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Margaritaria nobilis L.f. (Phyllanthaceae), a native Brazilian tree occurring mainly in the Amazon, is used in folk medicine for the treatment of abscesses (bark) and cancer-like symptoms (leaves). The present study evaluates the safety of its acute oral administration and its effects on nociception and plasma leakage. The chemical constitution of the leaf's ethanolic extract is determined by ultra-performance liquid chromatography-high-resolution mass spectrometry (LC-MS. Its acute oral toxicity is evaluated in female rats at a dose of 2000 mg/kg, evaluating the occurrence of deaths and Hippocratic, behavioral, hematological, biochemical, and histopathological changes, as well as food and water consumption and weight gain. Antinociceptive activity is evaluated in male mice with acetic-acid-induced peritonitis (APT) and formalin (FT) tests. An open field (OF) test is performed to verify possible interferences in the animals' consciousness or locomotion. LC-MS analysis shows the presence of 44 compounds classified as phenolic acid derivatives, flavonoids and O-glycosylated derivatives, and hydrolyzable tannins. No deaths or significant behavioral, histological, or biochemical changes are observed in the toxicity assessment. In nociception tests, M. nobilis extract significantly reduces abdominal contortions in APT, demonstrating selectivity for inflammatory components (FT second phase), not interfering in neuropathic components (FT first phase) or consciousness and locomotion levels in OF. Additionally, M. nobilis extract inhibits plasma acetic-acid-induced leakage. These data demonstrate the low toxicity of M. nobilis ethanolic extract, as well as its effectiveness in modulating inflammatory nociception and plasma leakage, possibly related to the flavonoids and tannins present in its composition.

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Ganoderma lucidum is a mushroom that has been widely used for centuries in Asian countries for its antiaging properties. It is popularly known as "Ling Zhi," "Reishi," and "Youngzhi," and because of its benefits, it is known as the "immortality mushroom." Pharmacological assays have revealed that G. lucidum ameliorates cognitive impairments through inhibition of ß-amyloid and neurofibrillary tangle formation, antioxidant effect, reduction of inflammatory cytokine release and apoptosis, genic expression modulation, among other activities. Chemical investigations on G. lucidum have revealed the presence of metabolites such as triterpenes, which are the most explored in this field, as well as flavonoids, steroids, benzofurans, and alkaloids; in the literature, these have also been reported to have mnemonic activity. These properties of the mushroom make it a potential source of new drugs to prevent or reverse memory disorders, as actual medications are able to only alleviate some symptoms but are unable to stop the progress of cognitive impairments, with no impact on social, familiar, and personal relevance. In this review, we discuss the cognitive findings of G. lucidum reported in the literature, converging the proposed mechanisms through the several pathways that underlie memory and cognition processes. In addition, we highlight the gaps that deserve particular attention to support future studies.

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This case report describes the long-term behavioral and cognitive alterations in a critically ill pediatric patient submitted to a ketamine sedation and analgesia protocol for 7 consecutive days in a pediatric intensive care unit. The infant exhibited withdrawal syndrome in the early withdrawal period, as measured using the Withdrawal Assessment Tool-1 (WAT-1). In the days following ketamine withdrawal, behavioral, motor, and cognitive impairment was observed, even after hospital discharge. At 20 days after admission to hospital, the infant still displayed language deficits compatible with the at-risk category for the appropriate age group on the development assessment (Denver-II Developmental Screening Test). The infant's mother reported that these impairments were not present before ketamine sedation. We therefore suggest that prolonged ketamine use may have contributed to the long-lasting behavioral and cognitive impairments observed in the critically ill infant. These adverse effects may be attributable to ketamine's pharmacological mechanism of action, by which the N-methyl-D-aspartate receptor-the central nervous system excitatory receptor responsible for memory and learning domains-is blockaded, disrupting long-term potentiation events. Our case highlights the need for clinical evaluation of ketamine agents and their associated risks in intensive care units to better clarify appropriate sedative and analgesic agents during neurodevelopmental periods of life.

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Psychoactive substances during pregnancy and lactation is a key problem in contemporary society, causing social, economic, and health disturbance. In 2010, about 30 million people used opioid analgesics for non-therapeutic purposes, and the prevalence of opioids use during pregnancy ranged from 1% to 21%, representing a public health problem. This study aimed to evaluate the long-lasting neurobehavioral and nociceptive consequences in adult offspring rats and mice exposed to morphine during intrauterine/lactation periods. Pregnant rats and mice were exposed subcutaneously to morphine (10 mg/kg/day) during 42 consecutive days (from the first day of pregnancy until the last day of lactation). Offspring were weighed on post-natal days (PND) 1, 5, 10, 15, 20, 30, and 60, and behavioral tasks (experiment 1) or nociceptive responses (experiment 2) were assessed at 75 days of age (adult life). Morphine-exposed female rats displayed increased spontaneous locomotor activity. More importantly, both males and female rats perinatally exposed to morphine displayed anxiety- and depressive-like behaviors. Morphine-exposed mice presented alterations in the nociceptive responses on the writhing test. This study showed that sex difference plays a role in pain threshold and that deleterious effects of morphine during pre/perinatal periods are nonrepairable in adulthood, which highlights the long-lasting clinical consequences related to anxiety, depression, and nociceptive disorders in adulthood followed by intrauterine and lactation morphine exposure.

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Propolis consists of a honeybee product, with a complex mix of substances that have been widely used in traditional medicine. Among several compounds present in propolis, caffeic acid phenethyl ester (CAPE), and pinocembrin emerge as two principal bioactive compounds, with benefits in a variety of body systems. In addition to its well-explored pharmacological properties, neuropharmacological activities have been poorly discussed. In an unprecedented way, the present review addresses the current finding on the promising therapeutic purposes of propolis, focusing on CAPE and pinocembrin, highlighting its use on neurological disturbance, as cerebral ischemia, neuroinflammation, convulsion, and cognitive impairment, as well as psychiatric disorders, such as anxiety and depression. In addition, we provide a critical analysis, discussion, and systematization of the molecular mechanisms which underlie these central nervous system effects. We hypothesize that the pleiotropic action of CAPE and pinocembrin, per se or associated with other substances present in propolis may result in the therapeutic activities reported. Inhibition of the pro-inflammatory cascade, antioxidant activity, and positive neurotrophic modulatory effects consist of the main molecular targets attributed to CAPE and pinocembrin in health benefits.

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Aniba canelilla (Kunth) Mez, popularly known as "casca preciosa" (precious bark), falsa canela (cinnamon-scented) Casca-do-maranhão (bark of maranhão), and Folha-preciosa (precious leaf), is an aromatic species of the Lauraceae family, widely distributed in the Amazon region. In traditional medicine, it is indicated for the treatment of a great diversity of diseases, including digestive, respiratory, inflam]matory, painful, and central nervous system disorders, it is administered mainly in the form of tea or decoction orally. Its essential oil is referred to as a natural antioxidant for food preservation and disease control, showing great potential for use in the cosmetics, perfumery, and pharmaceutical products sector. The present review aimed to discuss critically and comprehensively the ethnobotanical characteristics, phytochemical constitution, and scientifically tested biological properties of A. canelilla, systematizing the knowledge about the species and proposing new perspectives for research and development. The chemical composition of A. canelilla includes 1-nitro-2-phenylethane, metyleugenol, eugenol, safrol, anabasin, anbin, tannin, α-pinene, b-pinene, b-felandren, b-caryophyllene, b-sesquifelandren, p-cymene, linalool, α-copaene, and spatulenol. Researches with ethanolic extracts, essential oils, and major constituents (1-nitro-2-phenylethane and metyleugenol) have revealed antioxidant, antinociceptive, anti-inflammatory, cardio-modulating, hypotensive (vasorelaxant), hypnotic, anxiolytic, anticholinesterase, and antibiotic properties (trypanomicidal, leishmanicidal, and antifungal). Some of these effects are potentially beneficial for aging-related diseases treatment, such as cardio and cerebrovascular, chronic inflammatory, neurological, and degenerative diseases. However, it is necessary to advance in the research of its clinical use and development of therapeutic products.

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Varronia multispicata (Cham.) Borhidi (Cordiaceae), an herbaceous plant distributed in tropical and subtropical regions is native of Brazil and widely used in folk medicine to treat respiratory and digestive diseases, inflammation, and some types of infections. Thus, this study aimed to investigate acute oral toxicity, antinociceptive, and anti-inflammatory activities of dry aqueous extract of V. multispicata (AEVm) and to identify its compounds. Extract was obtained by lyophilized leaf infusion and its composition was analyzed by ultra-performance liquid chromatography-high resolution mass spectrometry (LC-MS). Acute oral toxicity was evaluated in female rats treated with AEVm (2,000 mg/kg) in a single oral dose. Mortality, body weight changes, feed and water intake, organ weights, histological and biochemical parameters were screened for 14 days. Antinociceptive activity was evaluated by writhing (WT), formalin (FT), and hot plate (HP) tests in male mice while anti-inflammatory activity was performed by carrageenan (CPE) and dextran (DPE)-induced paw edema tests and carrageenan-induced peritonitis (CP) test in male rats. Additionally, spontaneous open-field (OF) locomotion was evaluated. LC-MS analysis revealed the presence of flavonoids with biological activity. In toxicity evaluation, extract did not cause deaths in dose of 2,000 mg/kg, and there were no significant behavioral or biochemical alterations. Additionally, evidence of hepatoprotective and antioxidant activity was observed. In pharmacological evaluation AEVm showed dose-dependent antinociceptive activity in WT, with a median effective dose of 146.89 mg/kg, which showed selectivity by inflammatory base processes (FT first phase; p < 0.001), showing no activity in neuropathic nociception components (FT second phase and HP) or about consciousness and locomotion in OF. AEVm also showed significant anti-inflammatory activity, inhibiting CPE (p < 0.001) and cell migration (p < 0.05) and nitric oxide (NO) production (p < 0,01) in CP test. These data demonstrate that AEVm has low oral toxicity-with evidence of hepatoprotective and antioxidant properties-antinociceptive and anti-inflammatory activity, supporting V. multispicata traditional use, possibly related to flavonoids present in its constitution.

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Over the last years, heavy ethanol consumption by teenagers/younger adults has increased considerably among females. However, few studies have addressed the long-term impact on brain structures' morphology and function of chronic exposure to high ethanol doses from adolescence to adulthood in females. In line with this idea, in the current study we investigated whether heavy chronic ethanol exposure during adolescence to adulthood may induce motor impairments and morphological and cellular alterations in the cerebellum of female rats. Adolescent female Wistar rats (35 days old) were treated with distilled water or ethanol (6.5 g/kg/day, 22.5% w/v) during 55 days by gavage. At 90 days of age, motor function of animals was assessed using open field (OF), pole, beam walking and rotarod tests. Following completion of behavioral tests, morphological and immunohistochemical analyses of the cerebellum were performed. Chronic ethanol exposure impaired significantly motor performance of female rats, inducing spontaneous locomotor activity deficits, bradykinesia, incoordination and motor learning disruption. Moreover, histological analysis revealed that ethanol exposure induced atrophy and neuronal loss in the cerebellum. These findings indicate that heavy ethanol exposure during adolescence is associated with long-lasting cerebellar degeneration and motor impairments in female rats.

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Binge-like ethanol intake (BEI) is a socioeconomical problem among adolescents and increasingly affects women. BEI can leave a long-term imprint in the brain, but it is unknown if its effect on cognition and anxiety is cumulative on repeated binge-ethanol episodes. We now submitted female Wistar rats to repeated cycles of binge-like ethanol treatment by intragastrically administering ethanol (3.0 g/kg/day, 20% w/v ethanol; 3 days on/4 days off) starting at postnatal day 35 (PND35). To investigate the short-term effects of BEI during adolescence, rats underwent 1 or 4 cycles of BEI, being evaluated at PND37 and PND58, respectively: both groups displayed anxiety-like behavior in the open field and elevated plus-maze tests, as well as short-term memory deficits in the object recognition task; this was associated with transient decreases of BDNF levels and increases of GFAP levels in the hippocampus. To evaluate the short- and long-lasting effects of BEI in adulthood, rats were subjected to 8 cycles of BEI and evaluated after 7.5 h (PND86) or after 14 days of ethanol withdrawal (PND100). This caused a persistent anxiogenic profile whereas recognition memory was impaired on the short-term, but not 14 days post-administration. The reduced BDNF level observed shortly after BEI recovered upon withdrawal, whereas increased GFAP immunoreactivity was persistent up to 14 days post-administration in adulthood. These findings show that repeated binge-like ethanol episodes from adolescence to adulthood in female rats cause consistent and long-term alterations of anxiety and hippocampal astrogliosis, whereas they trigger a recognition memory deficit paralleled by lower hippocampal BDNF levels, both recovering upon ethanol withdrawal.

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Human exposure to relatively low levels of methylmercury is worrying, especially in terms of its genotoxicity. It is currently unknown as to whether exposure to low levels of mercury (below established limits) is safe. Genotoxicity was already shown in lymphocytes, but studies with cells of the CNS (as the main target organ) are scarce. Moreover, disturbances in the cell cycle and cellular proliferation have previously been observed in neuronal cells, but no data are presently available for glial cells. Interestingly, cells of glial origin accumulate higher concentrations of methylmercury than those of neuronal origin. Thus, the aim of this work was to analyze the possible genotoxicity and alterations in the cell cycle and cell proliferation of a glioma cell line (C6) exposed to a low, non-lethal and non-apoptotic methylmercury concentration. Biochemical (mitochondrial activity) and morphological (integrity of the membrane) assessments confirmed the absence of cell death after exposure to 3 µM methylmercury for 24 hours. Even without promoting cell death, this treatment significantly increased genotoxicity markers (DNA fragmentation, micronuclei, nucleoplasmic bridges and nuclear buds). Changes in the cell cycle profile (increased mitotic index and cell populations in the S and G2/M phases) were observed, suggesting arrest of the cycle. This delay in the cycle was followed, 24 hours after methylmercury withdrawal, by a decrease number of viable cells, reduced cellular confluence and increased doubling time of the culture. Our work demonstrates that exposure to a low sublethal concentration of MeHg considered relatively safe according to current limits promotes genotoxicity and disturbances in the proliferation of cells of glial origin with sustained consequences after methylmercury withdrawal. This fact becomes especially important, since this cellular type accumulates more methylmercury than neurons and displays a vital role protecting the CNS, especially in chronic intoxication with this heavy metal.

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There is increasing evidence that heavy ethanol exposure in early life may produce long-lasting neurobehavioral consequences, since brain structural maturation continues until adolescence. It is well established that females are more susceptible to alcohol-induced neurotoxicity and that ethanol consumption is increasing among women, especially during adolescence. In the present study, we investigated whether chronic ethanol exposure during adolescence through early adulthood in female rats may induce hippocampal histological damage and neurobehavioral impairments. Female rats were treated with distilled water or ethanol (6.5 g/kg/day, 22.5% w/v) by gavage from the 35(th)-90(th) day of life. Ethanol-exposed animals displayed reduced exploration of the central area and increased number of fecal boluses in the open field test indicative of anxiogenic responses. Moreover, chronic high ethanol exposure during adolescence induced marked impairments on short-term memory of female rats addressed on social recognition and step-down inhibitory avoidance tasks. These neurobehavioral deficits induced by ethanol exposure during adolescence through early adulthood were accompanied by the reduction of hippocampal formation volume as well as the loss of neurons, astrocytes and microglia cells in the hippocampus. These results indicate that chronic high ethanol exposure during adolescence through early adulthood in female rats induces long-lasting emotional and memory deficits associated with morphological and molecular alterations in the hippocampus.

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