Memantine Improves Memory and Neurochemical Damage in a Model of Maple Syrup Urine Disease.

Maple Syrup Urine Disease (MSUD) is a metabolic disease characterized by the accumulation of branched-chain amino acids (BCAA) in different tissues due to a deficit in the branched-chain alpha-ketoacid dehydrogenase complex. The most common symptoms are poor feeding, psychomotor delay, and neurological damage. However, dietary therapy is not effective. Studies have demonstrated that memantine improves neurological damage in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Therefore, we hypothesize that memantine, an NMDA receptor antagonist can ameliorate the effects elicited by BCAA in an MSUD animal model. For this, we organized the rats into four groups: control group (1), MSUD group (2), memantine group (3), and MSUD + memantine group (4). Animals were exposed to the MSUD model by the administration of BCAA (15.8 µL/g) (groups 2 and 4) or saline solution (0.9%) (groups 1 and 3) and treated with water or memantine (5 mg/kg) (groups 3 and 4). Our results showed that BCAA administration induced memory alterations, and changes in the levels of acetylcholine in the cerebral cortex. Furthermore, induction of oxidative damage and alterations in antioxidant enzyme activities along with an increase in pro-inflammatory cytokines were verified in the cerebral cortex. Thus, memantine treatment prevented the alterations in memory, acetylcholinesterase activity, 2',7'-Dichlorofluorescein oxidation, thiobarbituric acid reactive substances levels, sulfhydryl content, and inflammation. These findings suggest that memantine can improve the pathomechanisms observed in the MSUD model, and may improve oxidative stress, inflammation, and behavior alterations.

Antidepressant Effect of Sodium Butyrate is Accompanied by Brain Epigenetic Modulation in Rats Subjected to Early or Late Life Stress.

BACKGROUND: Major depression has a complex and multifactorial etiology constituted by the interaction between genetic and environmental factors in its development. OBJECTIVE: The aim of this study was to evaluate the effects of sodium butyrate (SD) on epigenetic enzyme alterations in rats subjected to animal models of depression induced by maternal deprivation (MD) or chronic mild stress (CMS). METHODS: To induce MD, male Wistar rats were deprived of maternal care during the first 10 days of life. To induce CMS, rats were subjected to the CMS for 40 days. Adult rats were then treated with daily injections of SD for 7 days. Animals were subjected to the forced swimming test (FST), and then, histone deacetylase (HDAC), histone acetyltransferase (HAT), and DNA methyltransferase (DNMT) activities were evaluated in the brain. RESULTS: MD and CMS increased immobility time in FST and increased HDAC and DNMT activity in the animal brains. SD reversed increased immobility induced by both animal models and the alterations in HDAC and DNMT activities. There was a positive correlation between enzyme activities and immobility time for both models. HDAC and DNMT activities also presented a positive correlation between themselves. CONCLUSION: These results suggest that epigenetics can play an important role in major depression pathophysiology triggered by early or late life stress and its treatment.

Behavioral and inflammatory changes in rats induced by a three-hit stress model: Implications for psychiatric disorders.

Many aspects of the impact of childhood trauma remain unknown, such as the age at which individuals are most vulnerable to trauma, whether traumatic experiences have more severe and lasting effects when experienced early in life, and whether early life trauma causes psychiatric conditions such as anxiety and major depressive disorder (MDD) that persist over time or evolve into other disorders. Thus, this study aimed to investigate the impact of traumatic experiences in childhood on susceptibility to mood disorders in adulthood, particularly MDD. Animal models were used to address these questions, and different stressor protocols at various stages of the offspring's life were used. Three-hit starting with injections of Poly: IC was performed on the 9th day of gestation and then considered the first stressor. After birth, the animals were exposed to the maternal deprivation (MD) protocol, which separated the pups from the mother 3 h a day during the first ten days of life. From the 60th day of life, the animals were divided to receive the chronic mild stress (CMS) protocol over 21 days. The stressors can induce anxiety-like behaviors, such as increased locomotor activity through a maternal immune activation protocol using Poly: IC and demonstrating depressive-like behaviors through the MD and CMS protocols. It also showed changes in brain structures for pro-inflammatory parameters, IL-1ß and TNF-α, and alterations in anti-inflammatory parameters, IL-4 and IL-10, at different ages of life. The study also found that regulating pro- and anti-inflammatory cytokines is necessary for appropriate neuronal behavior, and stress responses can be both friendly and enemy, with costs and benefits balanced to provide the best-fit result. In conclusion, phenotypic characteristics of animals' life history are shaped by signals transmitted directly or indirectly to developing animals, known as "predictive adaptive responses."

The involvement of neuroinflammation in an animal model of dementia and depression.

Alzheimer's disease (AD) and depression are inflammatory pathologies, leading to increased inflammatory response and neurotoxicity. Therefore, this study aimed to evaluate the effect of the treatment with fluoxetine and/or galantamine and/or donepezil on the levels of proinflammatory and anti-inflammatory cytokines in a mixed animal model of depression and dementia. Adult male Wistar rats underwent chronic mild stress (CMS) protocol for 40 days and were subjected to stereotaxic surgery for intra-hippocampal administration of amyloid-beta (Aꞵ) peptide or artificial cerebrospinal fluid (ACSF) to mimic the dementia animal model. On the 42nd day, animals were treated with water, galantamine, donepezil, and/or fluoxetine, orally for 17 days. On the 57th and 58th days, the Splash and Y-maze tests for behavior analysis were performed. The frontal cortex and hippocampus were used to analyze the tumor necrosis factor alfa (TNF-α), interleukin 1 beta (IL-1ꞵ), IL-6, and IL-10 levels. The results of this study show that animals subjected to CMS and administration of Aꞵ had anhedonia, cognitive impairment, increased TNF-α and IL-1ꞵ levels in the frontal cortex, and reduced IL-10 levels in the hippocampus. All treatment groups were able to reverse the cognitive impairment. Only donepezil did not decrease the TNF-α levels in the hippocampus. Fluoxetine + galantamine and fluoxetine + donepezil reversed the anhedonia. Fluoxetine reversed the anhedonia and IL-1ꞵ levels in the frontal cortex. In addition, fluoxetine + donepezil reversed the reduction of IL-10 levels in the hippocampus. The results indicate a pathophysiological interaction between AD and depression, and the association of medications in the future may be a possible therapeutic strategy to reduce inflammation, especially the fluoxetine-associated treatments.

Amelioration of Neurochemical Alteration and Memory and Depressive Behavior in Sepsis by Allopurinol, a Tryptophan 2,3-Dioxygenase Inhibitor.

BACKGROUND: In response to inflammation and other stressors, tryptophan is catalyzed by Tryptophan 2,3-Dioxygenase (TDO), which leads to activation of the kynurenine pathway. Sepsis is a serious condition in which the body responds improperly to an infection, and the brain is the inflammation target in this condition. OBJECTIVE: This study aimed to determine if the induction of TDO contributes to the permeability of the Blood-Brain Barrier (BBB), mortality, neuroinflammation, oxidative stress, and mitochondrial dysfunction, besides long-term behavioral alterations in a preclinical model of sepsis. METHODS: Male Wistar rats with two months of age were submitted to the sepsis model using Cecal Ligation and Perforation (CLP). The rats received allopurinol (Allo, 20 mg/kg, gavage), a TDO inhibitor, or a vehicle once a day for seven days. RESULTS: Sepsis induction increased BBB permeability, IL-6 level, neutrophil infiltrate, nitric oxide formation, and oxidative stress, resulting in energy impairment in 24h after CLP and Allo administration restored these parameters. Regarding memory, Allo restored short-term memory impairment and decreased depressive behavior. However, no change in survival rate was verified. CONCLUSION: In summary, TDO inhibition effectively prevented depressive behavior and memory impairment 10 days after CLP by reducing acute BBB permeability, neuroinflammation, oxidative stress, and mitochondrial alteration.

Depressive disorders and comorbidities among the elderly: a population-based study / Transtornos depressivos e algumas comorbidades em idosos: um estudo de base populacional

Objective The present study assessed the prevalence of depressive disorders and associated factors in a sample of elderly persons in the south of Santa Catarina. Methods A cross-sectional study based on population data was performed, evaluating 1021 elderly individuals aged between 60 and 79 years. Home interviews were carried out using the Portuguese version of the Mini International Neuropsychiatric Interview (MINI), in order to collect demographic data, information on hypertension and reports of acute myocardial infarction. The disorders studied were current depressive episode, dysthymia and a comorbidity of a depressive episode and dysthymia, representing double depression. The comparison of mean age and prevalence was made with the t-test and other associations were analyzed using the Chi-squared test. Results The prevalence of depression was 26.2%, while 5.5% of the sample suffered from dysthymia and 2.7% experienced double depression. Risk factors for depression were: nine or more years of schooling [PR = 1.44 (1.17 to 1.77); p <0.05] and being a current smoker [OR = 1.63 (1.30-2.05); p <0.05]. Dysthymia was associated with the male gender [OR = 6.46 (3.29 to 12.64); p <0.05], reports of hypertension [OR = 2.55 (1.53 to 4.24); p <0.05] and being either a current [OR = 1.86 (1.02 to 3.42); p <0.05] or past or former [OR = 2.89 (1.48 to 5.65); p <0.05] smoker. The same risk factors as for dysthymia were found for double depression: male [OR = 4.21 (1.80 to 9.81); p <0.05], reports of hypertension [OR = 8.11 (3.32 to 19.80); p <0.05], and being either a current [OR = 5.72 (1.64 to 19.93); p <0.05] or past [PR = 13.11 (3.75 to 45.86); p <0.05] smoker. Conclusions The present study shows that depressive disorders are a common phenomenon among the elderly. The results not only corroborated with other studies, but found slightly higher levels of depressive disorders among the elderly population.

Objetivo Avaliar a prevalência de transtornos depressivos e fatores associados em uma amostra de idosos no Sul de Santa Catarina. Método Estudo transversal com base de dados populacional, que avaliou 1.021 indivíduos idosos entre 60 e 79 anos. Foram realizadas entrevistas domiciliares com a versão em português do Mini International Neuropsychiatric Interview (MINI), coleta de dados sociodemográficos, informações sobre hipertensão arterial sistêmica, infarto agudo do miocárdio e tabagismo. Os transtornos estudados foram episódio depressivo atual, distimia e comorbidade entre episódio depressivo e distimia, caracterizando depressão dupla. A comparação das médias de idade e prevalências foi feita com o teste t Student, as demais associações foram analisadas pelo teste Qui-quadrado. Resultados A prevalência de depressão foi de 26,2%; distimia, 5,5%; e depressão dupla, 2,7%. Fatores de risco para depressão: nove anos ou mais de estudo [RP=1,44(1,17-1,77); p<0,05] e tabagismo atual [RP=1,63(1,30-2,05); p<0,05]. A distimia foi associada ao gênero masculino [RP=6,46(3,29-12,64); p<0,05], relato de hipertensão arterial [RP=2,55(1,53-4,24);p<0,05] e tabagismo, tanto atual [RP=1,86(1,02-3,42),p<0,05] quanto passado ou ex-tabagistas [RP=2,89(1,48-5,65); p<0,05]. Para a depressão dupla, repetiram os mesmos fatores de risco da distimia: gênero masculino [RP=4,21(1,80-9,81); p<0,05], relato de hipertensão arterial [RP=8,11(3,32-19,80); p<0,05], tabagismo atual [RP=5,72(1,64-19,93); p<0,05] e passado [RP=13,11(3,75-45,86); p<0,05]. Conclusão Os dados demonstram que quadros depressivos são fenômenos frequentes e atingem um percentual significativo de idosos. Adicionalmente, os transtornos depressivos foram associados a fatores sociodemográficos e doenças crônicas, como nível de escolaridade, tabagismo e hipertensão arterial.