Vitamin D and depression in older adults: lessons learned from observational and clinical studies.

Depression is a mental disorder triggered by the interaction of social, psychological and biological factors that have an important impact on an individual's life. Despite being a well-studied disease with several established forms of treatment, its prevalence is increasing, especially among older adults. New forms of treatment and prevention are encouraged, and some researchers have been discussing the effects of vitamin D (VitD) on depression; however, the exact mechanism by which VitD exerts its effects is not yet conclusive. In this study, we aimed to discuss the possible mechanisms underlying the association between VitD and depression in older adults. Therefore, we conducted a systematic search of databases for indexed articles published until 30 April 2021. The primary focus was on both observational studies documenting the association between VitD and depression/depressive symptoms, and clinical trials documenting the effects of VitD supplementation on depression/depressive symptoms, especially in older adults. Based on pre-clinical, clinical and observational studies, it is suggested that the maintenance of adequate VitD concentrations is an important issue, especially in older adults, which are a risk population for both VitD deficiency and depression. Nevertheless, it is necessary to carry out more studies using longitudinal approaches in low- and middle-income countries to develop a strong source of evidence to formulate guidelines and interventions.

Lower serum 25-hydroxycholecalciferol is associated with depressive symptoms in older adults in Southern Brazil.

BACKGROUND: Older adults are one of the most susceptible populations to depression, especially those living in low- and middle-income countries. As well, they are also considering a risk group for vitamin D deficiency. Low serum vitamin D has been associated with an increased risk of brain neuropsychiatry disorders. We aimed to investigate the association between serum 25-hydroxycholecalciferol concentrations and depressive symptoms in adults aged 60 years and over from southern Brazil. METHODS: A cross-sectional analysis was performed using data collected during 2013-2014 from the populational-based longitudinal EpiFloripa Aging Study (n = 1197). Serum 25-hydroxycholecalciferol concentrations were analyzed and classified according to the Endocrine Society reference values [sufficiency (≥ 30 ng/mL), insufficiency (21-29 ng/mL), and deficiency (≤ 20 ng/mL)]. Depressive symptoms were evaluated using the Geriatric Depression Scale (15-item GDS). Logistic regression was performed to assess depressive symptoms in each vitamin D category. The analysis was adjusted for sex, age, skin color, family income, leisure-time physical activities, social or religious groups attendance, morbidities, cognitive impairment, and dependence in activities of daily living. RESULTS: A total of 557 participants with complete data for exposure and outcome were enrolled in the analysis. Most of the sample participants were female (63.1%), age-range 60-69 years (42.2%), white skin color (85.1%), and vitamin D serum level samples were collected in autumn (50.7%). Depressive symptoms were present in 15.8% of the participants, and the prevalence was higher in individuals classified as deficient in vitamin D (23.2, 95% confidence interval [CI] = 15.6;32.9) and insufficiency (17.2, 95%CI = 11.0;25.9). The crude analysis showed that vitamin D deficient participants had 3.08 (CI = 1.53;6.20) times higher odds to present depressive symptoms compared to vitamin D sufficiency. After adjusting, the association was maintained [OR 2.27 (95%CI = 1.05;4.94). CONCLUSIONS: Serum 25-hydroxycholecalciferol deficiency was positively associated with depressive symptoms in older adults from southern Brazil.

An Update on the Biological Activities of Euterpe edulis (Juçara).

The palm tree Euterpe edulis, known as juçara, produces spherical and purple fruits, similar to those of the Euterpe oleracea and Euterpe precatoria palm trees, from which the common name açaí originates. Juçara fruit has been gaining prominence in the scientific world for its interesting nutritional composition, which is rich in antioxidants, and for its sustainable production model. Recently, relevant biological activities have been associated with the juçara fruit, and its use in alimentation has become an important nutritional, environmental, and economic alternative. The aim of this review is to compile recent scientific data about the phytochemical characterization and biological activities of E. edulis. A review of the literature was conducted in two electronic databases, Medline and Science Direct. The eligibility criteria were as follows: phytochemicals characterize of the E. edulis fruits and evaluate biological effects in vitro or in vivo with pulp, extract, juice, or product of juçara fruits. Investigations were excluded if they used other parts of the plant (seeds), did not assess biological activities, or have tested methodologies for compound extraction. From the identified reports, 25 articles were eligible for this study. The promotion of health benefits related to juçara fruits seems to have improved antioxidant activity in vivo, benefits to lipid and glycemic profiles, and modulation of inflammatory status in experimental studies in animals.

Glutamatergic system and mTOR-signaling pathway participate in the antidepressant-like effect of inosine in the tail suspension test.

Glutamatergic system and mTOR signaling pathway have been proposed to be important targets for pharmacological treatment of major depressive disorder. Previous studies have shown that inosine, an endogenous purine, is able to exert a remarkable antidepressant-like effect in mice. Nevertheless, the role of glutamatergic system and mTOR in this effect was not previously determined. This study was designed to investigate the possible modulation of NMDA receptors (NMDAR), AMPA receptors (AMPAR) and mTOR complex 1 (mTORC1) signaling pathway in the inosine anti-immobility effect in the tail suspension test (TST) in mice. Pre-treatment of mice with NMDA (0.1 pmol/mouse, NMDAR agonist, i.c.v.) and D-serine (30 µg/mouse, NMDAR co-agonist, i.c.v.) prevented inosine (10 mg/kg, i.p.) anti-immobility effect in the TST. In addition, a synergistic antidepressant-like effect was observed when a sub-effective dose of inosine (0.1 mg/kg, i.p.) was combined with sub-effective doses of NMDAR antagonists MK-801 (0.001 mg/kg, p.o.) or ketamine (0.1 mg/kg, i.p.). Conversely, the antidepressant-like effect elicited by inosine was not altered by pre-treatment with AMPAR antagonist, DNQX (2.5 µg/mouse, i.c.v.). The mTORC1 inhibitor rapamycin (0.2 nmol/mouse, i.c.v.) prevented the inosine anti-immobility effect in the TST. Noteworthy, inosine treatment did not change the immunocontent of the synaptic proteins PSD95, GluA1 and synapsin I. Mice locomotor activity assessed by open-field test, was not altered by treatments. Taken together, this study shows a pivotal role of NMDAR inhibition and mTORC1 activation for inosine antidepressant-like effect and extends the knowledge concerning the molecular mechanism and potential of inosine for antidepressant strategies.

Signaling pathways underlying the antidepressant-like effect of inosine in mice.

Inosine is a purine nucleoside formed by the breakdown of adenosine that elicits an antidepressant-like effect in mice through activation of adenosine A1 and A2A receptors. However, the signaling pathways underlying this effect are largely unknown. To address this issue, the present study investigated the influence of extracellular-regulated protein kinase (ERK)1/2, Ca2+/calmoduline-dependent protein kinase (CaMKII), protein kinase A (PKA), phosphoinositide 3-kinase (PI3K)/Akt, and glycogen synthase kinase 3beta (GSK-3ß) modulation in the antiimmobility effect of inosine in the tail suspension test (TST) in mice. In addition, we attempted to verify if inosine treatment was capable of altering the immunocontent and phosphorylation of the transcription factor cyclic adenosine monophosphatate (cAMP) response-binding element protein (CREB) in mouse prefrontal cortex and hippocampus. Intracerebroventricular administration of U0126 (5 µg/mouse, MEK1/2 inhibitor), KN-62 (1 µg/mouse, CaMKII inhibitor), H-89 (1 µg/mouse, PKA inhibitor), and wortmannin (0.1 µg/mouse, PI3K inhibitor) prevented the antiimmobility effect of inosine (10 mg/kg, intraperitoneal (i.p.)) in the TST. Also, administration of a sub-effective dose of inosine (0.1 mg/kg, i.p.) in combination with a sub-effective dose of AR-A014418 (0.001 µg/mouse, GSK-3ß inhibitor) induced a synergic antidepressant-like effect. None of the treatments altered locomotor activity of mice. Moreover, 24 h after a single administration of inosine (10 mg/kg, i.p.), CREB phosphorylation was increased in the hippocampus. Our findings provided new evidence that the antidepressant-like effect of inosine in the TST involves the activation of PKA, PI3K/Akt, ERK1/2, and CaMKII and the inhibition of GSK-3ß. These results contribute to the comprehension of the mechanisms underlying the purinergic system modulation and indicate the intracellular signaling pathways involved in the antidepressant-like effect of inosine in a preclinical test of depression.

Vitamin D serum concentration is prospectively associated with depressive symptoms in the EpiFloripa Aging Cohort Study: a structural equation modeling approach.

OBJECTIVE: To evaluate the direct, indirect, and total prospective effects of serum concentrations of [25(OH)D, 25-hydroxycolecalciferol] on depressive symptoms in older adults. METHODS: Data from the second (2013-2015) and third (2017-2019) waves of the EpiFloripa Aging Cohort Study (≥ 60 years) were analyzed. Depressive symptoms were assessed by the 15-item Geriatric Depression Scale (GDS-15). 25(OH)D levels were measured using the microparticle chemiluminescence method. A directed acyclic graph (DAG) was constructed to identify the minimum set of adjustments. Structural equation modeling (SEM) analysis was used to determine the effects of 25(OH)D on depressive symptoms. RESULTS: A total of 574 older adults' data were analyzed (63.1% female). In the follow-up (n=390), 16.2% of older adults presented high-severity of depressive symptoms (> or = 6 points). SEM analysis revealed a small direct and negative effect of 25(OH)D (ß=-0.11, P < 0.05), and a total negative effect (ß=-0.13; P < 0.05) on depressive symptoms on wave 3 (an increase of 25(OH)D led to a decrease on depressive symptoms). No direct effect on wave 2 and no indirect effect mediated by depressive symptoms in wave 2 were found. CONCLUSIONS: Findings indicate a prospective association between 25(OH)D and depressive symptoms, suggesting a long-term effect in older adults from southern Brazil.

Vatairea macrocarpa lectin (VML) induces depressive-like behavior and expression of neuroinflammatory markers in mice.

Lectins are proteins capable of reversible binding to the carbohydrates in glycoconjugates that can regulate many physiological and pathological events. Galectin-1, a ß-galactoside-binding lectin, is expressed in the central nervous system (CNS) and exhibits neuroprotective functions. Additionally, lectins isolated from plants have demonstrated beneficial action in the CNS. One example is a lectin with mannose-glucose affinity purified from Canavalia brasiliensis seeds, ConBr, which displays neuroprotective and antidepressant activity. On the other hand, the effects of the galactose-binding lectin isolated from Vatairea macrocarpa seeds (VML) on the CNS are largely unknown. The aim of this study was to verify if VML is able to alter neural function by evaluating signaling enzymes, glial and inflammatory proteins in adult mice hippocampus, as well as behavioral parameters. VML administered by intracerebroventricular (i.c.v) route increased the immobility time in the forced swimming test (FST) 60 min after its injection through a carbohydrate recognition domain-dependent mechanism. Furthermore, under the same conditions, VML caused an enhancement of COX-2, GFAP and S100B levels in mouse hippocampus. However, phosphorylation of Akt, GSK-3ß and mitogen-activated protein kinases named ERK1/2, JNK1/2/3 and p38(MAPK), was not changed by VML. The results reported here suggest that VML may trigger neuroinflammatory response in mouse hippocampus and exhibit a depressive-like activity. Taken together, our findings indicate a dual role for galactose binding lectins in the modulation of CNS function.

Association between adiposity and emergent depressive symptoms in a 10-years prospective cohort of older adults: The EpiFloripa Aging study.

BACKGROUND: The association between obesity and depressive symptoms has been described in the literature, but there is a scarcity of longitudinal data. This study aimed to verify the association between body mass index (BMI) and waist circumference and the incidence of depressive symptoms over a 10-year follow-up in a cohort of older adults. METHODS: Data from the first (2009-2010), second (2013-2014), and third (2017-2019) waves of the EpiFloripa Aging Cohort Study were used. Depressive symptoms were assessed by the 15-item Geriatric Depression Scale (GDS-15) and classified in significant depressive symptoms for those with ≥6 points. The Generalized Estimating Equations model was used to estimate the longitudinal association between BMI and waist circumference and depressive symptoms across a 10-year follow-up. RESULTS: The incidence of depressive symptoms (N = 580) was 9.9 %. The relationship between BMI and the incidence of depressive symptoms in older adults followed a U-shaped curve. Older adults with obesity had an incidence relative ratio of 76 % (IRR = 1.24, p = 0.035) for increasing the score of depressive symptoms after 10 years, compared to those with overweight. The higher category of waist circumference (Male: ≥102; Female: ≥88 cm) was associated with depressive symptoms (IRR = 1.09, p = 0.033), only in a non-adjusted analysis. LIMITATIONS: Relatively high follow-up dropout rate; Few individuals in the underweight BMI category; BMI must be considered with caution because it does not measure only fat mass. CONCLUSIONS: Obesity was associated with the incidence of depressive symptoms when compared with overweight in older adults.

Association between physical activity and vitamin D is partially mediated by adiposity in older adults: EpiFloripa Aging Cohort Study.

Studies have found that physical activity (PA) could be a protective factor and adiposity a risk factor for low serum 25-hydroxycholecalciferol (25(OH)D) concentration. This cross-sectional study hypothesized that PA could have a direct effect on 25(OH)D, and adiposity could be a mediating factor. Data from the second wave of the EpiFloripa Aging longitudinal study, collected during 2013 and 2014 (n = 1197) in Florianopolis, Santa Catarina, Brazil, was used. PA was measured using an accelerometer and classified as light PA (LPA), moderate and vigorous PA (MVPA), and total PA (TPA); 25(OH)D levels were measured using the microparticle chemiluminescence method. Body fat composition (%fat) was assessed using dual-energy X-ray absorptiometry. Structural equation modeling was performed to analyze the total, direct, and indirect effects of PA on %fat and 25(OH)D levels, presented using the standardized coefficient (ß). Participants with complete data were included in the analysis (n = 574, 66.7% female). MVPA showed a direct (ß = 0.11; P < .05) and total positive effect on 25(OH)D (ß = 0.12; P < .05). All models of PA had a direct negative effect on %fat. Additionally, a direct negative effect of %fat on 25(OH)D was observed in all models. A marginal and partial effect of %fat as a mediator of the relationship between MVPA and 25(OH)D was noted (ß = 0.01, P = .09). Our results show that PA presents a direct effect on serum 25(OH)D. %fat has a small contribution as a mediator of this relationship. These data suggest that an increase in MVPA and a decrease in %fat could be strategies to increase 25(OH)D levels in older adults.

Vitamin D, Depressive Symptoms, and Covid-19 Pandemic.

Since the COVID-19 outbreak, studies across diverse countries have strongly pointed toward the emergence of a mental health crisis, with a dramatic increase in the prevalence of depressive psychopathology and suicidal tendencies. Vitamin D deficiency has been associated with an increased risk of mental health problems as well as individual responses to stress. Studies have discussed the relationship between low serum vitamin D concentrations and depressive symptoms, suggesting that maintaining adequate concentrations of serum vitamin D seems to have a protective effect against it. Vitamin D was found to contribute to improved serotonergic neurotransmission in the experimental model of depression by regulating serotonin metabolism. The signaling of 1,25-dihydroxyvitamin D3, the active form of vitamin D, through vitamin D receptor (VDR) induces the expression of the gene of tryptophan hydroxylase 2 (TPH2), influences the expression of serotonin reuptake transporter (SERT) as well as the levels of monoamine oxidase-A (MAO-A), the enzyme responsible for serotonin catabolism. Vitamin D also presents a relevant link with chronobiological interplay, which could influence the development of depressive symptoms when unbalance between light-dark cycles occurs. In this Perspective, we discussed the significant role of vitamin D in the elevation of stress-related depressive symptoms during the COVID-19 pandemic. It is suggested that vitamin D monitoring and, when deficiency is detected, supplementation could be considered as an important healthcare measure while lockdown and social isolation procedures last during the COVID-19 pandemic.

Ketogenic diet, seizure control, and cardiometabolic risk in adult patients with pharmacoresistant epilepsy: a review.

Pharmacoresistant epilepsy causes serious deleterious effects on the patient's health and quality of life. For this condition, a ketogenic diet (KD) is a treatment option. The KD is a general term for a set of diets that contain high amounts of fat and low content of carbohydrates. The most prominent KD treatments are classical KD (4:1 ratio of fat to carbohydrate), modified Atkins diet (2:1 to 1:1 ratio), medium-chain triglycerides KD (with medium-chain triglyceride as a part of the fat content), and low glycemic index KD (using low glycemic carbohydrates). KD has been widely prescribed for children with epilepsy but not for adult patients. One of the main concerns about adult use of KD is its cardiovascular risk associated with high-fat and cholesterol intake. Therefore, this narrative review provides comprehensive information of the current literature on the effects of KD on lipid profile, glycemic-control biomarkers, and other cardiometabolic risk factors in adult patients with pharmacoresistant epilepsy.

Effects of Euterpe edulis Martius on inflammatory responses to high-intensity intermittent exercise: Crossover randomized trial.

OBJECTIVE: High-intensity intermittent exercise (HIIE) may enhance the antiinflammatory status. The juçara fruit juice (JFJ) has well-established antioxidant and antiinflammatory properties. This study investigated the effect of JFJ consumption on the inflammatory response to HIIE in physically active subjects. METHODS: In a randomized crossover design, 15 men were assigned to drink 250 mL of either JFJ or water (control) 1 h before a cycling HIIE session (seven sets of 60 s at 100% peak power output; 75 s recovery between sets). Blood samples were obtained before and at 0, 30, and 60 min post-HIIE, and the serum was analyzed for interleukin (IL)-6, IL-1ß, IL-8, IL-10, tumor necrosis factor-α, and cortisol. RESULTS: After HIIE, the IL-6 levels were higher than baseline (percent change) at 30 min (P = 0.041) and 60 min (P = 0.038) for the control, but were unaffected by JFJ. IL-10 was higher in the JFJ group than in the control at 30 min (d = â€’0.63). Tumor necrosis factor-α was lower than baseline at 30 min for the control (d = â€’0.71) and at 60 min for the JFJ group (d = â€’0.60). For control, cortisol increased to higher than the baseline at 30 and 60 min (d = 0.54 and d = 0.76, respectively). For the JFJ group, the cortisol levels were significantly higher than the baseline at 30 min (P = 0.022). Performance during sprints was higher in the JFJ group than in the control (P = 0.002). In the control group, performance was with both IL-6 (semipartial correlation; sr = -0.59, large effect size) and cortisol at 0 h (sr = -0.52, large effect size). CONCLUSIONS: JFJ intake attenuated the antiinflammatory response to HIIE, possibly resulting from a lower degree of muscle stress.

Adaptação de receitas culinárias de um programa de intervenção em habilidades culinárias para indivíduos com diabetes tipo 2: um estudo de viabilidade / Culinary recipes adaptation to a cooking skills intervention program for individuals with type 2 diabetes: a feasibility study

Introdução: Hábitos alimentares saudáveis e habilidades culinárias podem contribuir no tratamento de diabetes mellitus tipo 2. Objetivo: Este estudo visou adaptar nutricionalmente, testar e avaliar qualitativamente as características sensoriais de receitas culinárias para sua aplicação em um programa de intervenção culinária para indivíduos com diabetes tipo 2, denominado Nutrição e Culinária na Cozinha. Método: O programa Nutrição e Culinária na Cozinha é uma intervenção com oficinas culinárias práticas focadas na promoção das habilidades culinárias. As modificações das receitas foram baseadas no índice glicêmico dos ingredientes, depois testadas e discutidas por especialistas em nutrição por meio de oficinas de consenso. Realizaram-se grupos focais com indivíduos com diabetes tipo 2 para avaliar e discutir as características sensoriais das receitas culinárias. Resultados: As adaptações das receitas para atender à população com diabetes tipo 2 incluíram a substituição de arroz por couve-flor e macarrão por abobrinha, além do uso de frutas e especiarias em receitas doces em substituição a ingredientes com açúcares de adição e/ou edulcorantes Essas mudanças foram aprovadas pelos indivíduos com diabetes tipo 2. Conclusão: As receitas culinárias adaptadas poderão ser utilizadas em orientações dietéticas e em intervenções culinárias para promover hábitos alimentares que contribuam para o controle glicêmico.

Introduction: Healthy eating habits and cooking skills can contribute to the treatment of type 2 diabetes mellitus (T2DM). Objective: This study aimed to adapt, test, and qualitatively evaluate the sensory characteristics of food recipes for their application in a culinary intervention program for individuals with type 2 diabetes, called Nutrition and Culinary in the Kitchen. Methods: Nutrition and Culinary in the Kitchen is an intervention program with hands-on cooking classes focused on promoting cooking skills. Recipes' modifications were based on the glycemic index of ingredients, then tested and discussed by nutrition experts in consensus workshops. Individuals with type 2 diabetes assessed and discussed the sensory characteristics of recipes in focus groups. Results: Recipes adaptations to suit type 2 diabetes population included replacement of rice by cauliflower and pasta by zucchini, and the use of fruits and spices in sweet recipes instead of using added sugar ingredients and/or non-caloric sweeteners. Those changes were positively accepted by the individuals with type 2 diabetes. Conclusion: The adapted culinary recipes can be used in dietary guidelines and in cooking interventions to promote eating habits that contribute to glycemic control.

Subchronic administration of ascorbic acid elicits antidepressant-like effect and modulates cell survival signaling pathways in mice.

In this study, we examined the ability of subchronic ascorbic acid administration to produce an antidepressant-like effect in the mouse tail suspension test (TST). Moreover, we investigated the effect of this vitamin on hippocampal and cerebrocortical brain-derived neurotrophic factor (BDNF) immunocontent, phosphorylation of protein kinase B (AKT), extracellular signal-regulated kinase (ERK), p38MAPK and c-Jun. N-terminal kinase (JNK). Fluoxetine (10 mg/kg, positive control, po) or ascorbic acid (0.1 and 1 mg/kg, po), administered once daily for 21 days, produced a significant antidepressant-like effect in the TST. The significant effects obtained in protein immunocontents were: administration of ascorbic acid at 1 mg/kg induced an increase in AKT phosphorylation in cerebral cortex of mice. Ascorbic acid treatment (1 mg/kg), similar to fluoxetine, decreased hippocampal p38MAPK but did not alter ERK or JNK phosphorylation. These results extend the data about the antidepressant-like effect of ascorbic acid by exploring, for the first time, the intracellular pathways involved in its antidepressant properties after subchronic administration.

Nutritional challenges in older adults during the COVID-19 pandemic / Desafios nutricionais na saúde de idosos em tempos de pandemia da COVID-19

ABSTRACT It has been documented that the older adults of the population are at the greatest risk of mortality due to the coronavirus disease; consequently, they could be the population most affected by the measures of social isolation and reduction of virus contagion implemented worldwide. Social isolation can expose older adults to an increased nutritional risk due to factors such as socioeconomic insecurity, which could affect food acquisition and the need for support in daily tasks and meals. The institutionalized older adults often depend on food donations, which may have reduced due the economic crisis caused by the pandemic, and the aging process itself causes changes in nutritional necessitie and eating habits. In the coronavirus pandemic, nutritionists and dietitians can offer remote nutritional follow-up. Moreover, the government actions, such as the implementation of educational and social service programs, should be applied to support healthy aging and minimize exposure to nutritional risks and coronavirus disease.

RESUMO Tem sido documentado que os idosos são a população de maior risco para mortalidade por COVID-19. Consequentemente, pode ser a mais afetada pelas medidas de isolamento social e de redução de contágio pelo vírus implementadas em todo o mundo. O isolamento social pode expor os idosos ao risco nutricional aumentado devido a alguns fatores, como: a insegurança socioeconômica, a qual pode afetar a aquisição de alimentos; a necessidade de apoio nas tarefas e nas refeições diárias; a possível redução de doações de alimentos para idosos institucionalizados, em virtude da crise econômica ocasionada pela pandemia; e o próprio processo do envelhecimento, que causa alterações das necessidades nutricionais e do hábito de se alimentar. Contudo, no contexto da pandemia do novo coronavírus, nutricionistas podem oferecer acompanhamento nutricional remoto. Além disso, ações governamentais, como a implementação de programas educacionais e de serviço social, devem ser aplicadas para o envelhecimento saudável e para a minimização da exposição ao risco nutricional e à COVID-19.

TNF-α-induced depressive-like phenotype and p38(MAPK) activation are abolished by ascorbic acid treatment.

We investigated the effects of ascorbic acid on depressive-like behavior induced by tumor necrosis factor (TNF-α) in mice. Additionally, we examined the effects of combined administration of ascorbic acid and antidepressants, MK-801 and 7-nitroindazole in mice exposed or not to TNF-α and the capacity of TNF-α and ascorbic acid to modulate hippocampal and cerebrocortical phosphorylation of extracellular signal-regulated kinase (ERK), p38(MAPK) and c-Jun N-terminal kinase (JNK). In control animals, ascorbic acid reduced the immobility time in the tail suspension test (TST). Unilateral intracerebroventricular administration of TNF-α produced a depressive-like behavior in the TST, and the treatment with ascorbic acid prevented this effect. Sub-effective dose of ascorbic acid combined with sub-effective doses of fluoxetine, imipramine, bupropion, MK-801 or 7-nitroindazole produced a synergistic antidepressant-like effect in mice exposed or not to TNF-α. No treatment caused significant alterations in the locomotor activity of mice. Administration of TNF-α increased the phosphorylation of p38(MAPK) in hippocampus and cerebral cortex, and the treatment with ascorbic acid prevented this effect. Ascorbic acid increased phosphorylation of ERK1 in the hippocampus of saline- and TNF-α-treated animals, however it did not produce alterations in the cerebral cortex. No effects on phosphorylation of ERK2 or JNK were found. The observed effect of ascorbic acid seems to be associated, at least partially, with a reduced p38(MAPK) phosphorylation, activation of the monoaminergic systems as well as inhibition of N-methyl-D-aspartate (NMDA) receptors and nitric oxide (NO) synthesis.

Region-specific alterations of AMPA receptor phosphorylation and signaling pathways in the pilocarpine model of epilepsy.

Disturbances in glutamatergic transmission and signaling pathways have been associated with temporal lobe epilepsy (TLE) in humans. However, the profile of these alterations within specific regions of the hippocampus and cerebral cortex has not yet been examined. The pilocarpine model in rodents reproduces the main features of TLE in humans. The present study aims to characterize specific alterations of the glutamatergic transmission and signaling pathways in the dorsal (DH) and ventral hippocampus (VH) and temporal cortex (Ctx) of male adult Wistar rats 60 days after pilocarpine treatment (chronic period). The western blotting analyzes show a decrease of AMPA glutamate receptor subunit (GluA1)-Ser(845) phosphorylation; reduction of ERK1 and PKA activity; up-regulation of GFAP and down-regulation of the glutamate transporter EAAT2 expression in the DH. In contrast, in the VH it was observed a decrease of GluA1-Ser(831) phosphorylation and JNKp54 and PKC activity. In the Ctx, only ERK1 phosphorylation/activity decreased. The level of GluA1-Ser(845) phosphorylation and PKA activity (DH) and the level of GluA1-Ser(831) phosphorylation and PKC activity (VH) appear to be correlated, respectively. These findings suggest a differential imbalance of the signaling pathways involved in the site-specific phosphorylation of AMPA receptor in the hippocampus. Furthermore, we suggest that dorsal hippocampus is probably more susceptible to the impairment of glutamate uptake and gliose, since only this area displayed a significant decrease of EAAT2 and increment of GFAP. Taken together, our study suggests that specific neurochemical alterations take place in hippocampal sub regions. This approach may be valuable for understanding the onset of seizures and the alterations of neuronal excitability in specific regions and may help to establish therapeutic targets for treatment of this neuropathology.