Methylmercury neurotoxicity: Beyond the neurocentric view.

Mercury is a highly toxic metal widely used in human activities worldwide, therefore considered a global public health problem. Many cases of mercury intoxication have occurred in history and represent a huge challenge nowadays. Of particular importance is its methylated form, methylmercury (MeHg). This mercurial species induces damage to several organs in the human body, especially to the central nervous system. Neurological impairments such as executive, memory, motor and visual deficits are associated with MeHg neurotoxicity. Molecular mechanisms involved in MeHg-induced neurotoxicity include excitotoxicity due to glutamatergic imbalance, disturbance in calcium homeostasis and oxidative balance, failure in synaptic support, and inflammatory response. Although neurons are largely affected by MeHg intoxication, they only represent half of the brain cells. Glial cells represent roughly 50 % of the brain cells and are key elements in the functioning of the central nervous system. Particularly, astrocytes and microglia are deeply involved in MeHg-induced neurotoxicity, resulting in distinct neurological outcomes depending on the context. In this review, we discuss the main findings on astroglial and microglial involvement as mediators of neuroprotective and neurotoxic responses to MeHg intoxication. The literature shows that these responses depend on chemical and morphophysiological features, thus, we present some insights for future investigations, considering the particularities of the context, including time and dose of exposure, brain region, and species of study.

Exercise Reshapes the Brain: Molecular, Cellular, and Structural Changes Associated with Cognitive Improvements.

Physical exercise is well known as a non-pharmacological and holistic therapy believed to prevent and mitigate numerous neurological conditions and alleviate ageing-related cognitive decline. To do so, exercise affects the central nervous system (CNS) at different levels. It changes brain physiology and structure, promoting cognitive improvements, which ultimately improves quality of life. Most of these effects are mediated by neurotrophins release, enhanced adult hippocampal neurogenesis, attenuation of neuroinflammation, modulation of cerebral blood flow, and structural reorganisation, besides to promote social interaction with beneficial cognitive outcomes. In this review, we discuss, based on experimental and human research, how exercise impacts the brain structure and function and how these changes contribute to cognitive improvements. Understanding the mechanisms by which exercise affects the brain is essential to understand the brain plasticity following exercise, guiding therapeutic approaches to improve the quality of life, especially in obesity, ageing, neurodegenerative disorders, and following traumatic brain injury.

Mercury in the Amazon: The danger of a single story.

Amazon conservation is essential for the global future. Mercury is currently among the worst global pollutants and most (78.5%) of the South-American emissions are from the Amazon. Current Brazilian legislation on mining activities and trade of gold, and economic interests in soy, beef and large-scale projects such as dams, are key influences in mercury mobilization and emissions in the Amazon with the potential to affect the global environment. However, banning mercury in mining, while desirable, is not an efficient strategy if no other action is taken. The interconnected issues, such as exports (soy, beef and gold) and energy generation, must be addressed together to provide effective protection for human health and the environment. Realistically, to improve mercury emissions in the Amazon, we must stop looking solely at "the single story" (a limited view of reality) of supposedly "artisanal and small-scale gold mining" in the region and understand the complex economic, social, political, and international aspects of this problem. We propose some recommendations for international agencies, governments, communities and the private sector.

Hair mercury is associated with dyslipidemia and cardiovascular risk: An anthropometric, biochemical and genetic cross-sectional study of Amazonian vulnerable populations.

This cross-sectional study evaluated the association between human exposure to mercury and cardiovascular risk using lipid profile (including apolipoproteins) and genetic analysis of Amazonian riverine population. Anthropometric data (gender, age, height, weight, blood pressure, and neck and waist circumferences) of the participants were recorded. Total mercury and methylmercury (MeHg) content were quantified in hair by ICP-MS and GC-pyro-AFS system. Polymorphisms rs662799, rs693, rs429358 and rs7412 (of genes of apolipoproteins A-V, B, and E at positions 112 and 158, respectively) were genotyped by real-time PCR. The population presented a dyslipidemia profile significantly correlated with high mercury levels. The apolipoprotein B/apolipoprotein A-I (ApoB/ApoA-I) index was also positively correlated with mercury, supporting a possible causal relationship. Allelic distributions were similar to those described in other populations, suggesting that genetic susceptibility may not have a significant role in the lipid alterations found in this work. This study demonstrated for the first time: i) the relationship between mercury exposure and cardiovascular risk-related apolipoproteins in humans, ii) the ApoB levels and the ApoB/ApoA-I index as the risk factors more strongly associated to the mercury-related dyslipidemia in humans, and iii) the prevalence of high/moderate risk of acute myocardial infarction in the vulnerable and chronically exposed-populations of the Amazon, in addition to the genotypic profile of the three most frequent polymorphisms in apolipoproteins of relevance for cardiovascular risk. This early detection of lipid alterations is essential to prevent the development of cardiovascular diseases (CVD), especially in chronically exposed populations such as those found in the Amazon. Therefore, in addition to provide data for the Minamata Convention implementation, our work is in line with the efforts joined by all members of the World Health Organization committed to reducing premature deaths originating from non-communicable diseases by 25% in 2025, including CVD.

Plasticity of microglia.

Microglial cells are the scions of foetal macrophages which invade the neural tube early during embryogenesis. The nervous tissue environment instigates the phenotypic metamorphosis of foetal macrophages into idiosyncratic surveilling microglia, which are generally characterised by a small cell body and highly ramified motile processes that constantly scan the nervous tissue for signs of changes in homeostasis and allow microglia to perform crucial homeostatic functions. The surveilling microglial phenotype is evolutionarily conserved from early invertebrates to humans. Despite this evolutionary conservation, microglia show substantial heterogeneity in their gene and protein expression, as well as morphological appearance. These differences are age, region and context specific and reflect a high degree of plasticity underlying the life-long adaptation of microglia, supporting the exceptional adaptive capacity of the central nervous system. Microgliocytes are essential elements of cellular network formation and refinement in the developing nervous tissue. Several distinct patrolling modes of microglial processes contribute to the formation, modification, and pruning of synapses; to the support and protection of neurones through microglial-somatic junctions; and to the control of neuronal and axonal excitability by specific microglia-axonal contacts. In pathology, microglia undergo proliferation and reactive remodelling known as microgliosis, which is context dependent, yet represents an evolutionarily conserved defence response. Microgliosis results in the emergence of multiple disease and context-specific reactive states; in addition, neuropathology is associated with the appearance of specific protective or recovery microglial forms. In summary, the plasticity of microglia supports the development and functional activity of healthy nervous tissue and provides highly sophisticated defences against disease.

Living in the Southern Hemisphere: Metabolic Syndrome and Its Components in Amazonian Riverine Populations.

The metabolic syndrome (MetS) epidemic is a global challenge. Although developing countries (including Brazil, India, and South Africa) present a higher proportion of deaths by cardiovascular diseases than developed countries, most of our knowledge is from these developed countries. Amazonian riverine populations (ARP), as well as other vulnerable populations of the Southern Hemisphere, share low-income and traditional practices, among other features. This large cross-sectional study of ARP (n = 818) shows high prevalence of hypertension (51%) and obesity (23%). MetS was diagnosed in 38% of participants (especially in women and 60-69 years-old individuals) without the influence of ancestry. Only 7-8% of adults had no cardio-metabolic abnormalities related to MetS. Atherogenic dyslipidemia (low HDL-cholesterol) was generally observed, including in individuals without MetS. Still, slight differences were detected between settings with a clear predominance of hypertension in Tucuruí. Hypotheses on possible genetic influence and factors (nutrition transition and environmental pollutants -mercury) are proposed for future studies. Moreover, a roadmap to MetS progression based on the most prevalent components is provided for the development of tailored interventions in the Amazon (initially, individuals would present low HDL-cholesterol levels, later progressing to increased blood pressure characterizing hypertension, and ultimately reaching MetS with obesity). Our alarming results support the need to improve our knowledge on these vulnerable populations.

Human neurotoxicity of mercury in the Amazon: A scoping review with insights and critical considerations.

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 (Tapajós, 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.

Mercury: What can we learn from the Amazon?

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.

Astroglia-specific contributions to the regulation of synapses, cognition and behaviour.

Astrocytes are a heterogeneous population of neural cells with diverse structural, functional and molecular characteristics responsible for homeostasis and protection of the central nervous system (CNS). Unlike neurones, astrocytes do not generate action potentials, but employ fluctuations of cytosolic ions as a substrate for their excitability. Ionic signals are associated with neuronal activity and these signals initiate an array of responses ranging from the activation of plasmalemmal homeostatic transporters to the secretion of numerous signalling molecules including neuromodulators, neurotransmitter precursors, metabolic substrates, trophic factors and cytokines. Thus, astrocytes regulate the synaptic connectivity of the neuronal networks by supporting neurotransmitter metabolism, synaptogenesis, synaptic elimination and the synaptic plasticity that contributes to cognitive processing including learning, memory, emotionality and behaviour. Astroglia-specific regulatory pathways affect the most fundamental properties of neuronal networks from their excitability to synaptic connectivity. Thus, it is the concerted action of glia and neurones, which, through distinct mechanisms, produce the behavioural outputs of the ultimate control centre that we call the brain.

What Do Microglia Really Do in Healthy Adult Brain?

Microglia originate from yolk sac-primitive macrophages and auto-proliferate into adulthood without replacement by bone marrow-derived circulating cells. In inflammation, stroke, aging, or infection, microglia have been shown to contribute to brain pathology in both deleterious and beneficial ways, which have been studied extensively. However, less is known about their role in the healthy adult brain. Astrocytes and oligodendrocytes are widely accepted to strongly contribute to the maintenance of brain homeostasis and to modulate neuronal function. On the other hand, contribution of microglia to cognition and behavior is only beginning to be understood. The ability to probe their function has become possible using microglial depletion assays and conditional mutants. Studies have shown that the absence of microglia results in cognitive and learning deficits in rodents during development, but this effect is less pronounced in adults. However, evidence suggests that microglia play a role in cognition and learning in adulthood and, at a cellular level, may modulate adult neurogenesis. This review presents the case for repositioning microglia as key contributors to the maintenance of homeostasis and cognitive processes in the healthy adult brain, in addition to their classical role as sentinels coordinating the neuroinflammatory response to tissue damage and disease.

Antidepressant and Antiaging Effects of Açaí (Euterpe oleracea Mart.) in Mice.

Depression is a mental disorder that affects 300 million people of all ages worldwide, but fewer than half of those with the condition receive adequate treatment. In addition, the high pharmacological refractoriness (affecting 30%-50% of patients) and toxicity of some classical antidepressants support the pursuit of new therapies. People with this condition show depressed mood, loss of pleasure, high levels of oxidative stress, and accelerated biological aging (decreased telomere length and expression of the telomerase reverse transcriptase (TERT), the enzyme responsible for telomere maintenance). Because of the close relationship between depression and oxidative stress, nutraceuticals with antioxidant properties are excellent candidates for therapy. This study represents the first investigation of the possible antidepressant and antiaging effects of commercial samples of clarified açaí (Euterpe oleracea) juice (EO). This fruit is rich in antioxidants and widely consumed. In this study, mice were treated with saline or EO (10 µL/g, oral) for 4 days and then with saline or lipopolysaccharide (0.5 mg/kg, i.p.) to induce depressive-like behavior. Only four doses of EO were enough to abolish the despair-like and anhedonia behaviors and alterations observed in electromyographic measurements. The antidepression effect of EO was similar to that of imipramine and associated with antioxidant and antiaging effects (preventing lipid peroxidation and increasing TERT mRNA expression, respectively) in three major brain regions involved in depression (hippocampus, striatum, and prefrontal cortex). Additionally, EO significantly protected hippocampal cells, preventing neuronal loss associated with the depressive-like state and nitrite level increases (an indirect marker of nitric oxide production). Moreover, EO alone significantly increased TERT mRNA expression, revealing for the first time a potent antiaging action in the brain that suggests neuroprotection against long-term age-related consequences.

Adult Hippocampal Neurogenesis in Different Taxonomic Groups: Possible Functional Similarities and Striking Controversies.

Adult neurogenesis occurs in many species, from fish to mammals, with an apparent reduction in the number of both neurogenic zones and new neurons inserted into established circuits with increasing brain complexity. Although the absolute number of new neurons is high in some species, the ratio of these cells to those already existing in the circuit is low. Continuous replacement/addition plays a role in spatial navigation (migration) and other cognitive processes in birds and rodents, but none of the literature relates adult neurogenesis to spatial navigation and memory in primates and humans. Some models developed by computational neuroscience attribute a high weight to hippocampal adult neurogenesis in learning and memory processes, with greater relevance to pattern separation. In contrast to theories involving neurogenesis in cognitive processes, absence/rarity of neurogenesis in the hippocampus of primates and adult humans was recently suggested and is under intense debate. Although the learning process is supported by plasticity, the retention of memories requires a certain degree of consolidated circuitry structures, otherwise the consolidation process would be hampered. Here, we compare and discuss hippocampal adult neurogenesis in different species and the inherent paradoxical aspects.

In the Heart of the Amazon: Noncommunicable Diseases and Apolipoprotein E4 Genotype in the Riverine Population.

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.

Genetic Susceptibility to Neurodegeneration in Amazon: Apolipoprotein E Genotyping in Vulnerable Populations Exposed to Mercury.

Human exposure to mercury is a serious problem of public health in Amazon. As in other vulnerable populations throughout the world, Amazonian riverine populations are chronically exposed to this metal and some symptoms of mercury intoxication were already detected in these populations. However, studies on the genetic susceptibility to mercury toxicity in the Amazon are scarce, and they tested a limited number of individuals. In this context, apolipoprotein E gene (APOE) is a key element with a well-established association among their alleles and the neurodegenerative consequences of mercury intoxication. However, no studies have addressed APOE genotyping in Amazonian exposed populations. Additionally, epidemiological studies with APOE genotyping in Amazon have been restricted to indigenous populations. Therefore, this work analyzed for the first time the genotypic and allelic profiles of APOE in Amazonian riverine populations chronically exposed to mercury. Eight hundred and twenty three individuals were enrolled in our study donating blood (794) and/or hair (757). APOE genotyping was analyzed by real-time PCR. Total mercury and mercury species were quantified by ICP-MS and GC-pyro-AFS, respectively. Genomic ancestry markers were evaluated by multiplex-PCR reaction, separated by capillary electrophoresis on the ABI 3130 Genetic Analyzer instrument and analyzed on GeneMapper ID v3.2. The 𝜀3 and 𝜀3/𝜀3 were the most frequent allele and genotype, respectively, followed by 𝜀4 allele and 𝜀3/𝜀4 genotype. Only 𝜀2/𝜀2 genotype was not found, suggesting that the absence of this genotype is a generalized phenomenon in Amazon. Also, our data supported an association between the presence of APOE4 and the Amerindian origin in these populations. Fifty-nine individuals were identified at maximum risk with levels of mercury above 10 µg/g and the presence of APOE4. Interestingly, among individuals with high mercury content, APOE4-carriers had high mercury levels than APOE2-carriers, pointing to a different heavy metal accumulation according to the APOE allele. These data suggest that APOE4, in addition to a possible pharmacodynamic effect, may influence pharmacokinetically the mercury exposure causing its higher accumulation and leading to worse deleterious consequences. Our results may aid in the development of prevention strategies and health policy decision-making regarding these at-risk vulnerable populations.

Clarified Açaí (Euterpe oleracea) Juice as an Anticonvulsant Agent: In Vitro Mechanistic Study of GABAergic Targets.

Seizures affect about 50 million people around the world. Approximately 30% of seizures are refractory to the current pharmacological arsenal, so, the pursuit of new therapeutic alternatives is essential. Clarified Euterpe oleracea (EO) juice showed anticonvulsant properties similar to diazepam in an in vivo model with pentylenetetrazol, a GABAA receptor blocker. This study investigated the effects of EO on the main GABAergic targets for anticonvulsant drugs, analyzing the effect on the GABA receptor's benzodiazepine and picrotoxinin binding sites and the GABA uptake. Primary cultures of cortical neurons and astrocytes were treated with EO (0-25%) for up to 90 min. [3H]Flunitrazepam and [3H]TBOB binding, [3H]GABA uptake, cell viability, and morphology were assayed. Nonlethal concentrations of EO increased agonist binding and decreased antagonist binding in cortical neurons. Low concentrations significantly inhibited GABA uptake, especially in astrocytes, suggesting an accumulation of endogenous GABA in the synaptic cleft. The results demonstrate, for the first time, that EO can improve GABAergic neurotransmission via interactions with GABAA receptor and modulation of GABA uptake. Understanding these molecular mechanisms will help in the treatment of seizures and epilepsy, especially in developing countries where geographic isolation and low purchasing power are the main barriers to access to adequate treatment.

Large-scale projects in the amazon and human exposure to mercury: The case-study of the Tucuruí Dam.

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.

Is Low Non-Lethal Concentration of Methylmercury Really Safe? A Report on Genotoxicity with Delayed Cell Proliferation.

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.

Antidepressant drugs in convulsive seizures: Pre-clinical evaluation of duloxetine in mice.

Convulsive seizures (CS) are deleterious consequences of acute cerebral insults and prejudicial events in epilepsy, affecting more than 50 million people worldwide. Molecular mechanisms of depression and epilepsy include an imbalance between excitatory and inhibitory neurotransmission provoking oxidative stress (OS). OS is intimately linked to the origin and evolution of CS and is modulated by antidepressant and anticonvulsant drugs. Although newer antidepressants have exhibited a possible protective role in CS, studies analyzing serotonin and norepinephrine reuptake inhibitors merit to be further investigated. Thus, this study challenged the traditional model of pentylenetetrazol-induced CS, with only one administration of duloxetine. Male Swiss mice were treated with duloxetine (dose corresponding to the therapeutic range for human depression or greater, by allometric calculation; 10, 20 or 40 mg/kg), 30 min before pentylenetetrazol. Behavioral and electroencephalographic alterations were monitored. Lipid peroxidation, nitrites and catalase and superoxidase activities were measured in cortex. Behavioral and electroencephalographic results suggested a possible biphasic effect of duloxetine on CS, with anticonvulsant actions at therapeutic doses and a proconvulsant effect at higher doses. Duloxetine (20 mg/kg) also prevented lipid peroxidation and decreased catalase and superoxide dismutase activities in the cerebral cortex, with no influence on nitrites levels. These data demonstrated an anticonvulsant effect of duloxetine in CS for the first time. This extra anticonvulsant effect may allow the doses of anticonvulsants to be reduced, causing fewer side effects and possibly decreasing morbidity and mortality due to drug interactions in polytherapy.

Anticonvulsant properties of Euterpe oleracea in mice.

Açai (Euterpe oleracea Mart.), a highly consumed fruit in Amazon, is from a common palm with remarkable antioxidant properties. Because oxidative stress and seizures are intimately linked, this study investigated the potential neuroprotective and anticonvulsant effects of commercial clarified açai juice (EO). EO did not alter spontaneous locomotor activity. Four doses of EO were sufficient to increase latencies to both first myoclonic jerk and first generalized tonic-clonic seizure and significantly decrease the total duration of tonic-clonic seizures caused by pentylenetetrazol administration. Also, electrocortical alterations provoked by pentylenetetrazol were prevented, significantly decreasing amplitude of discharges and frequencies above 50 Hz. EO was also able to completely prevent lipid peroxidation in the cerebral cortex, showing a potent direct scavenging property. These results demonstrate for the first time that E. oleracea significantly protects against seizures and seizure-related oxidative stress, indicating an additional protection for humans who consume this fruit.

Genotoxicity of mercury: contributing for the analysis of Amazonian populations.

Mercury is an important source of environmental contamination affecting human beings throughout the world and especially in the Amazon. Riverside populations have been chronically exposed to relatively high levels of methylmercury for many years. Long-term effects of mercury exposure are not well known, but human genotoxicity was already showed in both in vitro and epidemiological studies. However, to date, only two studies were carried out in Amazonian populations with conflicting results and without comparing to a non-exposed population. Aiming to highlight this question and avoid interference factors, this work analyzed in vitro genotoxicity of mercury in blood lymphocytes of Amazonian individuals by two methods (micronucleus and chromosomal aberrations). Deleterious effects of low levels (1-500 µg/l or 0,004-2 µM) of methylmercury were only detected with the method to detect chromosomal aberrations. Mitotic index (proportion of cells in metaphase) was the parameter most sensible. Thus, this technique was applied for the analysis of an Amazonian non-exposed population (Panacauera) with similar social-economical characteristics of the exposed populations studied elsewhere. The mean of the mitotic index for Panacauera population was 0.0814 ± 0.0097. Inter-individual variability of this index had no relation with sex or age. This value was above those registered for some groups of exposed populations. This fact points to mercury as the main responsible for inhibiting the cell cycle and/or the loss of proliferative capacity of the cells. These results already support mitotic index as an essential parameter for the early diagnose of mercury genotoxicity in humans, and especially in Amazonian populations.