Vitamin D3 improves spatial memory and modulates cytokine levels in aged rats.

Vitamin D3 deficiency is associated with an increased risk of dementia. An association between vitamin D3 deficiency and subjective cognitive complaints in geriatric patients has been previously reported. This study aimed to evaluate the effects of two doses of vitamin D3 on spatial memory (using the Radial Maze) and cytokine levels [tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interleukin-10 (IL-10)] on 2-, 6-, 13-, 22-, and 31-month-old male Wistar rats. Animals were supplemented with vitamin D3 at doses of 42 IU/kg and 420 IU/kg for 21 days. A radial maze test was performed to evaluate spatial memory. After the behavioral test, the frontal cortex and hippocampus were dissected for enzyme immunoassay analyses to measure the cytokine levels (TNFα, IL-1ß, IL-6, and IL-10). Our results showed that vitamin D3 supplementation reversed spatial memory impairment at the supplemented doses (42 and 420 IU/kg) in 6-, 13-, and 22-month-old animals and at a dose of 420 IU/kg in 31-month-old animals. The lower dose (42 IU/kg) regulates both pro- and anti-inflammatory cytokines mainly in the frontal cortex. Our results suggest that vitamin D3 has a modulatory action on pro- and anti-inflammatory cytokines, since older animals showed increased cytokine levels compared to 2-month-old animals, and that vitamin D3 may exert an immunomodulatory effect on aging.

Detailed Characterization of Brain Dysfunction in a Long-Term Rodent Model of Critical Illness.

Critical illness encompasses a wide spectrum of life-threatening clinical conditions requiring intensive care. Our objective was to evaluate cognitive, inflammatory and cellular metabolism alterations in the central nervous system in an animal model of critical illness induced by zymosan. For this Wistar rats that were divided into Sham and zymosan. Zymozan was administered once intraperitoneally (30 g/100 g body weight) diluted in mineral oil. The animals were submitted to behavioral tests of octagonal maze, inhibitory avoidance and elevated plus maze. Brain structures (cortex, prefrontal and hippocampus) were removed at 24 h, 4, 7 and 15 days after zymosan administration for analysis of cytokine levels (TNF-α, IL-1b, IL-6 and IL-10), oxidative damage and oxygen consumption. Zymosan-treated animals presented mild cognitive impairment both in aversive (inhibitory avoidance) and non-aversive (octagonal maze) tasks by day 15. However, they did not show increase in anxiety (elevated-plus maze). The first neurochemical alteration found was an increase in brain pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) at day 4th in the hippocampus. In cortex, a late (7 and 15 days) increase in TNF-α was also noted, while the anti-inflammatory cytokine IL-10 decrease from 4 to 15 days. Oxygen consumption was decreased in the hippocampus and pre-frontal, but not cortex, only at 7 days. Additionally, it was observed a late (15 days) increase in oxidative damage parameters. This characterization of brain dysfunction in rodent model of critical illness reproduces some of the alterations reported in humans such neuropsychiatric disorders, especially depression, memory loss and cognitive changes and can add to the nowadays used models.

Ketamine, but not fluoxetine, rapidly rescues corticosterone-induced impairments on glucocorticoid receptor and dendritic branching in the hippocampus of mice.

Although numerous studies have investigated the mechanisms underlying the fast and sustained antidepressant-like effects of ketamine, the contribution of the glucocorticoid receptor (GR) and dendritic branching remodeling to its responses remain to be fully established. This study investigated the ability of a single administration of ketamine to modulate the GR and dendritic branching remodeling and complexity in the hippocampus of mice subjected to chronic corticosterone (CORT) administration. CORT was administered for 21 days, followed by a single administration of ketamine (1 mg ∕kg, i.p.) or fluoxetine (10 mg ∕kg, p.o., conventional antidepressant) in mice. On 22nd, 24 h after the treatments, GR immunocontent in the hippocampus was analyzed by western blotting, while the dendritic arborization and dendrite length in the ventral and dorsal dentate gyrus (DG) of the hippocampus was analyzed by Sholl analysis. Chronic CORT administration downregulated hippocampal GR immunocontent, but this alteration was completely reversed by a single administration of ketamine, but not fluoxetine. Moreover, CORT administration significantly decreased dendritic branching in the dorsal and ventral DG areas and caused a mild decrease in dendrite length in both regions. Ketamine, but not fluoxetine, reversed CORT-induced dendritic branching loss in the ventral and dorsal DG areas, regions associated with mood regulation and cognitive functions, respectively. This study provides novel evidence that a single administration of ketamine, but not fluoxetine, rescued the impairments on GR and dendritic branching in the hippocampus of mice subjected to chronic CORT administration, effects that may be associated with its rapid antidepressant response.

Oral administration of D-galactose increases brain tricarboxylic acid cycle enzymes activities in Wistar rats.

D-galactose (D-gal) is a carbohydrate widely distributed in regular diets. However, D-gal administration in rodents is associated with behavioral and neurochemical alterations similar to features observed in aging. In this regard, this study aimed to investigate the effects of D-gal exposure, in different periods, in rats' brain regions' activities of creatine kinase (CK) and tricarboxylic acid (TCA) cycle enzymes. Male adult Wistar rats received D-gal (100 mg/kg, gavage) for 1, 2, 4, 6 or 8 weeks. CK and TCA enzymes' activities were evaluated in rats' prefrontal cortex and hippocampus. In general, the results showed an increase in citrate synthase (CS) and succinate dehydrogenase (SDH) activities in animals treated with D-gal compared to the control group in the prefrontal cortex and hippocampus. Also, in the fourth week, the malate dehydrogenase (MD) activity increased in the hippocampus of rats that received D-gal compared to control rats. In addition, we observed an increase in the CK activity in the prefrontal cortex and hippocampus in the first and eighth weeks of treatment in the D-gal group compared to the control group. D-gal administration orally administered modulated TCA cycle enzymes and CK activities in the prefrontal cortex and hippocampus, which were also observed in aging and neurodegenerative diseases. However, more studies using experimental models are necessary to understand better the impact and contribution of these brain metabolic abnormalities associated with D-gal consumption for aging.

Folic acid prevents habituation memory impairment and oxidative stress in an aging model induced by D-galactose.

The present study aimed to evaluate the effect of folic acid treatment in an animal model of aging induced by D-galactose (D-gal). For this propose, adult male Wistar rats received D-gal intraperitoneally (100 mg/kg) and/or folic acid orally (5 mg/kg, 10 mg/kg or 50 mg/kg) for 8 weeks. D-gal caused habituation memory impairment, and folic acid (10 mg/kg and 50 mg/kg) reversed this effect. However, folic acid 50 mg/kg per se caused habituation memory impairment. D-gal increased the lipid peroxidation and oxidative damage to proteins in the prefrontal cortex and hippocampus from rats. Folic acid (5 mg/kg, 10 mg/kg, or 50 mg/kg) partially reversed the oxidative damage to lipids in the hippocampus, but not in the prefrontal cortex, and reversed protein oxidative damage in the prefrontal cortex and hippocampus. D-gal induced synaptophysin and BCL-2 decrease in the hippocampus and phosphorylated tau increase in the prefrontal cortex. Folic acid was able to reverse these D-gal-related alterations in the protein content. The present study shows folic acid supplementation as an alternative during the aging to prevent cognitive impairment and brain alterations that can cause neurodegenerative diseases. However, additional studies are necessary to elucidate the effect of folic acid in aging.

Diet-induced obesity causes hypothalamic neurochemistry alterations in Swiss mice.

The aim of this study was to assess inflammatory parameters, oxidative stress and energy metabolism in the hypothalamus of diet-induced obese mice. Male Swiss mice were divided into two study groups: control group and obese group. The animals in the control group were fed a diet with adequate amounts of macronutrients (normal-lipid diet), whereas the animals in the obese group were fed a high-fat diet to induce obesity. Obesity induction lasted 10 weeks, at the end of this period the disease model was validated in animals. The animals in the obese group had higher calorie consumption, higher body weight and higher weight of mesenteric fat compared to control group. Obesity showed an increase in levels of interleukin 1ß and decreased levels of interleukin 10 in the hypothalamus. Furthermore, increased lipid peroxidation and protein carbonylation, and decreased level of glutathione in the hypothalamus of obese animals. However, there was no statistically significant difference in the activity of antioxidant enzymes, superoxide dismutase and catalase. The obese group had lower activity of complex I, II and IV of the mitochondrial respiratory chain, as well as lower activity of creatine kinase in the hypothalamus as compared to the control group. Thus, the results from this study showed changes in inflammatory markers, and dysregulation of metabolic enzymes in the pathophysiology of obesity.

The oral administration of D-galactose induces abnormalities within the mitochondrial respiratory chain in the brain of rats.

D-Galactose (D-gal) chronic administration via intraperitoneal and subcutaneous routes has been used as a model of aging and Alzheimer disease in rodents. Intraperitoneal and subcutaneous administration of D-gal causes memory impairments, a reduction in the neurogenesis of adult mice, an increase in the levels of the amyloid precursor protein and oxidative damage; However, the effects of oral D-gal remain unclear. The aim of this study was to evaluate whether the oral administration of D-gal induces abnormalities within the mitochondrial respiratory chain of rats. Male Wistar rats (4 months old) received D-gal (100 mg/kg v.o.), during the 1st, 2nd, 4th, 6th or 8th weeks by oral gavage. The activity of the mitochondrial respiratory chain complexes was measured in the 1st, 2nd, 4th, 6th and 8th weeks after the administration of D-gal. The activity of the respiratory chain complex I was found to have increased in the prefrontal cortex and hippocampus in the 1st, 6th and 8th weeks, while the activity of the respiratory chain complex II increased in the 1st, 2nd, 4th, 6th and 8th weeks within the hippocampus and in the 2nd, 4th, 6th and 8th weeks within the prefrontal cortex. The activity of complex II-III increased within the prefrontal cortex and hippocampus in each week of oral D-gal treatment. The activity of complex IV increased within the prefrontal cortex and hippocampus in the 1st, 2nd, 6th and 8th weeks of treatment. After 4 weeks of treatment the activity increased only in hippocampus. In conclusion, the present study showed that the oral administration of D-gal increased the activity of the mitochondrial respiratory chain complexes I, II, II-III and IV in the prefrontal cortex and hippocampus. Furthermore, the administration of D-gal via the oral route seems to cause the alterations in the mitochondrial respiratory complexes observed in brain neurodegeneration.

The preventive effects of ascorbic acid supplementation on locomotor and acetylcholinesterase activity in an animal model of schizophrenia induced by ketamine.

Studies have shown that schizophrenic patients seem to have nutritional deficiencies. Ascorbic acid (AA) has an important antioxidant effect and neuromodulatory properties. The aim of this study was to evaluate the effects of AA on locomotor activity and the acetylcholinesterase activity (AChE) in an animal model of schizophrenia (SZ). Rats were supplemented with AA (0.1, 1, or 10 mg/kg), or water for 14 days (gavage). Between the 9th and 15th days, the animals received Ketamine (Ket) (25 mg/kg) or saline (i.p). After the last administration (30 min) rats were subjected to the behavioral test. Brain structures were dissected for biochemical analysis. There was a significant increase in the locomotor activity in Ket treated. AA prevented the hyperlocomotion induced by ket. Ket also showed an increase of AChE activity within the prefrontal cortex and striatum prevented by AA. Our data indicates an effect for AA in preventing alterations induced by Ket in an animal model of SZ, suggesting that it may be an adjuvant approach for the development of new therapeutic strategies within this psychiatric disorder.

The modulation of NMDA receptors and L-arginine/nitric oxide pathway is implicated in the anti-immobility effect of creatine in the tail suspension test.

The modulation of N-methyl-D-aspartate receptor (NMDAR) and L-arginine/nitric oxide (NO) pathway is a therapeutic strategy for treating depression and neurologic disorders that involves excitotoxicity. Literature data have reported that creatine exhibits antidepressant and neuroprotective effects, but the implication of NMDAR and L-arginine/nitric oxide (NO) pathway in these effects is not established. This study evaluated the influence of pharmacological agents that modulate NMDAR/L-arginine-NO pathway in the anti-immobility effect of creatine in the tail suspension test (TST) in mice. The NOx levels and cellular viability in hippocampal and cerebrocortical slices of creatine-treated mice were also evaluated. The anti-immobility effect of creatine (10 mg/kg, po) in the TST was abolished by NMDA (0.1 pmol/mouse, icv), D-serine (30 µg/mouse, icv, glycine-site NMDAR agonist), arcaine (1 mg/kg, ip, polyamine site NMDAR antagonist), L-arginine (750 mg/kg, ip, NO precursor), SNAP (25 µg/mouse, icv, NO donor), L-NAME (175 mg/kg, ip, non-selective NOS inhibitor) or 7-nitroindazole (50 mg/kg, ip, neuronal NOS inhibitor), but not by DNQX (2.5 µg/mouse, icv, AMPA receptor antagonist). The combined administration of sub-effective doses of creatine (0.01 mg/kg, po) and NMDAR antagonists MK-801 (0.001 mg/kg, po) or ketamine (0.1 mg/kg, ip) reduced immobility time in the TST. Creatine (10 mg/kg, po) increased cellular viability in hippocampal and cerebrocortical slices and enhanced hippocampal and cerebrocortical NO x levels, an effect potentiated by L-arginine or SNAP and abolished by 7-nitroindazole or L-NAME. In conclusion, the anti-immobility effect of creatine in the TST involves NMDAR inhibition and enhancement of NO levels accompanied by an increase in neural viability.

Folic acid prevented cognitive impairment in experimental pneumococcal meningitis.

Streptococcus pneumoniae is a common cause of bacterial meningitis, with a high mortality rate and neurological sequelae. In contrast, folic acid plays an important role in neuroplasticity and the preservation of neuronal integrity. In the present study, we evaluated the influence of folic acid on memory, oxidative damage, enzymatic defence, and brain-derived neurotrophic factor (BDNF) expression in experimental pneumococcal meningitis. In animals that received folic acid at a dose of 10 or 50 mg, there was a reduction in both crossing and rearing during an open-field task compared with the training session, demonstrating habituation memory. During a step-down inhibitory avoidance task, there was a difference between the training and the test sessions, demonstrating aversive memory. In the hippocampus, BDNF expression decreased in the meningitis group; however, adjuvant treatment with 10 mg of folic acid increased BDNF expression, decreased lipid peroxidation, protein carbonylation, nitrate/nitrite levels, and myeloperoxidase activity and increased superoxide dismutase activity. In frontal cortex adjuvant treatment with 10 mg of folic acid decreased lipid peroxidation and protein carbonylation. There is substantial interest in the role of folic acid and related pathways in nervous system function and in folic acid's potential therapeutic effects. Here, adjuvant treatment with vitamin B9 prevented memory impairment in experimental pneumococcal meningitis.

Effects of chronic administration of fenproporex on cognitive and non-cognitive behaviors.

Fenproporex (Fen) is an amphetamine-based anorectic; amphetamine use causes a broad range of severe cognitive deficits and anxiogenic-like effects. In this study we evaluated pharmacological effects of the chronic administration of Fen on cognitive and non-cognitive behaviors. Male adult Wistar rats received intraperitoneal administration of vehicle (control group) or Fen (6.25, 12.5 or 25 mg/kg) for 14 days; the animals were then subjected to habituation and object recognition tasks in open-field apparatus, and elevated plus-maze task. The administration of Fen (12.5 and 25 mg/kg) impaired habituation during the second exposure to the habituation task. In addition, the same doses of Fen also impaired the performance in object recognition task. In elevated plus-maze task, the administration of Fen (in all doses tested) induced anxiogenic-like effects in rats. Our results suggest that chronic Fen administration alters memory and induces anxiogenic-like effects in rats.

Maternal deprivation disrupts mitochondrial energy homeostasis in the brain of rats subjected to ketamine-induced schizophrenia.

Maternal deprivation (MD) appears to be one of the environmental factors involved in the pathophysiology of schizophrenia. A widely used animal model of the schizophrenia involves the administration of ketamine, a dissociative anesthetic, NMDA receptors noncompetitive antagonist, that induce symptoms such as schizophrenia. To clarify the molecular mechanism of schizophrenia induced by MD, we investigated alterations in energetic metabolism, oxidative stress and neurotrophic factor levels in the brain of rats following MD and/or a single administration of ketamine during adulthood. Male Wistar rats were subjected to MD for 10 days. Additionally, these animals received acute ketamine (5, 15 or 25 mg/kg by intraperitoneal route, i.p.) during adulthood, and 30 min later, they were killed and the prefrontal cortex (PFC), the hippocampus and the striatum were removed for molecular analyses. Ketamine 25 mg/kg and/or MD and Ketamine 15 and 5 mg/kg with MD decreased the creatine kinase (CK) activity in the hippocampus. The enzyme activity of succinate dehydrogenase (SDH) in the Krebs cycle had increased in the striatum following the administration of ketamine 25 mg/kg, MD per se or MD plus ketamine 5 and 15 mg/kg. MD per se or MD combined with ketamine in different doses increased the activity of mitochondrial complexes. The PFC of animals subjected to MD and administered with ketamine 5 mg/kg exhibited increased protein carbonyl content. In the hippocampus, ketamine 15 mg/kg, ketamine 25 mg/kg and MD each increased the carbonyl content. In the striatum, the TBARS levels were increased by the administration of ketamine 25 mg/kg. Finally, in the hippocampus, MD alone or in combination with ketamine reduced the Nerve Growth Factor (NGF) levels; however, the Brain-derived Neurotrophic Factor (BDNF) levels were unaltered. In the present study, we suggest that MD increased the risk of psychotic symptoms in adulthood, altering different parameters of energy and oxidative stress. Our results suggest that adverse experiences occurring early in life may sensitize specific neurocircuits to subsequent stressors, inducing vulnerability, and may help us understand the pathophysiological mechanisms involved in this disorder.

Alzheimer's Disease associated with Psychiatric Comorbidities.

Alzheimer's disease (AD) is the most common cause of dementia and has become a severe public health issue. It is estimated that globally, 35.6% of people have some form of dementia. This number is expected to double by 2030, and possibly even triple by 2050. The disease is associated with deficits in cognition/memory and a reduced ability in coping with everyday life. Moreover, patients can experience behavioral alterations such as mood swings, depression and hallucinations. Therefore, it is common to find the presence of neuropsychiatric comorbidities such as depression, schizophrenia and bipolar disorder during the course or development of AD. These disorders can become severe enough to interfere with the patients daily functioning, and can worsen the course of the disease. However, little is known about the causal relationship between psychiatric comorbidities and AD, or the reasons for the predisposition of some individuals to such disorders. Therefore, the purpose of this review is to clarify the causal relationship between depression, schizophrenia and bipolar disorder with AD.

Evaluation of acetylcholinesterase activity and behavioural alterations induced by ketamine in an animal model of schizophrenia.

OBJECTIVE: Cognitive deficits in schizophrenia play a crucial role in its clinical manifestation and seem to be related to changes in the cholinergic system, specifically the action of acetylcholinesterase (AChE). Considering this context, the aim of this study was to evaluate the chronic effects of ketamine in the activity of AChE, as well as in behavioural parameters involving learning and memory. METHODS: The ketamine was administered for 7 days. A duration of 24 h after the last injection, the animals were submitted to behavioural tests. The activity of AChE in prefrontal cortex, hippocampus and striatum was measured at different times after the last injection (1, 3, 6 and 24 h). RESULTS: The results indicate that ketamine did not affect locomotor activity and stereotypical movements. However, a cognitive deficit was observed in these animals by examining their behaviour in inhibitory avoidance. In addition, an increase in AChE activity was observed in all structures analysed 1, 3 and 6 h after the last injection. Differently, serum activity of AChE was similar between groups. CONCLUSION: Chronic administration of ketamine in an animal model of schizophrenia generates increased AChE levels in different brain tissues of rats that lead to cognitive deficits. Therefore, further studies are needed to elucidate the complex mechanisms associated with schizophrenia.

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.

Prevalence of cognitive impairment and associated factors in older people.

BACKGROUND: Older people are the fastest-growing age group, with the highest risk of cognitive impairment. This study assessed the prevalence and associated factors with cognitive impairment in community-dwelling older people. METHODS: Older people were interviewed and accomplished through sociodemographic and health questionnaires. The quantitative variables were described by mean and standard deviation or median and interquartile range. The significance level adopted was 5 % (p < 0.05). The association between the quantitative variables was evaluated using the Pearson or Spearman correlation coefficients. RESULTS: The research population comprised 165 long-lived adults aged ≥80. The youngest one was 80, and the oldest one was 94 years old. The participants were 84.8 ± 3.6 years old, female (63 %) with a mean of education of 2.9 ± 1.8 years. A poor performance in the Mini-Mental State Examination (MMSE) was found in 58 (35.2 %) individuals when adjusted for educational level. After adjustment for confounding factors, body mass index (BMI) (p = 0.09), total older adults' income (up to 1 minimum wage [mw], p = 0.023; over 1 to 2 mw, p = 0.023), functional disability (Moderate dependence 75 %, p = 0.038; Moderate dependence 50 %, p = 0.081; Moderate dependence 25 %, p = 0.054), and the anxiety scale (p = 0.032), remained associated with cognitive impairment. CONCLUSIONS: This study showed that BMI, total older adults' income, functional disability, and anxiety are related to cognitive impairment in long-lived adults. This study has some limitations, such as the fact that it is a cross-sectional study, the reduced number of individuals, and the fact that there were no comparisons among different ages and populations.

Sodium butyrate reverses the inhibition of Krebs cycle enzymes induced by amphetamine in the rat brain.

There is increasing interest in the possibility that mitochondrial impairment may play an important role in bipolar disorder (BD). The Krebs cycle is the central point of oxidative metabolism, providing carbon for biosynthesis and reducing agents for generation of ATP. Recently, studies have suggested that histone deacetylase (HDAC) inhibitors may have antimanic effects. The present study aims to investigate the effects of sodium butyrate (SB), a HDAC inhibitor, on Krebs cycle enzymes activity in the brain of rats subjected to an animal model of mania induced by D-amphetamine (D-AMPH). Wistar rats were first given D-AMPH or saline (Sal) for 14 days, and then, between days 8 and 14, rats were treated with SB or Sal. The citrate synthase (CS), succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) were evaluated in the prefrontal cortex, hippocampus, and striatum of rats. The D-AMPH administration inhibited Krebs cycle enzymes activity in all analyzed brain structures and SB reversed D-AMPH-induced dysfunction analyzed in all brain regions. These findings suggest that Krebs cycle enzymes' inhibition can be an important link for the mitochondrial dysfunction seen in BD and SB exerts protective effects against the D-AMPH-induced Krebs cycle enzymes' dysfunction.

The antidepressant-like effect of inosine in the FST is associated with both adenosine A1 and A 2A receptors.

Inosine is an endogenous purine nucleoside, which is formed during the breakdown of adenosine. The adenosinergic system was already described as capable of modulating mood in preclinical models; we now explored the effects of inosine in two predictive models of depression: the forced swim test (FST) and tail suspension test (TST). Mice treated with inosine displayed higher anti-immobility in the FST (5 and 50 mg/kg, intraperitoneal route (i.p.)) and in the TST (1 and 10 mg/kg, i.p.) when compared to vehicle-treated groups. These antidepressant-like effects started 30 min and lasted for 2 h after intraperitoneal administration of inosine and were not accompanied by any changes in the ambulatory activity in the open-field test. Both adenosine A1 and A2A receptor antagonists prevented the antidepressant-like effect of inosine in the FST. In addition, the administration of an adenosine deaminase inhibitor (1 and 10 mg/kg, i.p.) also caused an antidepressant-like effect in the FST. These results indicate that inosine possesses an antidepressant-like effect in the FST and TST probably through the activation of adenosine A1 and A2A receptors, further reinforcing the potential of targeting the purinergic system to the management of mood disorders.

Rivastigmine reverses cognitive deficit and acetylcholinesterase activity induced by ketamine in an animal model of schizophrenia.

Schizophrenia is one of the most disabling mental disorders that affects up to 1 % of the population worldwide. Although the causes of this disorder remain unknown, it has been extensively characterized by a broad range of emotional, ideational and cognitive impairments. Studies indicate that schizophrenia affects neurotransmitters such as dopamine, glutamate and acetylcholine. Recent studies suggest that rivastigmine (an acetylcholinesterase inhibitor) is important to improve the cognitive symptoms of schizophrenia. Therefore, the present study evaluated the protective effect of rivastigmine against the ketamine-induced behavioral (hyperlocomotion and cognitive deficit) and biochemical (increase of acetylcholinesterase activity) changes which characterize an animal model of schizophrenia in rats. Our results indicated that rivastigmine was effective to improve the cognitive deficit in different task (immediate memory, long term memory and short term memory) induced by ketamine in rats. Moreover, we observed that rivastigmina reversed the increase of acetylcholinesterase activity induced by ketamine in the cerebral cortex, hippocampus and striatum. However, rivastigmine was not able to prevent the ketamine-induced hyperlocomotion. In conslusion, ours results indicate that cholinergic system might be an important therapeutic target in the physiopathology of schizophrenia, mainly in the cognition, but additional studies should be carried.

COVID-19 and Brain Aging: What are the Implications of Immunosenescence?

The human lifespan is increasing, and mankind is aging. It is estimated that, until the year 2050, this population worldwide will reach 22% of the total world population. Along with aging, the human immunologic system changes, a process called immunosenescence or even inflammaging. The aging immune system increases mortality and morbidity in the elderly mainly because it loses its capacity to react against internal and external aggressions. There is a decrease in B and T lymphocytes and CD4+ lymphocytes lose the CD28 protein expression that is needed for costimulation, leading to reduced response to viral infections. This could be responsible for more deleterious consequences of coronavirus disease infection in the elderly. Besides that, the human brain ages, being more susceptible to damage and viral infections, such as COVID-19 infection. There are several pathways that could explain the susceptibility to the COVID-19 infection in the elderly brain, one of them is binding to ACE 2 receptors in cerebral cells through the spike protein. It has been reported that glial cells and neurons, in addition to endothelial and arterial smooth muscle cells in the brain, express the ACE 2 receptor, which would justify the neurological symptoms and consequences of the disease. This infection can have several clinical manifestations such as hemorrhagic stroke, delirium and long-term cognitive complaints, such as brain fog, polyneuropathies, short time memory complaints and insomnia. Although none of the studies could prove that there is a long-term neuronal damage, there are clinical sequelae that should be taken into account and more studies are necessary to know the consequences of the infection in the elderly brain.