What We Know about Euterpe Genus and Neuroprotection: A Scoping Review.

The Euterpe genus (mainly Euterpe oleracea Martius, Euterpe precatoria Martius, and Euterpe edulis Martius) has recently gained commercial and scientific notoriety due to the high nutritional value of its fruits, which are rich in polyphenols (phenolic acids and anthocyanins) and have potent antioxidant activity. These characteristics have contributed to the increased number of neuropharmacological evaluations of the three species over the last 10 years, especially açaí of the species Euterpe oleracea Martius. The fruits of the three species exert neuroprotective effects through the modulation of inflammatory and oxidative pathways and other mechanisms, including the inhibition of the mTOR pathway and protection of the blood-brain barrier, all of them intimately involved in several neuropathologies. Thus, a better understanding of the neuropharmacological properties of these three species may open new paths for the development of therapeutic tools aimed at preventing and treating a variety of neurological conditions.

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.

Eating in the Amazon: Nutritional Status of the Riverine Populations and Possible Nudge Interventions.

The Amazon is the largest tropical forest in the world and a source of healthy food, such as fruits and fish. Surprisingly, the Amazonian riverine population present an increased prevalence (as high as 58%) of non-communicable diseases, such as hypertension and insulin resistance, even higher than that described for the urban population of the Amazon. Therefore, this work aimed to analyze the nutritional status and associated risk of the riverine population. Body mass index, waist circumference (WC), waist-to-hip ratio, and neck circumference (NC) were evaluated, and risk analysis was assayed. Furthermore, data about occupation and the prevalence of consumers of the different groups of food were analyzed. All anthropometric parameters revealed high proportions of individuals at risk, WC and NC being the factors that had more high-risk women and men, respectively. Our data confirmed the characteristic profile of the riverine communities with a high number of fish consumers, but also observed different patterns probably associated to a phenomenon of nutrition transition. Based on our data, some nudge interventions that take into account the principles of behavior analysis are discussed and proposed for these populations, aiming to improve the nutritional status and avoid the long-term consequences of the results showed by this work.

Revisiting Astrocytic Roles in Methylmercury Intoxication.

Intoxication by heavy metals such as methylmercury (MeHg) is recognized as a global health problem, with strong implications in central nervous system pathologies. Most of these neuropathological conditions involve vascular, neurotransmitter recycling, and oxidative balance disruption leading to accelerated decline in fine balance, and learning, memory, and visual processes as main outcomes. Besides neurons, astrocytes are involved in virtually all the brain processes and perform important roles in neurological response following injuries. Due to astrocytes' strategic functions in brain homeostasis, these cells became the subject of several studies on MeHg intoxication. The most heterogenous glial cells, astrocytes, are composed of plenty of receptors and transporters to dialogue with neurons and other cells and to monitor extracellular environment responding tightly through fluctuation of cytosolic ions. The overall toxicity of MeHg might be determined on the basis of the balance between MeHg-mediated injury to neurons and protective responses from astrocytes. Although the role of neurons in MeHg intoxication is relatively well-established, the role of the astrocytes is only beginning to be understood. In this review, we update the information on astroglial modulation of the MeHg-induced neurotoxicity, providing remarks on their protective and deleterious roles and insights for future studies.

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.

Towards Therapeutic Alternatives for Mercury Neurotoxicity in the Amazon: Unraveling the Pre-Clinical Effects of the Superfruit Açaí (Euterpe oleracea, Mart.) as Juice for Human Consumption.

Methylmercury (MeHg) exposure is a serious problem of public health, especially in the Amazon. Exposure in riverine populations is responsible for neurobehavioral abnormalities. It was hypothesized that consumption of Amazonian fruits could protect by reducing mercury accumulation. This work analyzed the effects of commercial samples of Euterpe oleracea (EO) for human consumption (10 µL/g) against MeHg i.p. exposure (2.5 mg/Kg), using neurobehavioral (open field, rotarod and pole tests), biochemical (lipid peroxidation and nitrite levels), aging-related (telomerase reverse transcriptase (TERT) mRNA expression) and toxicokinetic (MeHg content) parameters in mice. Both the pole and rotarod tests were the most sensitive tests accompanied by increased lipid peroxidation and nitrite levels in brains. MeHg reduced TERT mRNA about 50% demonstrating a strong pro-aging effect. The EO intake, similar to that of human populations, prevented all alterations, without changing the mercury content, but avoiding neurotoxicity and premature aging of the Central Nervous System (CNS). Contrary to the hypothesis found in the literature on the possible chelating properties of Amazonian fruits consumption, the effect of EO would be essentially pharmacodynamics, and possible mechanisms are discussed. Our data already support the regular consumption of EO as an excellent option for exposed Amazonian populations to have additional protection against MeHg intoxication.

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.

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.

Selective effects of Euterpe oleracea (açai) on Leishmania (Leishmania) amazonensis and Leishmania infantum.

Leishmania (Leishmania) amazonensis and Leishmania infantum (=Leishmania chagasi) are protozoa that cause American cutaneous and visceral leishmaniasis, respectively. These diseases show a high incidence in developing countries such as Brazil. The treatments used for leishmaniasis are still limited due to their high cost and toxicity. Currently, some natural products are considered an important alternative source of new leishmanicidal agents. Euterpe oleracea Martius, a palm producing black fruits, is frequently consumed in the Amazon region, as a juice, known as açai, with potent antioxidant, anti-inflammatory and anticonvulsant properties. Interestingly, the biological activity of clarified açai juice (EO) on L. (L.) amazonensis and L. infantum (=L. chagasi) is unknown. Therefore, the mechanism of anti-leishmanial action of EO has been evaluated on L. (L.) amazonensis and L. infantum (=L. chagasi). EO reduced the number of promastigotes and caused morphological alterations, increased the production of reactive oxygen species (ROS) and induced cell death phenotypes probably seems by apoptosis in the promastigotes of L. (L.) amazonensis (IC50 = 1:40) and L. infantum (=L. chagasi) (IC50 = 1:38). EO also presented activity against Leishmania amastigotes. Treatment with EO for 72 h strongly reduced IL-17 cytokine levels at all tested concentrations and decreased the number of intracellular amastigotes in macrophages infected with L. (L.) amazonensis (IC50 = 1:30) and L. infantum (=L. chagasi) (IC50 = 1:38). Additionally, no cytotoxic effect was observed in murine macrophages treated with EO (72 h - CC50 > 1:1). Our results demonstrated that EO has leishmanicidal activity against two different species that cause American visceral and cutaneous leishmaniasis without cytotoxic effects for the host cell.

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.

Role for apolipoprotein E in neurodegeneration and mercury intoxication.

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.

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.