; 59.6%), followed by Chagasic (n=17; 9.9%). One-hundred thirty-one patients (76.6%) were hypertensive and 63 (36.8%) diabetic. Regarding HR, 101 patients had a HR ≤70 bpm (59.1%) and 70 patients (40.93%) had a HR >70 bpm (G2). Mean HR of G1 and G2 was 61.5±5.3 bpm and 81.8±9.5 bpm, respectively (p<0.001). Almost all patients (98.8%) were receiving carvedilol, prescribed at a mean dose of 42.1±18.5 mg/day in G1 and 42.5±21.1mg/day in G2 (p=0.911). Digoxin was used in 5.9% of patients of G1 and 8.5% of G2 (p=0.510). Mean dose of digoxin in G1 and G2 was 0.19±0.1 mg/day and 0.19±0.06 mg/day, respectively (p=0,999). Most patients (87.7%) used angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), and 56.7% used spironolactone. Mean dose of enalapril was 28.9±12.7 mg/day and mean dose of ARB was 87.8±29.8 mg/day. The doses of ACEI and ARB were adequate in most of patients. Conclusion The study revealed that HR of 40.9% of patients with HF was above 70 bpm, despite treatment with high doses of beta blockers. Further measures should be applied for HR control in HF patients who maintain an elevated rate despite adequate treatment with beta blocker. (Arq Bras Cardiol. 2020; 115(6):1063-1069)

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.

The role of vitamin C in stress-related disorders.

Stress-related disorders, such as depression and anxiety, present marked deficits in behavioral and cognitive functions related to reward. These are highly prevalent disabling conditions with high social and economic costs. Furthermore, a significant percentage of affected individuals cannot benefit from clinical intervention, opening space for new treatments. Although the literature data have reported limited and variable results regarding oxidative stress-related endpoints in stress-related disorders, the possible neuroprotective effect of antioxidant compounds, such as ascorbic acid (vitamin C), emerges as a possible therapy strategy for psychiatric diseases. Here, we briefly present background information on biological activity of ascorbic acid, particularly functions related to the CNS homeostasis. Additionaly, we reviewed the available information on the role of ascorbic acid in stress-related diseases, focusing on supplementation and depletion studies. The vitamin C deficiency is widely associated to stress-related diseases. Although the efficacy of this vitamin in anxiety spectrum disorders is less stablished, several studies showed that ascorbic acid supplementation produces antidepressant effect and improves mood. Interestingly, the modulation of monoaminergic and glutamatergic neurotransmitter systems is postulated as pivotal target for the antidepressant and anxiolytic effects of this vitamin. Given that ascorbic acid supplementation produces fast therapeutic response with low toxicity and high tolerance, it can be considered as a putative candidate for the treatment of mood and anxiety disorders, especially those that are refractory to current treatments. Herein, the literature was reviewed considering the potential use of ascorbic acid as an adjuvant in the treatment of anxiety and depression.

The effect of voluntary wheel running on the antioxidant status is dependent on sociability conditions.

Voluntary wheel running is widely used as a physical activity (PA) model in rodents, but most studies investigate the beneficial effects of this intervention in socially isolated mice. Social isolation stress (SIS) is associated with vulnerability to oxidative stress and reduced mitochondrial activity. Thus, the aim of this study was to investigate the effects of free access to a running wheel for 21 days on the various markers of the cellular redox/antioxidant status as well as mitochondrial function of mice subjected to SIS or maintained in groups of 3 in the homecage. SIS increased thiobarbituric acid reactive substance (TBARS) levels in the cerebral cortex, and PA intervention was not able to reverse such alteration. PA reduced TBARS levels in the liver of grouped mice and gastrocnemius of socially isolated mice. PA increased nonprotein thiol (NPSH) levels in the cerebral cortex of grouped mice. Furthermore, socially isolated mice presented lower glutathione peroxidase (GPx) activity in the cerebellum and gastrocnemius, and glutathione reductase (GR) activity in the cerebral cortex and liver. By contrast, SIS induced higher GPx activity in the cerebral cortex and heart. PA reduced GPx (cerebral cortex) and GR (cerebral cortex and liver) activities of socially isolated mice. SIS caused higher activity of mitochondrial complexes I and II in the cerebral cortex, and the PA paradigm was not able to alter this effect. Interestingly, the PA produced antidepressant-like effect at both SIS and control groups. In conclusion, the results showed the influence of SIS for the effects of PA on the antioxidant status, but not on the mitochondrial function and emotionality.

Multiple cellular targets involved in the antidepressant-like effect of glutathione.

A previous study demonstrated that glutathione (GSH) produces specific antidepressant-like effect in the forced swimming test (FST), a predictive test of antidepressant activity. The present study investigated the involvement of multiple cellular targets implicated in the antidepressant-like effect of GSH in the FST. The antidepressant-like effect of GSH (300 nmol/site, icv) lasted up to 3 h when mice were submitted to FST. The central administration of oxidized GSH (GSSG, 3-300 nmol/site) did not alter the behavior of mice submitted to the FST. Furthermore, the combined treatment of sub-effective doses of GSH (100 nmol/site, icv) with a sub-effective dose of classical antidepressants (fluoxetine 10 mg/kg, and imipramine 5 mg/kg, ip) presented synergistic effect by decreasing the immobility time in the FST. The antidepressant-like effect of GSH was abolished by prazosin (1 mg/kg, ip, α1-adrenoceptor antagonist), baclofen (1 mg/kg, ip, GABAB receptor agonist), bicuculline (1 mg/kg, ip, GABAA receptor antagonist), l-arginine (750 mg/kg, ip, NO precursor), SNAP (25 µg/site, icv, NO donor), but not by yohimbine (1 mg/kg, ip, α2-adrenoceptor antagonist). The NMDA receptor antagonists, MK-801(0.001 mg/kg, ip) or GMP (0.5 mg/kg, ip), potentiated the effect of a sub-effective dose of GSH in the FST. These results suggest that the antidepressant-like effect induced by GSH is connected to the activation of α1 adrenergic and GABAA receptors, as well as the inhibition of GABAB and NMDA receptors and NO biosyntesis. We speculate that redox-mediated signaling on the extracelular portion of cell membrane receptors would be a common mechanism of action of GSH.

Antidepressant-like and pro-neurogenic effects of physical exercise: the putative role of FNDC5/irisin pathway.

Physical exercise has been shown to exert antidepressant effects, but the mechanisms underlying this effect are not completely elucidated. Therefore, we aimed at investigating the antidepressant, pro-neurogenic, and neuroprotective effects of physical exercise and the possible role of FNDC5/irisin for this effect. Treadmill running was used as a protocol of physical exercise (45 min/day/5 days/week for 4 weeks) in female Swiss mice. Immobility time was registered in the tail suspension test (TST) and forced swim test (FST). Immunohistochemical analyses to evaluate hippocampal cell proliferation, neuronal survival, and neuronal commitment and maturation, as well as expression of FNDC5 C-terminal fragment were performed in the entire, dorsal, and ventral dentate gyrus (DG) of the hippocampus. Fluoro-Jade B staining was performed to evaluate degenerating neurons in DG. FNDC5 C-terminal and FNDC5/irisin immunocontents were analyzed by western blot. Exposure to physical exercise reduced the immobility time both in the TST and the FST. This antidepressant-like effect was accompanied by an increase in hippocampal cell proliferation, hippocampal neuronal differentiation, and neuronal survival in the dorsal and ventral DG. Fluoro-Jade B staining was reduced in entire and dorsal DG in exercised mice. Finally, physical exercise also resulted in increased number of FNDC5-positive cells in the hippocampal DG as well as elevated FNDC5 C-terminal and FNDC5/irisin immunocontent in the entire hippocampus. The results suggest that the FNDC5 C-terminal fragment/irisin pathway may be implicated in the antidepressant-like, pro-neurogenic, and neuroprotective effects of treadmill running.

Is Current Drug Therapy for Heart Failure Sufficient to Control Heart Rate of Patients? / O Tratamento Medicamentoso Habitual é Suficiente para Manter o Controle da Frequência Cardíaca nos Pacientes com Insuficiência Cardíaca?

BACKGROUND: Studies have shown that heart failure (HF) patients with heart rate (HR) < 70 bpm have had a better clinical outcome and lower morbidity and mortality compared with those with HR > 70 bpm. However, many HF patients maintain an elevated HR. OBJECTIVE: To evaluate HR and the prescription of medications known to reduce mortality in HF patients attending an outpatient cardiology clinic. METHODS: We consecutively evaluated patients seen in an outpatient cardiology clinic, aged older than 18 years, with diagnosis of HF and left ventricular ejection fraction (LVEF) < 45%. Patients with sinus rhythm were divided into two groups - HR ≤ 70 bpm (G1) and HR > 70 bpm (G2). The Student's t-test and the chi-square test were used in the statistical analysis, and a p-value < 0.05 was considered statistically significant. The SPSS software was used for the analyses. RESULTS: A total of 212 consecutive patients were studied; 41 (19.3%) had atrial fibrillation or had a pacemaker implanted and were excluded from the analysis, yielding 171 patients. Mean age of patients was 63.80 ± 11.77 years, 59.6% were men, and mean LVEF 36.64±7.79%. The most prevalent HF etiology was ischemic (n=102; 59.6%), followed by Chagasic (n=17; 9.9%). One-hundred thirty-one patients (76.6%) were hypertensive and 63 (36.8%) diabetic. Regarding HR, 101 patients had a HR ≤70 bpm (59.1%) and 70 patients (40.93%) had a HR >70 bpm (G2). Mean HR of G1 and G2 was 61.5±5.3 bpm and 81.8±9.5 bpm, respectively (p<0.001). Almost all patients (98.8%) were receiving carvedilol, prescribed at a mean dose of 42.1±18.5 mg/day in G1 and 42.5±21.1mg/day in G2 (p=0.911). Digoxin was used in 5.9% of patients of G1 and 8.5% of G2 (p=0.510). Mean dose of digoxin in G1 and G2 was 0.19±0.1 mg/day and 0.19±0.06 mg/day, respectively (p=0,999). Most patients (87.7%) used angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), and 56.7% used spironolactone. Mean dose of enalapril was 28.9±12.7 mg/day and mean dose of ARB was 87.8±29.8 mg/day. The doses of ACEI and ARB were adequate in most of patients. CONCLUSION: The study revealed that HR of 40.9% of patients with HF was above 70 bpm, despite treatment with high doses of beta blockers. Further measures should be applied for HR control in HF patients who maintain an elevated rate despite adequate treatment with beta blocker. (Arq Bras Cardiol. 2020; 115(6):1063-1069).

FUNDAMENTO: Estudos revelam que pacientes com insuficiência cardíaca (IC) e frequência cardíaca (FC) <70 batimentos por minuto (bpm) evoluem melhor e têm menor morbimortalidade em comparação com FC >70. Entretanto, muitos pacientes com IC mantêm FC elevada. OBJETIVO: Avaliar se os pacientes acompanhados em ambulatório de cardiologia têm sua FC controlada e como estava a prescrição dos medicamentos que reduzem a mortalidade na IC. MÉTODOS: Foram analisados de forma consecutiva pacientes que passaram em consulta e que já acompanhavam em ambulatório de cardiologia, idade > 18 anos e com diagnóstico de IC e fração de ejeção do ventrículo esquerdo (FEVE) <45%. Os pacientes em ritmo sinusal foram divididos em dois grupos: FC ≤70 bpm (G1) e FC >70 bpm (G2). Na análise estatística, foram utilizados os testes t de Student, Qui-quadrado. Foi considerado significante p <0,05. Utilizamos o programa Statistical Package for the Social Sciences (SPSS) para análise. RESULTADOS: Foram avaliados 212 pacientes de forma consecutiva. Destes, 41 (19,3%) apresentavam fibrilação atrial ou eram portadores de marca-passo e foram excluídos desta análise; assim, 171 pacientes foram analisados. Os pacientes em ritmo sinusal tinham idade média de 63,80 anos (±11,77), sendo 59,6% homens e FEVE média de 36,64% (±7,79). Com relação à etiologia, a isquêmica estava presente em 102 pacientes (59,65%), enquanto a cardiopatia chagásica em 17 pacientes (9,9%); 131 pacientes eram hipertensos (76,6%), enquanto 63 pacientes (36,84%) eram diabéticos. Quanto à FC, 101 pacientes apresentaram FC ≤70 bpm (59,06%) G1 e 70 pacientes (40,93%) FC >70 bpm (G2). A FC média no G1 foi de 61,53 bpm (±5,26) e no G2, 81,76 bpm (±9,52), p <0,001. A quase totalidade dos pacientes (98,8%) estava sendo tratada com carvedilol prescrito na dose média de 42,14 mg/dia (±18,55) no G1 versus 42,48 mg/dia (±21,14) no G2, p=0,911. A digoxina foi utilizada em 5,9% dos pacientes no G1 versus 8,5% no G2, p=0,510. A dose média de digoxina no G1 foi de 0,19 mg/dia (±0,06) e no G2 foi de 0,19 mg/dia (±0,06), p=0,999. A maioria dos pacientes (87,72%) utilizou o inibidor da enzima de conversão da angiotensina (IECA) ou bloqueador do receptor da angiotensina (BRA), e 56,72% utilizaram espironolactona. A dose média de enalapril foi de 28,86 mg/dia (±12,68) e de BRA foi de 87,80 mg/dia (±29,80). A maioria dos pacientes utilizou IECA ou BRA e com doses adequadas. CONCLUSÃO: O estudo revelou que 40,93% dos pacientes estavam com FC acima de 70 bpm, apesar de o betabloqueador ter sido prescrito para praticamente todos os pacientes e em doses elevadas. Outras medidas precisam ser adotadas para manter a FC mais controlada nesse grupo de frequência mais elevada. (Arq Bras Cardiol. 2020; 115(6):1063-1069).

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.

The possible beneficial effects of creatine for the management of depression.

Depression, a highly prevalent neuropsychiatric disorder worldwide, causes a heavy burden for the society and is associated with suicide risk. The treatment of this disorder remains a challenge, since currently available antidepressants provide a slow and, often, incomplete response and cause several side effects that contribute to diminish the adhesion of patients to treatment. In this context, several nutraceuticals have been investigated regarding their possible beneficial effects for the management of this neuropsychiatric disorder. Creatine stands out as a supplement frequently used for ergogenic purpose, but it also is a neuroprotective compound with potential to treat or mitigate a broad range of central nervous systems diseases, including depression. This review presents preclinical and clinical evidence that creatine may exhibit antidepressant properties. The focus is given on the possible molecular mechanisms underlying its effects based on the results obtained with different animal models of depression. Finally, evidence obtained in animal models of depression addressing the possibility that creatine may produce rapid antidepressant effect, similar to ketamine, are also presented and discussed.

Subchronic administration of creatine produces antidepressant-like effect by modulating hippocampal signaling pathway mediated by FNDC5/BDNF/Akt in mice.

Creatine has been shown to play a significant role in the pathophysiology and treatment of major depressive disorder (MDD) in preclinical and clinical studies. However, the biological mechanisms underlying its antidepressant effect is still not fully elucidated. This study investigated the effect of creatine (p.o.) administered for 21 days in the behavior of mice submitted to tail suspension test (TST), a predictive test of antidepressant activity. Creatine reduced the immobility time in the TST (1-10 mg/kg), without affecting locomotor activity, a finding consistent with an antidepressant profile. Creatine administration increased the ubiquitous creatine kinase (uCK) and creatine kinase brain isoform (CK-B) mRNA in the hippocampus of mice. Taking into account that PGC-1α induces FNDC5/irisin expression mediating BDNF-dependent neuroplasticity, the effect of creatine administration (1 mg/kg, p. o.) on the hippocampal PGC-1α, FNDC5 and BDNF gene expression was investigated. Creatine treatment increased PGC-1α, FNDC5 and BDNF mRNA in the hippocampus as well as BDNF immunocontent. The involvement of BDNF downstream intracellular signaling pathway mediated by Akt, proapoptotic proteins BAX and BAD and antiapoptotic proteins Bcl2 and Bcl-xL was also investigated following creatine treatment. Creatine increased Akt phosphorylation (Ser 473), and Bcl2 mRNA and protein levels, and Bcl-xL mRNA, whereas BAD mRNA was decreased following creatine administration in the hippocampus. Altogether these results indicate that creatine antidepressant-like effect may be dependent on Akt activation and increased expression of the neuroprotective proteins in the hippocampus of mice. The obtained data reinforce the antidepressant property of creatine and highlight the role of these molecular targets in the pathophysiology of MDD.

Antidepressant effects of creatine on amyloid ß1-40-treated mice: The role of GSK-3ß/Nrf2 pathway.

Alzheimer's disease (AD) is characterized by progressive synaptic dysfunction and neuronal lost in specific brain areas including hippocampus, resulting in memory/learning deficits and cognitive impairments. In addition, non-cognitive symptoms are reported in AD patients, such as anxiety, apathy and depressed mood. The current antidepressant drugs present reduced efficacy to improve depressive symptoms in AD patients. Here, we investigated the ability of creatine, a compound with neuroprotective and antidepressant properties, to counteract amyloid ß1-40 peptide-induced depressive-like behavior in mice. Moreover, we addressed the participation of the intracellular signaling pathway mediated by glycogen synthase kinase-3ß (GSK-3ß)/nuclear factor erythroid-2-related factor 2 (Nrf2) in the creatine effects. Aß1-40 administration (400 pmol/mouse, i.c.v.) increased the immobility time in the tail suspension test and decreased the grooming time and increased latency to grooming in the splash test, indicative of depressive-like behavior. These impairments were attenuated by creatine (0.01 and 10 mg/kg, p.o.) and fluoxetine (10 mg/kg, p.o., positive control). No significant alterations on locomotor performance were observed in the open field. Aß1-40 administration did not alter hippocampal phospho-GSK-3ß (Ser9)/total GSK-3ß, total GSK-3ß and heme oxygenase-1 (HO-1) immunocontents. However, Aß1-40-infused mice treated with creatine (0.01 mg/kg) presented increased phosphorylation of GSK-3ß(Ser9) and HO-1 immunocontent in the hippocampus. Fluoxetine per se increased GSK-3ß(Ser9) phosphorylation, but did not alter HO-1 levels. In addition, Aß1-40 administration increased hippocampal glutathione (GSH) levels as well as glutathione reductase (GR) and thioredoxin reductase (TrxR) activities, and these effects were abolished by creatine and fluoxetine. This study provides the first evidence of the antidepressive-like effects of creatine in Aß1-40-treated mice, which were accompanied by hippocampal inhibition of GSK-3ß and modulation of antioxidant defenses. These findings indicate the potential of creatine for the treatment of depression associated with AD.

Locomotor Treadmill Training Promotes Soleus Trophism by Mammalian Target of Rapamycin Pathway in Paraplegic Rats.

Assisted-treadmill training, may be helpful in promoting muscle mass preservation after incomplete spinal cord injury (SCI). However, biological mechanism involved in this process is still not fully understood. This study investigated the effects of locomotor treadmill training on muscle trophism mediated by protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) in paraplegic rats. Adult female Wistar rats underwent an incomplete thoracic SCI induced by compression using an aneurysm clip. After 7 days, injured animals started a 3-week locomotor treadmill training with body weight-support and manual step help. Soleus trophism was measured by muscle weight and transverse myofiber cross-sectional area (CSA). An enzyme-linked immunosorbent assay (ELISA) and western blot analysis were used to detect brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), Akt, mTOR and p70S6K in paretic soleus. Trained animals did not show locomotor improved, but present an increase in muscle weight and myofiber CSA. Furthermore, the levels of Akt, p70S6K phosphorylation, mTOR and TrkB receptor were increased by training in soleus. In contrast, muscle BDNF levels were significantly reduced after training. The results suggest locomotor treadmill training partially reverts/prevents soleus muscle hypotrophy in rats with SCI. Furthermore, this study provided the first evidence that morphological muscle changes were caused by Akt/mTOR/p70S6K signaling pathway and TrkB up-regulation, which may increase the sensitivity of muscle, reducing autocrine signaling pathway demand of BDNF for cell growth.

Central irisin administration affords antidepressant-like effect and modulates neuroplasticity-related genes in the hippocampus and prefrontal cortex of mice.

Evidence has indicated that the practice of physical exercise has antidepressant effects that might be associated with irisin release and BDNF signaling. In this study we investigated the effects of the central administration of irisin or BDNF in predictive tests of antidepressant properties paralleled with the gene expression of peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex of mice. Irisin (0.5-1 ng/mouse, i.c.v.) reduced the immobility time in the tail suspension test (TST) and forced swim test (FST), without altering locomotion in the open field test (OFT). Irisin reduced the immobility time in the TST up to 6 h after its administration. Irisin administration (6 h) increased PGC-1α mRNA in the hippocampus and prefrontal cortex and reduced (1 h) PGC-1α mRNA in the prefrontal cortex. FNDC5 and BDNF mRNA expression was decreased (1 h) in both structures and remained reduced up to 6 h in the prefrontal cortex. Moreover, BDNF administered at 0.25 µg/mouse, i.c.v. (1 and 6 h before the test) reduced the immobility time in the TST. BDNF administration reduced PGC-1α mRNA in the hippocampus (6 h) and prefrontal cortex (1 and 6 h). It also increased FNDC5 mRNA expression in the hippocampus (1 and 6 h), but reduced the expression of this gene and also BDNF mRNA in the prefrontal cortex (1 and 6 h). None of the treatments altered BDNF protein levels in both structures. In conclusion, irisin presents a behavioral antidepressant profile similar to BDNF, an effect associated with the modulation of gene expression of PGC-1α, FNDC5 and BDNF, reinforcing the pivotal role of these genes in mood regulation.

The APPswe/PS1A246E mutations in an astrocytic cell line leads to increased vulnerability to oxygen and glucose deprivation, Ca2+ dysregulation, and mitochondrial abnormalities.

Growing evidence suggests a close relationship between Alzheimer's Disease (AD) and cerebral hypoxia. Astrocytes play a key role in brain homeostasis and disease states, while some of the earliest changes in AD occur in astrocytes. We have therefore investigated whether mutations associated with AD increase astrocyte vulnerability to ischemia. Two astroglioma cell lines derived from APPSWE /PS1A246E (APP, amyloid precursor protein; PS1, presenilin 1) transgenic mice and controls from normal mice were subjected to oxygen and glucose deprivation (OGD), an in vitro model of ischemia. Cell death was increased in the APPSWE /PS1A246E line compared to the control. Increasing extracellular calcium concentration ([Ca2+ ]) exacerbated cell death in the mutant but not in the control cells. In order to explore cellular Ca2+ homeostasis, the cells were challenged with ATP or thapsigargin and [Ca2+ ] was measured by fluorescence microscopy. Changes in cytosolic Ca2+ concentration ([Ca2+ ]c ) were potentiated in the APPSWE /PS1A246E transgenic line. Mitochondrial function was also altered in the APPSWE /PS1A246E astroglioma cells; mitochondrial membrane potential and production of reactive oxygen species were increased, while mitochondrial basal respiratory rate and ATP production were decreased compared to control astroglioma cells. These results suggest that AD mutations in astrocytes make them more sensitive to ischemia; Ca2+ dysregulation and mitochondrial dysfunction may contribute to this increased vulnerability. Our results also highlight the role of astrocyte dyshomeostasis in the pathophysiology of neurodegenerative brain disorders.

Ursolic acid affords antidepressant-like effects in mice through the activation of PKA, PKC, CAMK-II and MEK1/2.

BACKGROUND: Ursolic acid has been shown to display antidepressant-like effects in mice through the modulation of monoaminergic systems. In this study, we sought to investigate the involvement of signaling pathways on the antidepressant-like effects of ursolic acid. METHODS: Mice were treated orally with ursolic acid (0.1mg/kg) and, 45min later they received the followings inhibitors by intracerebroventricular route: H-89 (PKA inhibitor, 1µg/mouse), KN-62 (CAMK-II inhibitor, 1µg/mouse), chelerythrine (PKC inhibitor, 1µg/mouse), U0126 (MEK1/2 inhibitor, 5µg/mouse), PD98059 (MEK1/2 inhibitor, 5µg/mouse), wortmannin (PI3K irreversible inhibitor, 0.1µg/mouse) or LY294002 (PI3K inhibitor, 10 nmol/mouse). Immobility time of mice was registered in the tail suspension test (TST). RESULTS: The anti-immobility effect of ursolic acid in the TST was abolished by the treatment of mice with H-89, KN-62, chelerythrine, U0126 or PD98059, but not with wortmannin or LY294002. CONCLUSIONS: These results suggest that activation of PKA, PKC, CAMK-II, MEK1/2 may underlie the antidepressant-like effects of ursolic acid.