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.

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.

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'.