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.

Sepsis compromises post-ischemic stroke neurological recovery and is associated with sex differences.

AIMS: Infection is a complication after stroke and outcomes vary by sex. Thus, we investigated if sepsis affects brain from ischemic stroke and sex involvement. MAIN METHODS: Male and female Wistar rats, were submitted to middle cerebral artery occlusion (MCAO) and after 7 days sepsis to cecal ligation and perforation (CLP). Infarct size, neuroinflammation, oxidative stress, and mitochondrial activity were quantified 24 h after CLP in the prefrontal cortex and hippocampus. Survival and neurological score were assessed up to 15 days after MCAO or 8 days after CLP (starting at 2 h after MCAO) and memory at the end. KEY FINDINGS: CLP decreased survival, increased neurological impairments in MCAO females. Early, in male sepsis following MCAO led to increased glial activation in the brain structures, and increased TNF-α and IL-1ß in the hippocampus. All groups had higher IL-6 in both tissues, but the hippocampus had lower IL-10. CLP potentiated myeloperoxidase (MPO) in the prefrontal cortex of MCAO male and female. In MCAO+CLP, only male increased MPO and nitrite/nitrate in hippocampus. Males in all groups had protein oxidation in the prefrontal cortex, but only MCAO+CLP in the hippocampus. Catalase decreased in the prefrontal cortex and hippocampus of all males and females, and MCAO+CLP only increased this activity in males. Female MCAO+CLP had higher prefrontal cortex complex activity than males. In MCAO+CLP-induced long-term memory impairment only in females. SIGNIFICANCE: The parameters evaluated for early sepsis after ischemic stroke show a worse outcome for males, while females are affected during long-term follow-up.

Nutritional strategies cause memory damage and alter biochemical parameters without causing neuroinflammation.

Obesity results from an energy imbalance and has been considered an epidemic due to its increasing rates worldwide. It is classified as a low-grade chronic inflammatory disease and has associated comorbidities. Different nutritional strategies are used for the purpose of weight loss, highlighting low-carbohydrate (LC) diets, ketogenic diets, and intermittent fasting (IF). These strategies can lead to metabolic and behavioral changes as they stimulate different biochemical pathways. Therefore, this study evaluated memory, energy metabolism, neuroinflammation, oxidative stress, and antioxidant defense parameters in mice subjected to an LC diet, ketogenic diet (KD), or IF. Eighty male Swiss mice, 60 days old, were divided into 4 groups: control, LC, KD, or IF. Body weight was measured weekly, and food intake every 48 h. After 15 days of nutritional interventions, the animals were subjected to the behavioral object recognition test and subsequently euthanized. Then, visceral fat was removed and weighed, and the brain was isolated for inflammatory and biochemical analysis. We concluded from this study that the LC and KD strategies could damage memory, IF improves the production of adenosine triphosphate (ATP), and the LC, KD, and IF strategies do not lead to neuroinflammatory damage but present damage at the level of oxidative stress.

Implications of the endocannabinoid system and the therapeutic action of cannabinoids in autism spectrum disorder: A literature review.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, onset in early childhood and associated with cognitive, social, behavioral, and sensory impairments. The pathophysiology is still unclear, and it is believed that genetic and environmental factors are fully capable of influencing ASD, especially cell signaling and microglial functions. Furthermore, the endocannabinoid system (ECS) participates in the modulation of various brain processes and is also involved in the pathophysiological mechanisms of this condition. Due to the health and quality of life impacts of autism for the patient and his/her family and the lack of effective medications, the literature has elucidated the possibility that Cannabis phytocannabinoids act favorably on ASD symptoms, probably through the modulation of neurotransmitters, in addition to endogenous ligands derived from arachidonic acid, metabolizing enzymes and even transporters of the membrane. These findings support the notion that there are links between key features of ASD and ECS due to the favorable actions of cannabidiol (CBD) and other cannabinoids on symptoms related to behavioral and cognitive disorders, as well as deficits in communication and social interaction, hyperactivity, anxiety and sleep disorders. Thus, phytocannabinoids emerge as therapeutic alternatives for ASD.

Antidepressant and anxiolytic-like effects of ayahuasca in rats subjected to LPS-induced neuroinflammation.

The objective of this study was to evaluate the behavioral response of ayahuasca in rats submitted to neuroinflammation through the intraperitoneal application of lipopolysaccharide (0.63 mg/kg/mL). Eighty animals, male, about 90 days old, were divided into control and LPS groups and later into prevention and treatment subgroups. The prevention subgroup was administered ayahuasca or saline solution, via gavage, at a dose of 4 mL/kg one hour before applying LPS or saline, while the treatment subgroup received the same dose of the respective substances 24 h after intraperitoneal applications. Behavioral parameters were evaluated using open field (anxiety-like) and forced swimming (depressive-like) tests. A decrease in LPS/AYA rats in the prevention and treatment subgroups regarding anxiety-like behavior was observed. As for the depressive-like behavior, there was a decrease in the group induced to the disease model, both in the prevention subgroup (when compared to the SAL/SAL, SAL/AYA, and LPS/AYA with LPS/SAL groups) and in the treatment (when comparing SAL/SAL and LPS/AYA with LPS/SAL). This study concludes the anxiolytic and antidepressant potential of ayahuasca in an animal model of neuroinflammation, possibly due to the antineuroinflammatory effects already reported of the compound.

Epidemiology of COVID-19 Among Indigenous Populations in Brazil.

BACKGROUND: Due to social and geographical isolation, indigenous people are more vulnerable to adverse conditions; however, there is a lack of data on the epidemics' impact on these populations. Thus, this article's objective was to describe the epidemiological situation of COVID-19 in indigenous communities in Brazil. METHODS: This descriptive observational study was carried out in indigenous communities in the municipality of Amaturá (Amazonas, Brazil). Individuals from the Alto Rio Solimões Special Indigenous Sanitary District (DSEI) who met the Sars-Cov-2 infection case definitions during the period between January and August 2020 were included. For case notification, the definitions adopted by the Ministry of Health of Brazil and by the Special Secretariat for Indigenous Health were considered. RESULTS: Out of the entire population served by the Alto Rio Solimões DSEI (n = 2890), 109 indigenous people were suspected of having been infected with Sars-Cov-R during the study period; a total of 89 cases were actually confirmed (rate: 3.08 cases/100,000 inhabitants). Most patients diagnosed with COVID-19 were female (56.2%), with a mean age of 32.4 (± 23.6) years. Predominant symptoms were fever (76.4%), dry cough (64%), and headache (60.7%). Complications occurred in 7.9% of the patients; no deaths were reported. CONCLUSION: These results enhance the observation that indigenous populations, even if relatively isolated, are exposed to COVID-19. The disease cases assessed showed a favorable evolution, which does not mean reducing the need for caring of this population.

Cannabis sativa as a Treatment for Obesity: From Anti-Inflammatory Indirect Support to a Promising Metabolic Re-Establishment Target.

Introduction: Obesity is defined as an excess of accumulation of fat that can be harmful to health. Storage of excess fat in the adipose tissue triggers an inflammatory process, which makes obesity a low-grade chronic inflammatory disease. Obesity is considered a complex and multifactorial disease; hence, no intervention strategy appears to be an ideal treatment for all individuals. Therefore, new therapeutic alternatives are often studied for the treatment of this disease. Currently, herbal medicines are gaining ground in the treatment of obesity and its comorbidities. In this context, much attention is being paid to Cannabis sativa derivatives, and their therapeutic functions are being widely studied, including in treating obesity. Objective: Highlight the pharmacological properties of Δ9-tetrahydrocannabivarin (THCV), Δ9-tetrahydrocannabidinol (THC), and cannabidiol (CBD), the predominant isolated components of Cannabis sativa, as well as its therapeutic potential in the treatment of obesity. Methods: This is a narrative review that shows the existing scientific evidence on the clinical application of Cannabis sativa as a possible treatment for obesity. Data collection was performed in the PubMed electronic database. The following word combinations were used: Cannabis and obesity, Cannabis sativa and obesity, THCV and obesity, THC and obesity, CBD and obesity, and Cannabis sativa and inflammation. Results: Evidence shows that Cannabis sativa derivatives have therapeutic potential due to their anti-inflammatory properties. In addition, people who use cannabis have a lower body mass index than those who do not, making the plant an option to reduce and reverse inflammation and comorbidities in obesity. Conclusion: It is concluded that phytocannabinoids derived from Cannabis sativa have therapeutic potential due to its anti-inflammatory, antioxidant, and neuroprotective properties, making the plant a study option to reduce and reverse inflammation and comorbidities associated with obesity.

Sexually transmitted infections in indigenous communities of the Alto Rio Solimões / Infecções sexualmente transmissíveis em comunidades indígenas do Alto Rio Solimões

Introduction: The prevalence of sexually transmitted infections (STI) among indigenous communities is an appalling issue related to Brazilian public health, as there is an increasing underreporting and neglect related to the study and care of these people. Objective: To determine the prevalence of STI in the indigenous population of the Alto Rio Solimões. Methods: STI diagnostic records from the database of the Indigenous Health Care Information System - SIASI, of the indigenous communities of the Alto Rio Solimões, belonging to the Nova Itália base, in Amazonas, were evaluated during the period from January 2010 to August 2020. Sociodemographic data were also evaluated to determine the profile of the diagnosed indigenous population and the geographical and temporal distribution of cases. Results: The overall prevalence rate of STIs was 3.91% (113 notifications of STI in the population of 2890 indigenous people). The largest number of diagnosed cases was in Nova Itália (60.17%). The ethnic group with the highest number of cases was Tikuna (92.03%). Among the STI studied, gonorrhea / chlamydia had the highest prevalence (68.14%), followed by Hepatitis B (13.27%) and Syphilis (10.61%). Most cases were found among women (71.7%), aged 30­34 years. Conclusion: A higher prevalence of STIs was observed in indigenous women, mainly from the Nova Itália town and the Tikuna ethnic group.

Introdução: A prevalência das infecções sexualmente transmissíveis (IST) entre comunidades indígenas é um tema consternador relacionado à saúde pública brasileira, pois há crescente subnotificação e negligência relacionada ao estudo e ao cuidado desses povos. Objetivo: Determinar a prevalência de IST na população indígena do Alto Rio Solimões. Métodos: Foram avaliados os registros diagnósticos de IST da base de dados do Sistema de Informação da Atenção à Saúde Indígena (SIASI), das comunidades indígenas do Alto Rio Solimões, pertencentes ao polo-base de Nova Itália, no Amazonas, durante o período de janeiro de 2010 a agosto de 2020. Também foram avaliados dados sociodemográficos para determinação do perfil da população indígena diagnosticada e a distribuição geográfica e temporal dos casos. Resultados: A taxa de prevalência geral de IST foi de 3,91% (113 notificações de IST na população de 2.890 indígenas). O maior número de casos diagnosticados foi em Nova Itália (60,17%). A etnia com maiores números de casos foi a Tikuna (92,03%). Entre as IST estudadas, gonorreia/clamídia tiveram a maior prevalência (68,14%), seguidas por hepatite B (13,27%) e sífilis (10,61%). A maioria dos casos ocorreu entre mulheres (71,7%) e na faixa de 30­34 anos. Conclusão: Observou-se maior prevalência de IST em mulheres indígenas, principalmente do município de Nova Itália e da etnia Tikuna

Prevalência do transtorno depressivo maior em pessoas com dependência química / Prevalence of major depressive disorder in people with chemical addiction / Prevalencia del trastorno depressive major en personas con adicción

OBJETIVO: verificar a prevalência do Transtorno Depressivo Maior em pessoas com dependência química. MÉTODO: estudo transversal com a aplicação da entrevista estruturada para os transtornos do DSM-V em 183 indivíduos internados em comunidades terapêuticas de acolhimento para dependentes químicos, localizadas no sul de Santa Catarina, durante o de ano de 2019. RESULTADOS: todos os participantes não realizaram consulta psiquiátrica ao ingressar na instituição e a maioria não realizou consulta psiquiátrica regular (94,5%). Constatou-se que 89 participantes (55,3%) possuíam critérios diagnósticos para o Transtorno Depressivo Maior e 59,1% destes possuíam adicção ao álcool (p<0,028). CONCLUSÃO: o diagnóstico do transtorno depressivo deve-se consolidar como uma variável importante para a eficácia do tratamento, visto que sua prevalência é elevada e possui repercussões sobre a qualidade do tratamento e tempo de institucionalização.

OBJECTIVE: to verify the prevalence of Major Depressive Disorder in people with chemical dependence. METHOD: cross-sectional study with the application of the structured interview for the DSM-V disorders in 183 individuals admitted to therapeutic communities for chemical dependents, located in the south of Santa Catarina, during the year 2019. RESULTS: All participants did not have a psychiatric consultation when entering the institution and the majority did not have a regular psychiatric consultation (94.5%). It was found that 89 participants (55.3%) had diagnostic criteria for Major Depressive Disorder and 59.1% of these had alcohol addiction (p<0.028). CONCLUSION: the diagnosis of depressive disorder should be consolidated as an important variable for the effectiveness of treatment, since its prevalence is high and has repercussions on the quality of treatment and time of institutionalization.

OBJECTIVO: verificar la prevalencia del transtorno depressivo major en personas con adicción. METODO: estudio transversal con aplicación de la entrevista estructurada para los transtornos del DSM-V en 183 personas internadas en comunides de tratamiento de adicción en el departamento de Santa Catarina durante el ano de 2019. RESULTADOS: la totalidad de los pacientes no realizaron cita con psiquiatra al ingressar en las instituiciones y la mayoria no realiza visitas regulares al psiquiatra (94,5%). Se observó que 89 participantes (55,3%) tenian critérios diagnósticos para depressión y 59,1% de ellos eram adictos al álcohol (p<0,028). CONCLUSIÓN: el diagnóstico del transtorno depressivo debe consolidarse como una variable importante para la eficácia del tratamiento, pues su prevalencia es elevada y pose repercursiones sobre la calidad del tratamiento y el tiempo de permanencia en las comunidades.

Psychiatric hospitalizations in Brazil: exploratory and trend analysis from 2009 to 2019 / Internações psiquiátricas no Brasil: análise exploratória e de tendência de 2009 a 2019

ABSTRACT Objective: To examine the rates of psychiatric hospitalization and the average length of stay, in Brazil, from 2009 to 2019, according to sociodemographic variables and character of the hospitalization (elective or urgency). Methods: This is an ecological study, with data collected from the Hospital Information System of the Unified Health System (SIH/SUS). Hospital admission rates were described according to diagnosis, sex, and age group. Percentage variation and rate ratios were calculated. To evaluate the time series, the data were submitted to linear regression analysis. Results: The rate of hospitalization for mental disorders decreased from 14.2/10,000 in 2009 to 11.2 in 2019, with the most significant variation occurring between mental and behavioral disorders due to alcohol use. The men had about twice as many episodes as the women in all the years evaluated. Higher rates were found in the age group of 30 and 59 years. The length of stay also decreased in the period. Besides, the urgency character presented almost 82% of the total hospitalizations. Conclusions: There was a reduction in hospital admissions for mental disorders in the analyzed period, demonstrating the relevance of mental health care changes resulting from the Psychiatric Reform.

RESUMO Objetivo: Examinar as taxas de hospitalização psiquiátrica e o tempo médio dessas internações, no Sistema Único de Saúde (SUS) do Brasil, de 2009 a 2019, segundo variáveis sociodemográficas e caráter da internação (eletiva ou urgência). Métodos: Trata-se de um estudo ecológico, com dados coletados do Sistema de Informações Hospitalares (SIH/SUS). Foram descritas as taxas de internação hospitalar conforme diagnóstico, sexo e faixa etária. Calcularam-se a variação percentual e a razão das taxas. Para avaliação da série temporal, os dados foram submetidos à análise de regressão linear. Resultados: A taxa de internação hospitalar por transtornos mentais reduziu de 14,2/10.000 em 2009 para 11,2 em 2019, tendo a maior variação ocorrido entre os transtornos mentais e comportamentais devidos ao uso de álcool. O sexo masculino apresentou cerca de duas vezes mais episódios que o sexo feminino, em todos os anos avaliados. Maiores taxas foram verificadas na faixa etária de 30 e 59 anos. O tempo de internação também apresentou redução no período. Além disso, o caráter de urgência apresentou quase 82% do total de internações. Conclusões: Houve redução das internações hospitalares por transtornos mentais no período analisado, demonstrando a relevância das mudanças na assistência em saúde mental advindas da Reforma Psiquiátrica.

Stanniocalcin 1 Inhibits the Inflammatory Response in Microglia and Protects Against Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy is a serious consequence of sepsis, triggered by the host response against an infectious agent, that can lead to brain damage and cognitive impairment. Several mechanisms have been proposed in this bidirectional communication between the immune system and the brain after sepsis as neuroinflammation, oxidative stress, and mitochondrial dysfunction. Stanniocalcin-1 (STC-1), an endogen neuroprotective protein, acts as an anti-inflammatory and suppresses superoxide generation through induction of uncoupling proteins (UCPs) in the mitochondria. Here, we demonstrated a protective role of STC-1 on inflammatory responses in vitro, in activated microglia stimulated with LPS, and on neuroinflammation, oxidative stress, and mitochondrial function in the hippocampus of rats subjected to an animal model of sepsis by cecal ligation and puncture (CLP), as well the consequences on long-term memory. Recombinant human STC-1 (rhSTC1) suppressed the pro-inflammatory cytokine production in LPS-stimulated microglia without changing the UCP-2 expression. Besides, rhSTC1 injected into the cisterna magna decreased acute hippocampal inflammation and oxidative stress and increased the activity of complex I and II activity of mitochondrial respiratory chain and creatine kinase at 24 h after sepsis. rhSTC1 was effective in preventing long-term cognitive impairment after CLP. In conclusion, rhSTC1 confers significant neuroprotection by inhibiting the inflammatory response in microglia and protecting against sepsis-associated encephalopathy in rats.

Anti-inflammatory activity of ayahuasca: therapeutical implications in neurological and psychiatric diseases.

Ayahuasca is a decoction with psychoactive properties, used for millennia for therapeutic and religious purposes by indigenous groups and the population of amazonian countries. As described in this narrative review, it is essentially constituted by ß-carbolines and tryptamines, and it has therapeutic effects on behavioral disorders due to the inhibition of the monoamine oxidase enzyme and the activation of 5-hydroxytryptamine receptors, demonstrated through preclinical and clinical studies. It was recently observed that the pharmacological response presented by ayahuasca is linked to its anti-inflammatory action, attributed mainly to dimethyltryptamines (N, N-dimethyltryptamine and 5-methoxy-N, N-dimethyltryptamine), which act as endogenous systemic regulators of inflammation and immune homeostasis, also through sigma-1 receptors. Therefore, since neuroinflammation is among the main pathophysiological mechanisms related to the development of neurological and psychiatric diseases, we suggest, based on the available evidence, that ayahuasca is a promising and very safe therapeutic strategy since extremely high doses are required to reach toxicity. However, even so, additional studies are needed to confirm such evidence, as well as the complete elucidation of the mechanisms involved.

NLRP3 Activation Contributes to Acute Brain Damage Leading to Memory Impairment in Sepsis-Surviving Rats.

Sepsis survivors present acute and long-term cognitive impairment and the pathophysiology of neurological dysfunction in sepsis involves microglial activation. Recently, the involvement of cytosolic receptors capable of forming protein complexes called inflammasomes have been demonstrated to perpetuate neuroinflammation. Thus, we investigated the involvement of the NLRP3 inflammasome activation on early and late brain changes in experimental sepsis. Two-month-old male Wistar rats were submitted to the sepsis model by cecal ligation and perforation (CLP group) or laparotomy only (sham group). Immediately after surgery, the animals received saline or NLRP3 inflammasome formation inhibitor (MCC950, 140 ng/kg) intracerebroventricularly. Prefrontal cortex and hippocampus were isolated for cytokine analysis, microglial and astrocyte activation, oxidative stress measurements, nitric oxide formation, and mitochondrial respiratory chain activity at 24 h after CLP. A subset of animals was followed for 10 days for survival assessment, and then behavioral tests were performed. The administration of MCC950 restored the elevation of IL-1ß, TNF-α, IL-6, and IL-10 cytokine levels in the hippocampus. NLRP3 receptor levels increased in the prefrontal cortex and hippocampus at 24 h after sepsis, associated with microglial, but not astrocyte, activation. MCC950 reduced oxidative damage to lipids and proteins as well as preserved the activity of the enzyme SOD in the hippocampus. Mitochondrial respiratory chain activity presented variations in both structures studied. MCC950 reduced microglial activation, decreased acute neurochemical and behavioral alteration, and increased survival after experimental sepsis.

A current overview of cannabinoids and glucocorticoids in facilitating extinction of aversive memories: potential extinction enhancers.

Emotional learning is extremely important for the survival of an individual. However, once acquired, emotional associations are not always expressed. The regulation of emotional responses under different environmental conditions is essential for mental health. Indeed, pathologic feelings of fear and anxiety are defining features of many serious psychiatric illness, including post-traumatic stress disorder (PTSD) and specific phobias. The simplest form of regulation of emotional responses is extinction, in which the conditioned response to a stimulus decreases when reinforcement (stimulus) is omitted. In addition to modulating basal anxiety states, recent studies suggest an important role for the endocannabinoid (eCB) and glucocorticoid systems in the modulation of emotional states and extinction of aversive memories in animals. The purpose of this review is to briefly outline the animal models of fear extinction and to describe how these have been used to examine the potential of extinction enhancing agents which specifically alter the eCB and glucocorticoid systems. Pharmacological manipulations of these systems by agents such as cannabinoid or glucocorticoid agonists can enhance the extinction process and avoid the retention of memories which have the potential to trigger trauma. A better understanding of these findings through animal models highlights the possibilities of using combined extinction enhancing agents in exposure-based psychotherapies for anxiety disorders related to inappropriate retention of aversive memories. This article is part of a special issue entitled 'Cognitive Enhancers'.