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Leprosy, also known as Hansen’s disease, continues to have a substantial impact on infectious diseases throughout the world. Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae and shows a wide clinical and immunopathological spectrum related to the immune response of the host. This disease affects the skin and other internal organs with a predilection to infect Schwann cells, which play an active role during axonal degeneration, affecting peripheral nerves and promoting neurological damage. This chronic inflammation influences immune function, leading to neuroimmune disorders. Leprosy is also associated with neuroimmune reactions, including type 1 (reverse) and type 2 (erythema nodosum leprosum) reactions, which are immune-mediated inflammatory complications that can occur during the disease and appear to worsen dramatically; these complications are the main concerns of patients. The reactions may induce neuritis and neuropathic pain that progressively worsen with irreversible deformity and disabilities responsible for the immunopathological damage and glial/neuronal death. However, the neuronal damage is not always associated with the reactional episode. Also, the efficacy in the treatment of reactions remains low because of the nonexistence of a specific treatment and missing informations about the immunopathogenesis of the reactional episode. There is increasing evidence that peripheral neuron dysfunction strongly depends on the activity of neurotrophins. The most important neurotrophin in leprosy is nerve growth factor (NGF), which is decreased in the course of leprosy, as well as the presence of autoantibodies against NGF in all clinical forms of leprosy and neuroimmune reactions. The levels of autoantibodies against NGF are decreased by the immunomodulatory activity of cyclosporin A, which mainly controls pain and improves motor function and sensitivity. Therefore, the suppression of anti-NGF and the regulation of NGF levels can be attractive targets for immunomodulatory treatment and for controlling the neuroimmune reactions of leprosy, although further studies are needed to clarify this point.

Seizures and epilepsy are some of the most common serious neurological disorders, with approximately 80% of patients living in developing/underdeveloped countries. However, about one in three patients do not respond to currently available pharmacological treatments, indicating the need for research into new anticonvulsant drugs (ACDs). The GABAergic system is the main inhibitory system of the brain and has a central role in seizures and the screening of new ACD candidates. It has been demonstrated that the action of agents on endocannabinoid receptors modulates the balance between excitatory and inhibitory neurotransmitters; however, studies on the anticonvulsant properties of endocannabinoids from plant oils are relatively scarce. The Amazon region is an important source of plant oils that can be used for the synthesis of new fatty acid amides, which are compounds analogous to endocannabinoids. The synthesis of such compounds represents an important approach for the development of new anticonvulsant therapies.

Human exposure to mercury is a major public health concern, causing neurological outcomes such as motor and visual impairment and learning disabilities. Currently, human exposure in the Amazon is among the highest in the world. A recent systematic review (doi:10.1016/j.jtemb.2018.12.001), however, highlighted the lack of high-quality studies on mercury-associated neurotoxicity. There is, therefore, a need to improve research and much to still learn about how exposure correlates with disease. In this review, we discuss studies evaluating the associations between neurological disturbances and mercury body burden in Amazonian populations, to generate recommendations for future studies. A systematic search was performed during July 2020, in Pubmed/Medline, SCOPUS and SCIELO databases with the terms (mercury*) and (Amazon*). Four inclusion criteria were used: original article (1), with Amazonian populations (2), quantifying exposure (mercury levels) (3), and evaluating neurological outcomes (4). The extracted data included characteristics (as year or origin of authorship) and details of the research (as locations and type of participants or mercury levels and neurological assessments). Thirty-four studies, most concentrated within three main river basins (Tapajos, Tocantins, and Madeira) and related to environmental exposure, were found. Mercury body burden was two to ten times higher than recommended and main neurological findings were cognitive, vision, motor, somatosensory and emotional deficits. Important insights are described that support novel approaches to researching mercury exposure and intoxication, as well as prevention and intervention strategies. As a signatory country to the Minamata Convention, Brazil has the opportunity to play a central role in improving human health and leading the research on mercury intoxication.

The Tucuruí Dam is one of the largest dams ever built in the Amazon. The area is not highly influenced by gold mining as a source of mercury contamination. Still, we recently noted that one of the most consumed fishes (Cichla sp.) is possibly contaminated with methylmercury. Therefore, this work evaluated the mercury content in the human population living near the Tucuruí Dam. Strict exclusion/inclusion criteria were applied for the selection of participants avoiding those with altered hepatic and/or renal functions. Methylmercury and total mercury contents were analyzed in hair samples. The median level of total mercury in hair was above the safe limit (10µg/g) recommended by the World Health Organization, with values up to 75µg/g (about 90% as methylmercury). A large percentage of the participants (57% and 30%) showed high concentrations of total mercury (≥ 10µg/g and ≥ 20µg/g, respectively), with a median value of 12.0µg/g. These are among the highest concentrations ever detected in populations living near Amazonian dams. Interestingly, the concentrations are relatively higher than those currently shown for human populations highly influenced by gold mining areas. Although additional studies are needed to confirm the possible biomagnification and bioaccumulation of mercury by the dams in the Amazon, our data already support the importance of adequate impact studies and continuous monitoring. More than 400 hydropower dams are operational or under construction in the Amazon, and an additional 334 dams are presently planned/proposed. Continuous monitoring of the populations will assist in the development of prevention strategies and government actions to face the problem of the impacts caused by the dams.

Mercury is among the ten most dangerous chemicals for public health, and is a priority concern for the 128 signatory countries of the Minamata Convention. Mercury emissions to the atmosphere increased 20% between 2010 and 2015, with South America, Sub-Saharan Africa and Southeast Asia as the main contributors. Approximately 80% of the total mercury emissions in South America is from the Amazon, where the presence of the metal is ubiquitous and highly dynamic. The presence of this metal is likely increasing, with global consequences, due to events of the last two years including extensive biomass burning and deforestation, as well as mining activities and the construction of large-scale projects, such as dams. Here we present a concise profile of this mobilization, highlighting the human exposure to this metal in areas without mining history. Mercury reaches the food chain in its most toxic form, methylmercury, intoxicating human populations through the intake of contaminated fish. Amazonian populations present levels over 6 ppm of hair mercury and, according to the 175:250:5:1 ratio for methylmercury intake : mercury hair : mercury brain : mercury blood, consume 2–6 times the internationally recognized reference doses. This exposure is alarmingly higher than that of other populations worldwide. A possible biphasic behavior of the mercury-related phenomena, with consequences that may not be observed in populations with lower levels, is hypothesized, supporting the need of improving our knowledge of this type of chronic exposure. It is urgent that we address this serious public health problem in the Amazon, especially considering that human exposure may be increasing in the near future. All actions in this region carry the potential to have global repercussions.

The Amazon River basin is the largest tropical forest in the world. Most of the Amazon belongs to Brazil, a developing country that currently faces huge challenges related to the consolidation of its universal healthcare system. Noncommunicable diseases (NCDs) are the leading cause of death in Brazil, accounting for 74% of all deaths, and NCDs are probably underestimated in Amazonian population because of their geographical isolation and the precariousness of riverine communities. Important risk factors, such as genetic susceptibility, remain undetermined in the riverine population. This study performed fasting blood sugar (FBS) and blood pressure measurements and investigated the presence of the ε4 allele of apolipoprotein E (APOE4) to determine the prevalence of diabetes, hypertension and the genetic risk of NCDs. FBS and APOE4 were measured in blood samples from 763 participants using spectrometry and real-time PCR, 67.5% showed altered measurements, and 57.9% had never been diagnosed or treated. Altered FBS was found in 28.3% of the participants, hypertension in 57.6% and APOE4 in 32.0%. The health profile of the riverine population appears to differ from that of urban population in the Amazon. Additional risk factors for NCDs, such as environmental contamination and nutritional transition, may contribute more than increased genetic susceptibility to the prevalence of altered FBS and hypertension. Our results will help guide the development of preventive strategies and governmental actions for more effective management of NCDs in the Amazon area.

Heavy metals, such as methylmercury, are key environmental pollutants that easily reach human beings by bioaccumulation through the food chain. Several reports have demonstrated that endocrine organs, and especially the pituitary gland, are potential targets for mercury accumulation; however, the effects on the regulation of hormonal release are unclear. It has been suggested that serum prolactin could represent a biomarker of heavy metal exposure. The aim of this study was to evaluate the effect of methylmercury on prolactin release and the role of the nitrergic system using prolactin secretory cells (the mammosomatotroph cell line, GH3B6). Exposure to methylmercury (0-100 μM) was cytotoxic in a time- and concentration-dependent manner, with an LC50 higher than described for cells of neuronal origin, suggesting GH3B6 cells have a relative resistance. Methylmercury (at exposures as low as 1 μM for 2 h) also decreased prolactin release. Interestingly, inhibition of nitric oxide synthase by N-nitro-L-arginine completely prevented the decrease in prolactin release without acute neurotoxic effects of methylmercury. These data indicate that the decrease in prolactin production occurs via activation of the nitrergic system and is an early effect of methylmercury in cells of pituitary origin. MAUÉS, L. A. L. Dr. Docente da Universidade Federal do Pará, Campus Universitário de Altamira MACCHI, B. de M. Dr. Docente da Universidade Federal do Pará, Instituto de Ciências Biológicas CRESPO LÓPEZ, M. E. Dr. Docente da Universidade Federal do Pará, Insituto de Ciências Biológicas

Mercury is a heavy metal responsible for human intoxication worldwide and especially in the Amazon, where both natural and anthropogenic sources are responsible for exposure in riverine populations. Methylmercury is the most toxic specie of mercury with recognized neurotoxicity due to its affinity for the central nervous system. S100B protein is a well-established biomarker of brain damage and it was recently associated with mercury-related neurotoxicity. Accurate measurement is especially challenging in isolated/remote populations due to the difficulty of adequate sample conservation, therefore here we use S100B mRNA levels in blood as a way to assay mercury neurotoxicity. We hypothesized that individuals from chronically exposed populations showing mercury levels above the limit of 10 μg/g in hair would present increased levels of S100B mRNA, likely due to early brain damage. A total of 224 riverine individuals were evaluated for anthropometric data (age, body mass index), self-reported symptoms of mercury intoxication, c-reactive protein in blood, and mercury speciation in hair. Approximately 20% of participants showed mercury levels above the limit, and prevalence for most symptoms was not different between individuals exposed to high or low mercury levels. Rigorous exclusion criteria were applied to avoid confounding factors and S100B mRNA in blood was tested by RT-qPCR. Participants with ≥10 μg/g of mercury had S100B mRNA levels over two times higher than that of individuals with lower exposure. A significant correlation was also detected between mercury content in hair and S100B mRNA levels in blood, supporting the use of the latter as a possible candidate to predict mercury-induced neurotoxicity. This is the first report of an association between S100B mRNA and mercury exposure in humans. The combination of both exposure and intoxication biomarkers could provide additional support for the screening and early identification of high-risk individuals in isolated populations and subsequent referral to specialized centers.

Mercury intoxication is a serious public health problem and a worldwide concern. The Minamata Convention on Mercury has been signed by 128 countries and endorsed by the World Health Organization with the recommendation of promoting the management of epidemiological information. The Central Nervous System is the main target organ for mercury. Symptoms of intoxication include altered motor coordination, visual and tactile dysfunction and paralysis, caused by neurodegeneration with a key role for oxidative damage. Recently, some studies have demonstrated a correlation between mercury intoxication and isoforms of apolipoprotein E (ApoE). In this review, epidemiological data and hypotheses about the possible molecular mechanisms underlying the association between ApoE and mercury intoxication are assessed. Based on the evidence and the neuropathological changes that the presence of ApoE4 and mercury neurotoxicity have in common, we propose a convergent action of both factors. ApoE4 seems to potentiate the damage caused by mercury. Increased knowledge of this interaction using epidemiological and pre-clinical studies is essential to improve prevention strategies to adequately manage intoxicated patients.

Mercury is a hazardous metal that has become an important issue of environmental contamination in Amazon areas. Human intoxication by mercury causes sensory deficits, motor dysfunction, delayed psychomotor development, genotoxicity, and several other health problems. One of the major cellular mechanisms of mercury toxicity is the oxidative stress which may lead to membrane peroxidation and generation of reactive oxygen species. The antioxidant defense, which includes scavenger compounds such as glutathione and antioxidant enzymes such as catalase, might prevent these injuries to occur. Thus, the objective of this work was to evaluate hair mercury levels and the strength of antioxidant defenses, evaluated by glutathione levels and catalase activity in the blood of exposed and non-exposed women living in Amazon populations. For each location, no statistically significant difference (P

Mercury is an extremely dangerous environmental contaminant responsible for episodes of human intoxication throughout the world. Methylmercury, the most toxic compound of this metal, mainly targets the central nervous system, accumulating preferentially in cells of glial origin and causing oxidative stress. Despite studies demonstrating the current exposure of human populations, the consequences of mercury intoxication and concomitant use of drugs targeting the central nervous system (especially drugs used in long-term treatments, such as analgesics) are completely unknown. Morphine is a major option for pain management; its global consumption more than quadrupled in the last decade. Controversially, morphine has been proposed to function in oxidative stress independent of the activation of the opioid receptors. In this work, a therapeutic concentration of morphine partially protected the cellular viability of cells from a C6 glioma cell line exposed to methylmercury. Morphine treatment also reduced lipid peroxidation and totally prevented increases in nitrite levels in those cells. A mechanistic study revealed no alteration in sulfhydryl groups or direct scavenging at this opioid concentration. Interestingly, the opioid antagonist naloxone completely eliminated the protective effect of morphine against methylmercury intoxication, pointing to opioid receptors as the major contributor to this action. Taken together, the experiments in the current study provide the first demonstration that a therapeutic concentration of morphine is able to reduce methylmercury-induced oxidative damage and cell death by activating the opioid receptors. Thus, these receptors may be a promising pharmacological target for modulating the deleterious effects of mercury intoxication. Although additional studies are necessary, our results support the clinical safety of using this opioid in methylmercury-intoxicated patients, suggesting that normal analgesic doses could confer an additional degree of protection against the cytotoxicity of this xenobiotic.