Ecotoxicological effects of the emerging contaminant ivermectin on Rhinella arenarum: A comparative study of active ingredient and commercial formulation.

Ivermectin (IVM) is a broad-spectrum veterinary antiparasitic used worldwide in cattle breeding. The aim of this study was to evaluate the lethal effects of the active ingredient and a commercial formulation of IVM (1 % active ingredient) in the embryonic stage (S. 4-6) and larval stage (S. 25) of the South American amphibian Rhinella arenarum through chronic standardized bioassays. Also, behavior analysis and oxidative stress and cholinergic effects biomarkers were analyzed at 1, 10 and 100 µg IVM/L concentrations. For the embryonic stage, the active ingredient (96 h- LC50: 15900 µg/L) was more toxic than the commercial formulation (96 h-LC50: 51230 µg/L) during the acute period, while at chronic exposure the commercial formulation was more toxic (504 h-LC50: 10.25 µg/L), compared to the active ingredient (504 h-LC50: 312.80 µg/L). For the larval stage, in acute exposure, the active ingredient (96 h-LC50: 800 µg/L) was more toxic than the commercial formulation (96 h-LC50: 1550 µg/L). In the chronic exposure, the commercial formulation (504 h-LC50: 77.33 µg/L) was more toxic than the active ingredient (504 h-LC50: 195.25 µg/L). Overall, larvae exhibited greater sensitivity to both the active ingredient and the commercial formulation. However, during chronic exposure, embryos were more sensitive to the commercial formulation than larvae. The commercial formulation primarily induced oxidative stress, and both forms of the compound affected behavior and cholinergic effect biomarkers, even at low environmentally relevant concentrations (1 µg/L). These results highlight the potential impact of IVM on aquatic ecosystems.

The GSTP1 rs1695 Polymorphism Is Associated with Mercury Levels and Neurodevelopmental Delay in Indigenous Munduruku Children from the Brazilian Amazon.

Genetic polymorphisms may influence mercury (Hg) toxicity. The aims of this study were to evaluate individual factors, such as the presence of the GSTP1 rs1695 polymorphism, associated with internal Hg dose and child neurodevelopment in indigenous people from the Brazilian Amazon chronically exposed to Hg. Eighty-two indigenous children were clinically evaluated, hair Hg was measured, and the GSTP1 rs1695 polymorphism was genotyped. The mean age was 4.8 years, the median Hg was 5.5 µg/g, and 93.8% of children exceeded the safe limit (2.0 µg/g). Fish consumption was associated with Hg levels (p = 0.03). The GSTP1 rs1695 A>G polymorphism was in the Hardy-Weinberg equilibrium and the highest prevalence of the GSTP1 AA genotype (80%) was found in Sawré Aboy, which had the highest Hg levels (10 µg/g) among the studied villages. The Hg levels tended to increase over the years in males and in carriers of the GSTP1 AA genotype (0.69 µg/g and 0.86 µg/g, respectively). Nine children failed the neurodevelopmental test, all of whom had Hg > 2.0 µg/g, and 88.9% carried the GSTP1 AA or AG genotypes, previously associated with the highest internal Hg doses and neurocognitive disorders. The genetic counseling of this population is important to identify the individuals at greater risk for neurodevelopmental disorders resulting from chronic Hg exposure.

Cannabidiol protects mouse hippocampal neurons from neurotoxicity induced by amyloid ß-peptide25-35.

Alzheimer's disease (AD), the most prevalent form of dementia worldwide, is a significant health concern, according to the World Health Organization (WHO). The neuropathological diagnostic criteria for AD are based on the deposition of amyloid-ß peptide (Aß) and the formation of intracellular tau protein tangles. These proteins are associated with several overlapping neurodegenerative mechanisms, including oxidative stress, mitochondrial dysfunction, lipid peroxidation, reduced neuronal viability, and cell death. In this context, our study focuses on the potential therapeutic use of cannabidiol (CBD), a non-psychotropic cannabinoid with antioxidant and anti-inflammatory effects. We aim to evaluate CBD's neuroprotective role, particularly in protecting hippocampal neurons from Aß25-35-induced toxicity. Our findings indicate that CBD significantly improves cell viability and decreases levels of lipid peroxidation and oxidative stress. The results demonstrate that CBD possesses a robust potential to rescue cells from induced neurotoxicity through its antioxidant properties. Additionally, the neuroprotective effect of CBD may be associated with the modulation of the endocannabinoid system. These findings suggest that CBD could be a promising compound for adjuvant treatments in neurodegenerative processes triggered by amyloid-ß peptide.

Neurotoxicity of crack cocaine exposure: evidence from a systematic review of in vitro and in vivo studies.

Several studies suggest that crack cocaine users exhibit higher prevalence of both psychiatric and psychosocial problems, with an aggressive pattern of drug use. Nevertheless, few experimental studies attempted to verify the neurotoxicity after crack cocaine exposure, especially when compared with other routes of cocaine administration. This systematic review aimed to verify whether in vitro and/or in vivo crack cocaine exposure is more neurotoxic than cocaine exposure (snorted or injected). A search was performed in the PubMed, EMBASE, Scopus, Web of Science, and LILACS databases for in vitro and in vivo toxicological studies conducted with either rats or mice, with no distinction with regard to sex or age. Other methods including BioRxiv, BDTD, Academic Google, citation searching, and specialist consultation were also adopted. Two independent investigators screened the titles and abstracts of retrieved studies and subsequently performed full-text reading and data extraction. The quality of the included studies was assessed by the Toxicological data Reliability assessment Tool (ToxRTool). The study protocol was registered with the Prospective Registry of Systematic Reviews (PROSPERO; CRD42022332250). Of the twelve studies included, three were in vitro and nine were in vivo studies. According to the ToxRTool, most studies were considered reliable either with or without restrictions, with no one being considered as not reliable. The studies found neuroteratogenic effects, decreased threshold for epileptic seizures, schizophrenic-like symptoms, and cognitive deficits to be associated with crack cocaine exposure. Moreover, both in vitro and in vivo studies reported a worsening in cocaine neurotoxic effect caused by the anhydroecgonine methyl ester (AEME), a cocaine main pyrolysis product, which is in line with the more aggressive pattern of crack cocaine use. This systematic review suggests that crack cocaine exposure is more neurotoxic than other routes of cocaine administration. However, before the scarcity of studies on this topic, further toxicological studies are necessary.

Effects of the AMPAR Antagonist, Perampanel, on Cognitive Function in Rats Exposed to Neonatal Iron Overload.

Iron accumulation has been associated with the pathogenesis of neurodegenerative diseases and memory decline. As previously described by our research group, iron overload in the neonatal period induces persistent memory deficits and increases oxidative stress and apoptotic markers. The neuronal insult caused by iron excess generates an energetic imbalance that can alter glutamate concentrations and thus trigger excitotoxicity. Drugs that block glutamatergic receptor eligibly mitigate neurotoxicity; among them is perampanel (PER), a reversible AMPA receptor (AMPAR) antagonist. In the present study, we sought to investigate the neuroprotective effects of PER in rats subjected to iron overload in the neonatal period. Recognition and aversive memory were evaluated, AMPAR subunit phosphorylation, as well as the relative expression of genes such as GRIA1, GRIA2, DLG4, and CAC, which code proteins involved in AMPAR anchoring. Male rats received vehicle or carbonyl iron (30 mg/kg) from the 12th to the 14th postnatal day and were treated with vehicle or PER (2 mg/kg) for 21 days in adulthood. The excess of iron caused recognition memory deficits and impaired emotional memory, and PER was able to improve the rodents' memory. Iron increased the phosphorylation of GLUA1 subunit, which was reversed by PER. Furthermore, iron overload increased the expression of the GRIA1 gene and decreased the expression of the DLG4 gene, demonstrating the influence of metal accumulation on the metabolism of AMPAR. These results suggest that iron can interfere with AMPAR functionality, through altered phosphorylation of its subunits, and the expression of genes that code for proteins critically involved in the assembly and anchoring of AMPAR. The blockade of AMPAR with PER is capable of partially reversing the cognitive deficits caused by iron overload.

NCS-1 protein regulates TRPA1 channel through the PI3K pathway in breast cancer and neuronal cells.

The physical and functional interaction between transient receptor potential channel ankyrin 1 (TRPA1) and neuronal calcium sensor 1 (NCS-1) was assessed. NCS-1 is a calcium (Ca2+) sensor found in many tissues, primarily neurons, and TRPA1 is a Ca2+ channel involved not only in thermal and pain sensation but also in conditions such as cancer and chemotherapy-induced peripheral neuropathy, in which NCS-1 is also a regulatory component.We explored the interactions between these two proteins by employing western blot, qRT-PCR, co-immunoprecipitation, Ca2+ transient monitoring with Fura-2 spectrophotometry, and electrophysiology assays in breast cancer cells (MDA-MB-231) with different levels of NCS-1 expression and neuroblastoma cells (SH-SY5Y).Our findings showed that the expression of TRPA1 was directly correlated with NCS-1 levels at both the protein and mRNA levels. Additionally, we found a physical and functional association between these two proteins. Physically, the NCS-1 and TRPA1 co-immunoprecipitate. Functionally, NCS-1 enhanced TRPA1-dependent Ca2+ influx, current density, open probability, and conductance, where the functional effects depended on PI3K. Conclusion: NCS-1 appears to act not only as a Ca2+ sensor but also modulates TRPA1 protein expression and channel function in a direct fashion through the PI3K pathway. These results contribute to understanding how Ca2+ homeostasis is regulated and provides a mechanism underlying conditions where Ca2+ dynamics are compromised, including breast cancer. With a cellular pathway identified, targeted treatments can be developed for breast cancer and neuropathy, among other related diseases.

Cuban Policosanol (Raydel®) Exerts Higher Antioxidant and Anti-Glycation Activities than Chinese Policosanol (BOC Sciences) in Reconstituted High-Density Lipoproteins: In Vivo Anti-Inflammatory Activities in Zebrafish and Its Embryos.

The present study compares sugarcane-wax purified policosanols sourced from Cuba (Raydel®) and China (BOC Sciences) and utilized following the synthesis of reconstituted high-density lipoproteins (rHDL). The two policosanols exhibited distinctly different ingredient ratios of long-chain aliphatic alcohols, particularly 1-octacosanol (C28) and 1-tetratriacotanol (C34). After synthesizing rHDL with apolipoprotein A-I (apoA-I), the two policosanols bound well with phospholipid and apoA-I to form the discoidal rHDL. Notably, rHDL-1, containing Cuban policosanol, displayed the largest particle diameter at approximately 78 ± 3 nm. In contrast, both control rHDL (rHDL-0) and rHDL containing Chinese policosanol (rHDL-2) exhibited smaller particles, with diameters of approximately 58 ± 3 nm and 61 ± 2 nm, respectively. Furthermore, rHDL-1 demonstrated enhanced anti-glycation activity, safeguarding apoA-I from degradation within HDL, and displayed the antioxidant ability to inhibit LDL oxidation. A microinjection of each rHDL into zebrafish embryos in the presence of carboxymethyllysine (CML) revealed rHDL-1 to have the strongest antioxidant activity with the highest embryo survivability and normal developmental morphology. Dermal application to recover the wound revealed rHDL-1 to have the highest wound-healing activity (75%) and survivability (92%) in the cutaneous wound area in the presence of CML. In adult zebrafish, injecting CML (250 µg) caused acute death and hyperinflammation, marked by heightened neutrophil infiltration and interleukin (IL)-6 production in liver. However, co-administering rHDL-1 notably increased survival (85%) and exhibited strong anti-inflammatory properties, reducing IL-6 production while improving the blood lipid profile. However, a co-injection of rHDL-2 resulted in the lowest survivability (47%) with more hepatic inflammation. In conclusion, Cuban policosanol (Raydel®) has more desirable properties for the in vitro synthesis of rHDL with stronger anti-glycation and antioxidant activities than those of Chinese policosanol (BOC Sciences). Moreover, Raydel-policosanol-integrated rHDL demonstrates a noteworthy effect on accelerated wound healing and robust anti-inflammatory properties, leading to increased survivability in zebrafish embryos and adults by effectively suppressing CML-induced hyperinflammation.

From gains to gaps? How Selective Androgen Receptor Modulator (SARM) YK11 impact hippocampal function: In silico, in vivo, and ex vivo perspectives.

Selective Androgen Receptor Modulators (SARMs), particularly (17α,20E)-17,20-[(1-methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic-acid-methyl-ester (YK11), are increasingly popular among athletes seeking enhanced performance. Serving as an Androgen Receptor (AR) agonist, YK11 stimulates muscle growth while inhibiting myostatin. Our study delved into the impact of YK11 on the rat hippocampus, analyzing potential alterations in neurochemical mechanisms and investigating its synergistic effects with exercise (EXE), based on the strong relationship between SARM users and regular exercise. Utilizing Physiologically Based Pharmacokinetic (PBPK) modeling, we demonstrated YK11 remarkable brain permeability, with molecular docking analysis revealing YK11 inhibitory effects on 5-alpha-reductase type II (5αR2), suggesting high cell bioavailability. Throughout a 5-week experiment, we divided the animals into the following groups: Control, YK11 (0.35 g/kg), EXE (swimming exercise), and EXE + YK11. Our findings showed that YK11 displayed a high binding affinity with AR in the hippocampus, influencing neurochemical function and modulating aversive memory consolidation, including the downregulation of the BDNF/TrkB/CREB signaling, irrespective of EXE combination. In the hippocampus, YK11 increased pro-inflammatory IL-1ß and IL-6 cytokines, while reducing anti-inflammatory IL-10 levels. However, the EXE + YK11 group counteracted IL-6 effects and elevated IL-10. Analysis of apoptotic proteins revealed heightened p38 MAPK activity in response to YK11-induced inflammation, initiating the apoptotic cascade involving Bax/Bcl-2/cleaved caspase-3. Notably, the EXE + YK11 group mitigated alterations in Bcl-2 and cleaved caspase-3 proteins. In conclusion, our findings suggest that YK11, at anabolic doses, significantly alters hippocampal neurochemistry, leading to impairments in memory consolidation. This underscore concerns about the misuse risks of SARMs among athletes and challenges common perceptions of their minimal side effects.

Multilevel assessment of carbamazepine effects: An integrative approach using zebrafish early-life stages.

Carbamazepine (CBZ) is the most commonly used drug in epilepsy treatment, and its metabolites are commonly detected among persistent pharmaceuticals in the aquatic environment. This study aimed to investigate CBZ effects on early-life-stage zebrafish (Danio rerio) (from 2 to 168 hpf) by employing of an integrative approach linking endpoints from molecular to individual level: (i) development; (ii) locomotor activity; (iii) biochemical markers (lactate dehydrogenase, glutathione-S-transferase, acetylcholinesterase and catalase) and (iv) transcriptome analysis using microarray. A 168 h - LC50 of 73.4 mg L-1 and a 72 h - EC50 of 66.8 mg L-1 for hatching were calculated while developmental effects (oedemas and tail deformities) were observed at CBZ concentrations above 37.3 mg L-1. At the biochemical level, AChE activity proved to be the most sensitive parameter, as evidenced by its decrease across all concentrations tested (∼25% maximum reduction, LOEC (lowest observed effect concentration) < 0.6 µg L-1). Locomotor behaviour seemed to be depressed by CBZ although this effect was only evident at the highest concentration tested (50 mg L-1). Molecular analysis revealed a dose-dependent effect of CBZ on gene expression. Although only 25 genes were deregulated in organisms exposed to CBZ when compared to controls, both 0.6 and 2812 µg L-1 treatments impaired gene expression related to development (e.g. crygmxl1, org, klf2a, otos, stx16 and tob2) and the nervous system (e.g. Rtn3, Gdf10, Rtn3), while activated genes were associated with behavioural response (e.g. prlbr and taar). Altogether, our results indicate that environmentally relevant CBZ concentrations might affect biochemical and genetic traits of fish. Thus, the environmental risk of CBZ cannot be neglected, especially in a realistic scenario of constant input of domestic effluents into aquatic systems.

Single-Nucleotide Polymorphisms Associated with Mercury Levels and Neurological Symptoms: An Overview.

Mercury (Hg) pollution is a global public health concern because of its adverse effects on the environment and health. Single-nucleotide polymorphisms (SNPs) have been associated with Hg levels and outcomes. The aim of this review was to describe the research and discuss the evidence on the genetic susceptibility of Hg-exposed individuals to the development of neurocognitive disorders. A systematic review was performed to identify the genes/SNPs associated with Hg toxicokinetics and that, therefore, affect neurological function in exposed populations. Observational and experimental studies were identified by screening three databases. Thirteen articles were included (quality score 82-100%) and 8124 individuals were evaluated. Hg exposure was mainly fish consumption (77%) and, in 31% of the studies, the Hg levels exceeded the reference limits. Genetic susceptibility to higher Hg levels and neurotoxicity risk in Hg poisoning were associated with eight (ALAD rs1800435, CYP3A4 rs2740574, CYP3A5 rs776746, CYP3A7 rs2257401, GSTP1 rs1695, MT1A rs8052394, MT1M rs2270836, and MT4 rs11643815) and three (MT1A rs8052394, MT1M rs2270837, and MT2A rs10636) SNPs, respectively, and rs8052394 was associated with both outcomes. The MT1A rs8052394 SNP may be used as a susceptibility biomarker to identify individuals at greater risk for higher Hg levels and the development of neurocognitive disorders in metal-exposed populations.

Long-Term Environmental Methylmercury Exposure Is Associated with Peripheral Neuropathy and Cognitive Impairment among an Amazon Indigenous Population.

Widespread contamination of the Amazon basin with mercury has been reported to occur since at least the mid-80s due to heavy gold mining activity. Although initial studies have indicated that this may lead to deleterious neurological consequences to the indigenous populations living in the region, further research is needed to better characterize the neurological burden of such long-term exposure. With this aim, a cross-sectional exploratory study has been conducted with the Yanomami indigenous population residing in a northern Amazon region. All participants underwent a structured interview; detailed neurological examination, including assessment for cognitive, motor, coordination, and sensory functions; and laboratorial testing for serum hemoglobin, blood glucose, and methylmercury levels in hair samples. This study enrolled 154 individuals of 30.9 ± 16.8 years of age, of which 56.1% were female. Mean methylmercury levels in hair were 3.9 ± 1.7 µg/g. Methylmercury levels in hair > 6.0 µg/g were found in 10.3%. Among participants with hair methylmercury levels ≥ 6.0 µg/g, the prevalences of peripheral neuropathy and reduced cognitive performance were, respectively, 78.8% (95%CI 15-177%, p = 0.010) and 95.9% (95%CI 16-230.8%, p = 0.012) higher than those of individuals with lower levels. These results suggest that chronic mercury exposure may lead to significant and potentially irreversible neurotoxicity to Yanomami population living in the northern Amazon basin.

Critical period of exposure to mercury and the diagnostic of autism spectrum disorder: A systematic review.

Autism spectrum disorder (ASD) is characterized by repetitive behaviors and deficits in social interaction. Its etiology is not completely clear, but both genetic and environmental factors contribute to and influence its development and course. The increased number of autism cases in recent years has been strongly associated with increased exposure to heavy metals. Mercury (Hg) has gained prominence in the scientific literature as a result of its presence as an urban pollutant and well-described neurotoxicity. This review assessed the relationship between Hg exposure in the pre- and post-natal period and ASD. The systematic review identified observational clinical studies and pre-clinical trials in journals indexed in the PubMed, Embase, ProQuest, and LILACS databases. The aim of this study was to investigate the association between exposure to Hg and ASD and to define the critical period of exposure. A total of 57 articles were selected for this review, with 35 articles (61.40%) identifying a positive association between ASD and Hg, while 22 articles (38.60%) did not find the same outcome. The biological samples most used to analyze Hg body burdens were hair (36.84%) and blood (36.84%). Most case-control studies found an increase in Hg levels in individuals with ASD who were exposed to a polluted environment in the post-natal period. Taken together, the studies suggest that these patients have a deficient detoxification system, and this could worsen the symptoms of the disorder. However, new studies addressing the influence of Hg on the post-natal nervous system and its relationship with ASD should be carried out.

Neurotoxicity of glyphosate: Focus on molecular mechanisms probably associated with alterations in cognition and behavior.

In recent decades, glyphosate and glyphosate-based herbicides (GBH) have been extensively used in agriculture all over the world. Initially, they were considered safe, but rising evidence suggests that these molecules reach the central nervous system producing metabolic, functional, and permanent alterations that impact cognition and behavior. This theoretical and non-systematic review involved searching, integrating, and analyzing preclinical evidence regarding the effects of acute, sub-chronic, and chronic exposure to glyphosate and GBH on cognition, behavior, neural activity, and development in adult and juvenile rodents following perinatal exposition. In addition, this review gathers the mechanisms underlying the neurotoxicity of glyphosate mediating cognitive and behavioral alterations. Furthermore, clinical evidence of the effects of exposition to GBH on human health and its possible link with several neurological disorders was revised.

Embryotoxic Effects of Pesticides in Zebrafish (Danio rerio): Diflubenzuron, Pyriproxyfen, and Its Mixtures.

Diflubenzuron (DFB) and pyriproxyfen (PPF) are larvicides used in crops to control insect plagues. However, these pesticides are known to impact non-target organisms like fish and mammals. Here, we aimed at assessing the embryotoxicity of purified DFB, PPF, and their mixtures in a non-target organism-zebrafish. Zebrafish embryos were exposed to different concentrations for 120 h: 0.025, 0.125, 0.25, 1.25, 2.5, and 10 mg/L of purified PPF and purified DFB, while we used 0.025 mg/L PPF + 10 mg/L DFB (Mix A), 0.125 mg/L PPF + 10 mg/L DFB (Mix B), and 0.25 mg/L PPF + 10 mg/L DFB (Mix C) for the mixtures of PPF + DFB. We observed mortality, teratogenicity, and cardiotoxicity. For the neurotoxicity tests and evaluation of reactive oxygen species (ROS) levels in the brain, embryos were exposed for 120 h to 0.379 and 0.754 mg/L of PPF and 0.025 and 0.125 mg/L of DFB. We established the LC50 for PPF as 3.79 mg/L, while the LC50 for DFB was not determinable. Survival and hatching were affected by PPF concentrations above 0.125 mg/L, DFB concentrations above 1.25 mg/L, and the lower pesticide mixtures. PPF exposure and mixtures induced different types of malformations, while a higher number of malformations were observed for the mixtures, suggesting a potentiating effect. Pesticides diminished avoidance responses and increased the levels of ROS across all concentrations, indicating neurotoxicity. Our findings underscore the detrimental impact of PPF and DFB exposure, spanning from biochemistry to morphology. There is a critical need to reconsider the global use of these pesticides and transition to more ecologically friendly forms of pest control, raising an alarm regarding repercussions on human and animal health and well-being.

Pupil size change in agricultural workers exposed to pesticides.

CLINICAL RELEVANCE: Pupil size evaluation using clinical examination may be important for detecting and monitoring individuals at risk of neurotoxic effects from chemical exposure, as it may enable early intervention and the implementation of preventive measures. BACKGROUND: This work aimed to investigate the association between pesticide exposure and pupil size. Pupil size is regulated by muscarinic and nicotinic receptors, and it is well-established that common pesticide chemicals disrupt this regulation. METHODS: Twenty agricultural workers exposed to pesticides, and twenty participants not exposed, underwent visual screening, and pupil size evaluation under mesopic and photopic conditions. Additionally, signs of neurotoxicity and pesticide exposure in both groups were evaluated using the modified version of the neurotoxic symptoms questionnaire (Q16) and measuring cholinesterase (AChE) levels in blood, respectively. RESULTS: Agricultural workers exposed to pesticides had a score indicating medium-high level of neurotoxicity (49.85 (SD ± 8.94)) which was significantly higher (t (36) = 7.659, p ≤ 0.0001) than non-exposed participants who had low levels of neurotoxicity (27.25 SD ± 8.86). There was a significant difference in pupil size (mm) under mesopic (t (19) 4.42 p = 0.003) and scotopic (t (19) 4.63, p = 0.0002) conditions between the two groups. Additionally, there was a significant difference in AChE blood levels (t (19) 2.94 p = 0.008) between exposed and non-exposed participants, indicating that exposed workers had low levels of this enzyme (average exposed group 3381 U/L (SD ± 1306)) compared to the non-exposed group (average non-exposed group 4765 U/L (SD ± 1300)). A significant negative correlation between AChE levels, years of exposure, and pupil size was found. The latter finding importantly showed that smaller pupils are associated with the accumulation of acetylcholine or a decrease in the activity of the enzyme AChE. CONCLUSION: Pupil size of agricultural workers exposed to pesticides can be abnormal and is associated with neurotoxicity as indicated by symptomatology and cholinesterase levels. Evaluation of pupil size may be useful for clinically detecting neurotoxicity.

Mechanisms Associated with Cognitive and Behavioral Impairment Induced by Arsenic Exposure.

Arsenic (As) is a metalloid naturally present in the environment, in food, water, soil, and air; however, its chronic exposure, even with low doses, represents a public health concern. For a long time, As was used as a pigment, pesticide, wood preservative, and for medical applications; its industrial use has recently decreased or has been discontinued due to its toxicity. Due to its versatile applications and distribution, there is a wide spectrum of human As exposure sources, mainly contaminated drinking water. The fact that As is present in drinking water implies chronic human exposure to this metalloid; it has become a worldwide health problem, since over 200 million people live where As levels exceed safe ranges. Many health problems have been associated with As chronic exposure including cancer, cardiovascular diseases, gastrointestinal disturbances, and brain dysfunctions. Because As can cross the blood-brain barrier (BBB), the brain represents a target organ where this metalloid can exert its long-term toxic effects. Many mechanisms of As neurotoxicity have been described: oxidative stress, inflammation, DNA damage, and mitochondrial dysfunction; all of them can converge, thus leading to impaired cellular functions, cell death, and in consequence, long-term detrimental effects. Here, we provide a current overview of As toxicity and integrated the global mechanisms involved in cognitive and behavioral impairment induced by As exposure show experimental strategies against its neurotoxicity.

The Essential Role of Astrocytes in Neurodegeneration and Neuroprotection.

Astrocytes are glial cells that perform several fundamental physiological functions within the brain. They can control neuronal activity and levels of ions and neurotransmitters, and release several factors that modulate the brain environment. Over the past few decades, our knowledge of astrocytes and their functions has rapidly evolved. Neurodegenerative diseases are characterized by selective degeneration of neurons, increased glial activation, and glial dysfunction. Given the significant role played by astrocytes, there is growing interest in their potential therapeutic role. However, defining their contribution to neurodegeneration is more complex than was previously thought. This review summarizes the main functions of astrocytes and their involvement in neurodegenerative diseases, highlighting their neurotoxic and neuroprotective ability.

Epigenetic regulation exerted by Caliphruria subedentata and galantamine: an in vitro and in silico approach for mimic Alzheimer's disease.

At the interface between genes and environment, epigenetic mechanisms, including DNA methylation and histone modification, regulate neurogenic processes such as differentiation, proliferation, and maturation of neural stem cells. However, these mechanisms are altered in Alzheimer's disease (AD), a neurodegenerative condition that mainly affects older adults. Since epigenetic mechanisms are known to be reversible, a number of molecules from natural sources are being studied as epigenetic regulators in AD. Recently, in vitro and in silico studies have shown that C. subedentata and its alkaloids modulated neurotoxicity. However, studies exploring the epigenetic activity of these alkaloids are limited. We conducted a set of bioassays to evaluate neuronal differentiation and the sensitivity of undifferentiated SH-SY5 cells against a neurotoxic stimulus. In addition, we analyzed the methylation profiles in genes such as APP, PSI, and BACE1 due to their role in amyloid processing. Docking and molecular dynamic analysis were used to explore the effect exerted by C. subedentata alkaloids on the regulation of histone deacetylases (HDAC2, HDAC3 and HDAC7). The results demonstrated that C. subedentata and galantamine induce neuronal differentiation and protect the undifferentiated SH-SY5Y cells against Aß(1-42)-induced neurotoxicity. The methylation profiles of the studied genes show no statistically significant differences between C. subedentata, galantamine. However, these findings should be interpreted with caution, since small changes in methylation promoters in the brain could not be easily detected. Results from in silico approaches describe for the first time the potential promissing epigenetic effects of galantamine by regulating HDAC3 and HDAC7 modification.Communicated by Ramaswamy H. Sarma.