Neurotoxicity and behavioral disorders induced in mice by acute exposure to the diamide insecticide chlorantraniliprole.

Diamide insecticides activate ryanodine receptors expressed in lepidopteran skeletal muscle and promote Ca2+ release in the sarcoplasmic reticulum, causing abnormal contractions and paralysis, leading to death of the pest. Although they had been thought not to act on nontarget organisms, including mammals, adverse effects on vertebrates were recently reported, raising concerns about their safety in humans. We investigated the neurotoxicity of the acute no-observed-adverse-effect level of chlorantraniliprole (CAP), a diamide insecticide, in mice using clothianidin (CLO), a neonicotinoid insecticide, as a positive control. The CLO-administered group showed decreased locomotor activities, increased anxiety-like behaviors, and abnormal human-audible vocalizations, while the CAP-administered group showed anxiety-like behaviors but no change in locomotor activities. The CAP-administered group had greater numbers of c-fos-immunoreactive cells in the hippocampal dentate gyrus, and similar to the results in a CLO-administered group in our previous study. Blood corticosterone levels increased in the CLO-administered group but did not change in the CAP-administered group. Additionally, CAP was found to decreased 3-Methoxytyramine and histamine in mice at the time to maximum concentration. These results suggest that CAP-administered mice are less vulnerable to stress than CLO-administered mice, and the first evidence that CAP exposure increases neuronal activity and induces anxiety-like behavior as well as neurotransmitter disturbances in mammals.

A Technical Guide to Sampling the Beagle Dog Nervous System for General Toxicity and Neurotoxicity Studies.

Beagle dogs are a key nonrodent species in nonclinical safety evaluation of new biomedical products. The Society of Toxicologic Pathology (STP) has published "best practices" recommendations for nervous system sampling in nonrodents during general toxicity studies (Toxicol Pathol 41[7]: 1028-1048, 2013), but their adaptation to the Beagle dog has not been defined specifically. Here we provide 2 trimming schemes suitable for evaluating the unique neuroanatomic features of the dog brain in nonclinical toxicity studies. The first scheme is intended for general toxicity studies (Tier 1) to screen test articles with unknown or no anticipated neurotoxic potential; this plan using at least 7 coronal hemisections matches the STP "best practices" recommendations. The second trimming scheme for neurotoxicity studies (Tier 2) uses up to 14 coronal levels to investigate test articles where the brain is a suspected or known target organ. Collection of spinal cord, ganglia (somatic and autonomic), and nerves for dogs during nonclinical studies should follow published STP "best practices" recommendations for sampling the central (Toxicol Pathol 41[7]: 1028-1048, 2013) and peripheral (Toxicol Pathol 46[4]: 372-402, 2018) nervous systems. This technical guide also demonstrates the locations and approaches to collecting uncommonly sampled peripheral nervous system sites.

Transient chemotherapy-induced alopecia after successful reversal of 5-fluorouracil myelosuppression and neurotoxicosis in a 9-month-old dog.

BACKGROUND: 5-Fluorouracil (5-FU) cream is a common human topical chemotherapy agent with potentially fatal neurotoxic effects on dogs if accidentally ingested. There are seldom reports in veterinary literature describing the successful outcome of intervention after accidental ingestion of 5-FU cream. CASE SUMMARY: A 9-month-old spayed female labradoodle presented 14 h after ingesting an unknown amount of 40 g tube of Efudex cream (5% 5-FU). The dog presented in status epilepticus, which was managed with benzodiazepines and levetiracetam in conjunction with induced coma and mechanical ventilation. No further seizure activity occurred throughout the ensuing 5 days of hospitalisation; however, myelosuppression was featured. The dog was discharged home after 5 days of hospitalisation. Three days post discharge, the dog was noted to develop focal alopecia around the eyes and temporal region. 14 days after discharge, the alopecia progressed to a majority of the head and body. CONCLUSION: To the authors' knowledge, this is the first report that documents the enduring adverse effects of 5-FU cream after survival of the initial episode, including an earlier onset of myelosuppression and diffuse alopecia. Successful treatment of accidental 5-FU ingestion is possible several hours after the initial event with minimal long-term consequences.

Interactive effects of freshwater acidification and selenium pollution on biochemical changes and neurotoxicity in Oreochromis mossambicus.

Effect of selenium and acidification in freshwater environment was assessed solitary but no reports are available on the impacts of both factors act together. In the present study, effects of combined simultaneous exposure to selenium (Se) and low pH were assessed in Mozambique tilapia, Oreochromis mossambicus. Responses were measured based on antioxidant defenses (enzymatic SOD, CAT, GPx and non-enzymatic GSH), biotransformation enzyme (GST), metallothionein levels (MT), oxidative damage (LPO, CP), Na+/K+-ATPase (NKA) activity in gills and liver tissues and neurotoxicity (acetylcholinesterase, AChE) response in brain tissue. Fish were exposed to combined treatment at different pH levels (7.5, control (optimum pH for tilapia growth); 5.5, low pH) and Se concentrations (0, 10, and 100 µg L-1). Toxicity levels of Se were not significantly different under control and low pH indicating that pH did not affect Se toxicity. Levels of GSH and MT were enhanced in Se-exposed fish at both pH. Combined effects of high Se concentration and low pH decreased SOD and CAT activities and increased those of GPx and GST. However, organisms were not able to prevent cellular damage (LPO and CP), indicating a condition of oxidative stress. Furthermore, inhibition of Na+/K+-ATPase activity was showed. Additionally, neurotoxicity effect was observed by inhibition of cholinesterase activity in organisms exposed to Se at both pH conditions. As a result, the combined stress of selenium and freshwater acidification has a slight impact on antioxidant defense mechanisms while significantly inhibiting cholinesterase and Na+/K + -ATPase activity in fish. The mechanisms of freshwater acidification mediating the toxic effects of trace non-metal element on freshwater fish need to investigate further.

Cadmium chloride-induced transgenerational neurotoxicity in zebrafish development.

As an important environmental pollutant, the heavy metal cadmium has a significant negative impact on the stability of the ecological environment and on organismal health. Previous studies have shown that cadmium chloride can damage the nervous, skeletal, endocrine, and reproductive systems, but to our knowledge, the effects of cadmium on the behavior, neurotransmitter levels, and neuronal development in the offspring of exposed animals have not been reported. In the present study, sexually-mature zebrafish were exposed to cadmium chloride at different concentrations for 60 days, and in this background, behavior, neurotransmitters level, neuro-development and neurotransmitter metabolism was investigated in the F1 offspring. The results showed that exposure of the parental zebrafish to cadmium chloride resulted swimming speed and distance of F1 offspring significantly reduced; the levels of neurotransmitters, such as dopamine, serotonin, and acetylcholine is disrupted. neuro-development and neurotransmitter metabolism related genes expression pattern was altered, which cause zebrafish F1 offspring developmental neurotoxicity. These findings provide further insights into the harm posed by cadmium chloride to the aquatic ecosystems.

Developmental Neurotoxicity of the Harmful Algal Bloom Toxin Domoic Acid: Cellular and Molecular Mechanisms Underlying Altered Behavior in the Zebrafish Model.

BACKGROUND: Harmful algal blooms (HABs) produce potent neurotoxins that threaten human health, but current regulations may not be protective of sensitive populations. Early life exposure to low levels of the HAB toxin domoic acid (DomA) produces long-lasting behavioral deficits in rodent and primate models; however, the mechanisms involved are unknown. The zebrafish is a powerful in vivo vertebrate model system for exploring cellular processes during development and thus may help to elucidate mechanisms of DomA developmental neurotoxicity. OBJECTIVES: We used the zebrafish model to investigate how low doses of DomA affect the developing nervous system, including windows of susceptibility to DomA exposure, structural and molecular changes in the nervous system, and the link to behavioral alterations. METHODS: To identify potential windows of susceptibility, DomA (0.09-0.18 ng) was delivered to zebrafish through caudal vein microinjection during distinct periods in early neurodevelopment. Following exposure, structural and molecular targets were identified using live imaging of transgenic fish and RNA sequencing. To assess the functional consequences of exposures, we quantified startle behavior in response to acoustic/vibrational stimuli. RESULTS: Larvae exposed to DomA at 2 d postfertilization (dpf), but not at 1 or 4 dpf, showed consistent deficits in startle behavior at 7 dpf, including lower responsiveness and altered kinematics. Similarly, myelination in the spinal cord was disorganized after exposure at 2 dpf but not 1 or 4 dpf. Time-lapse imaging revealed disruption of the initial stages of myelination. DomA exposure at 2 dpf down-regulated genes required for maintaining myelin structure and the axonal cytoskeleton. DISCUSSION: These results in zebrafish reveal a developmental window of susceptibility to DomA-induced behavioral deficits and identify altered gene expression and disrupted myelin structure as possible mechanisms. The results establish a zebrafish model for investigating the mechanisms of developmental DomA toxicity, including effects with potential relevance to exposed sensitive human populations. https://doi.org/10.1289/EHP6652.

Mass Occurrence of Anatoxin-a- and Dihydroanatoxin-a-Producing Tychonema sp. in Mesotrophic Reservoir Mandichosee (River Lech, Germany) as a Cause of Neurotoxicosis in Dogs.

In August 2019, three dogs died after bathing in or drinking from Mandichosee, a mesotrophic reservoir of the River Lech (Germany). The dogs showed symptoms of neurotoxic poisoning and intoxication with cyanotoxins was considered. Surface blooms were not visible at the time of the incidents. Benthic Tychonema sp., a potential anatoxin-a (ATX)-producing cyanobacterium, was detected in mats growing on the banks, as biofilm on macrophytes and later as aggregations floating on the lake surface. The dogs' pathological examinations showed lung and liver lesions. ATX and dihydroanatoxin-a (dhATX) were detected by LC-MS/MS in the stomachs of two dogs and reached concentrations of 563 and 1207 µg/L, respectively. Anatoxins (sum of ATX and dhATX, ATXs) concentrations in field samples from Mandichosee ranged from 0.1 µg/L in the open water to 68,000 µg/L in samples containing a large amount of mat material. Other (neuro)toxic substances were not found. A molecular approach was used to detect toxin genes by PCR and to reveal the cyanobacterial community composition by sequencing. Upstream of Mandichosee, random samples were taken from other Lech reservoirs, uncovering Tychonema and ATXs at several sampling sites. Similar recent findings emphasize the importance of focusing on the investigation of benthic toxic cyanobacteria and applying appropriate monitoring strategies in the future.

Neurotoxic Plants that Poison Livestock.

In the western United States, poisonous plants most often affect grazing livestock, and the related livestock losses are estimated to cost the grazing livestock industry more than $200 million annually. Many of these toxic plants contain neurotoxins that damage or alter the function of neurologic cells in the central and peripheral nervous systems. The objectives of this article are to present common North American neurotoxic plants, including conditions of poisoning, clinical disease, pathologic changes, and available diagnostics, to identify poisoned animals and the potential prognosis for poisoned animals.

Memory state and hippocampal histomorphology in Wistar rat following monosodium glutamate-induced neurotoxicity; role of aqueous extract of Aloe Barbadensis

This study assessed the effect of varying doses of aqueous extract of Aloe barbadensis on the cellular changes of hippocampal cells, oxidative and memory state of Wistar rats following monosodium glutamate-induced neurotoxicity. Eighty Wistar rats (8 weeks) were randomly as-signed into 4 groups of 20 rats; Group 1 received 3 mL/kg of distilled water. Groups 2, 3 and 4 received 3 g/kg/day of MSG. In addition, groups 3 and 4 received 100 and 200 mg/kg/day of AB ex-tract respectively. Administration was done orally for 28 days in all groups. Five rats per group were sacrificed weekly over a 4-week period. Memory was assessed using radial arm maze on the last day of administration. Following brain harvest, one cerebral hemisphere was homogenized for oxidative state assessment, while the other was fixed in 10% neutral buffered formalin and stained with H&E for hippocampal histomorphology. Data obtained were analyzed using student t-test and p value < 0.05 was considered significant. Across the 4-week period, group 2 rats showed significant increase in time spent to identify baited arms, significant reduction in density of apparentlynormal neurons and oligodendrocyte in CA 1-3 regions of hippocampus, and significant increase in reduced glutathione when compared with other groups. However, no significant differences were noted between groups 1, 3 and 4 for the above stated parameters. The study concluded that MSG caused hippocampal neuronal and oligodendrocytes degeneration and impairment of memory. These anomalies are prevented by 100 and 200 mg/kg of Aloe barbadensis

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Neurolathyrism in goat (Capra hircus) kid: Model development.

The present study was undertaken to develop an animal model to study neurolathyrism. For this purpose 24 goat (Capra hircus) kids (new born, 15 days old) were divided into four groups. Group I Control, Group II Low toxin (0.17 g% ß-ODAP containing grass pea), Group III high toxin (0.96 g% ß-ODAP containing grass pea) and Group IV high toxin (0.96 g% ß-ODAP containing grass pea flour (powder) fortified with 5 mg% pure ß-ODAP). The experiment was continued for 3 months. Clinical examination was carried out weekly. Muscle conduction velocity (MCV), nerve conduction velocity (NCV), blood and urinary ß-ODAP, nitrite in blood and cerebrospinal fluid (CSF) examination were performed by standard methods. Clinical examination showed neurolathyrism symptoms in three kids. The abnormal MCV and NCV were observed in all the experimental animals. Blood nitrite, blood and urine ß-ODAP levels were significantly increased in experimental groups. Three kids were affected with neurolathyrism due to consumption of grass pea irrespective of its ß-ODAP content and kid may serve as a neurolathyrism model.

Tremorgenic syndrome caused by Ipomoea pes caprae in cattle / Síndrome tremorgênica causada pela ingestão de Ipomoea pes caprae em bovinos

Poisonous plants are a significant cause of death among adult cattle in Brazil. Plants that affect the central nervous system are widely spread throughout the Brazilian territory and comprise over 30 toxic species, including the genus Ipomoea, commonly associated with a lysosomal storage disease and a tremorgenic syndrome in livestock. We describe natural and experimental Ipomoea pes caprae poisoning in cattle from a herd in the Northside of Rio de Janeiro, Brazil. Affected cattle presented episodes of severe ataxia, abnormal posture followed by falling, muscular tremor, contraction, and spasticity, more prominent in the limbs, intensified by movement and forthcoming, and recumbence. Grossly, a substantial amount of leaves and petioles were found in the rumen. Histopathological examination showed degenerative neuronal changes, mostly in cerebellar Purkinje cells, which were confirmed with Bielschowsky silver. The characteristic clinical changes and mild histological lesion strongly suggested a tremorgenic syndrome. Lectin- immunohistochemistry evaluation reinforced this hypothesis; all lectins tested failed to react with affect neurons and Purkinje cells, which ruled out an underlying lysosomal storage disease. One calf given I. pes caprae leaves experimentally developed clinical signs similar to natural cases. On the 28th day of the experiment, the plant administration was suspended, and the calf recovered within four days. I. pes caprae's spontaneous tremorgenic syndrome in cattle is conditioned to exclusive feeding for several months. We were able to experimentally reproduce toxic clinical signs 12 days following the ingestion.(AU)

A intoxicação por plantas tóxicas está entre as três causas de morte mais importantes em bovinos adultos no Brasil. O grupo das plantas que causam alterações neurológicas, muito bem representada no país, encerra mais de trinta espécies tóxicas, entre as quais do gênero Ipomoea, amplamente distribuídas no território brasileiro. As plantas tóxicas desse gênero podem causar doenças do armazenamento ou síndrome tremorgênica. Descrevem-se a intoxicação natural e reprodução experimental por Ipomoea pes caprae em bovinos, verificada no norte do Estado do Rio de Janeiro. Foram observados episódios de intensa ataxia locomotora, postura anormal seguida de queda, incapacidade de levantar-se, tremores, contrações, espasticidades musculares nos membros, intensificados após estimulação ou a simples aproximação e decúbito. Nos bovinos afetados há mais de 6 meses, os sinais clínicos tornavam-se permanentes. À necropsia havia apenas significativa quantidade de folhas e pecíolos da planta no rúmen. O estudo histopatológico evidenciou lesões neuronais degenerativas principalmente nos neurônios de Purkinje. A impregnação argêntica pela técnica de Bielschowsky ratificou esses achados microscópicos. As lesões histológicas sutis associadas ao quadro clínico indicam que trata-se de intoxicação tremorgênica. O fato de não haver nenhum armazenamento intracitoplasmático, confirmado pelo resultado do estudo lectino-histoquímico (não houve afinidade das lectinas Con-A, WGA e sWGA e de outras lectinas empregadas aos neurônios de Purkinje e outros neurônios afetados), é suficiente para descartar a possibilidade de tratar-se de doença do armazenamento. No bezerro intoxicado experimentalmente verificaram-se sinais clínicos semelhantes, entretanto, com a interrupção do fornecimento da planta no 28º dia, os sinais clínicos desapareceram após quatro dias. I. pes caprae causa síndrome tremorgênica espontânea em bovinos, quando ingerida como alimentação exclusiva durante períodos prolongados (muitos meses). Experimentalmente, os primeiros sinais clínicos da intoxicação foram reproduzidos após 12 dias de ingestão da planta.(AU)

Impacts of nanoplastics on bivalve: Fluorescence tracing of organ accumulation, oxidative stress and damage.

The outcomes of this research offer novel insights into the toxic effects of nanoparticles (i.e., nanoplastics or other nanomaterials) on the benthos. Herein, this study aimed to evaluate the accumulation pathway, distribution characteristics and potential biotoxicity of polystyrene nanoplastics in C. fluminea. The results revealed that nanoplastics could accumulate in the mantle through adherence, in the visceral mass through ingestion and in the gill through respiration. The gill, intestine and stomach were the main accumulation organs for nanoplastics. The aggregation of nanoplastics was observed in C. fluminea, which may exacerbate their biotoxicity. Moreover, oxidative stress was observed in the visceral mass, gill and mantle. Liver damage, neurotoxicity and intestinal inflammation were caused by imbalance in the antioxidation system. Analysis of IBR values showed that the visceral mass had a more effective response to oxidative stress than the gill and mantle after exposure to nanoplastics.

Approaches for a field diagnosis of abamectin poisoning in calves / Abordagem para um diagnóstico a campo da intoxicação por abamectina em bezerros

An approach for the diagnosis of an abamectin outbreak in calves in the field is described and discussed. In a Midwestern Brazilian property, nine out of a 52 newborn calves were affected and died, making up for morbidity, mortality, and lethality ratios of 17.3%, 17.3%, and 100%, respectively. Major clinical signs included tremors in various muscle groups, inability to stand, and difficult, wheezing breathing. Each affected calf had been treated subcutaneously with abamectin (0.4mg/kg/body weight). No lesions were found at necropsy or at histological examination. Major diseases of newborn calves were included in the differential diagnosis.(AU)

Uma abordagem para o diagnóstico de um surto de abamectina em bezerros a campo é descrita e discutida. Numa propriedade do Centro-Oeste brasileiro, nove de um lote de 52 bezerros de 3 dias de idade foram afetados e morreram, perfazendo quocientes de morbidade, mortalidade e letalidade, respectivamente, de 17,3%, 17,3% e 100%. Os principais sinais clínicos incluíam tremores em vários grupos musculares, incapacidade em se manter em pé, e respiração difícil e estertorosa. Cada bezerro afetado havia sido tratado por via subcutânea com abamectina, na dose de 0,4mg/kg/peso corporal. Não foram encontradas lesões na necropsia, nem no exame histológico. As principais doenças de bezerros recém-nascidos foram incluídas no diagnóstico diferencial.(AU)

Avaliação neurocomportamental e níveis de acetilcolinesterase cerebral em ratos expostos subcronicamente ao fipronil / Neurobehavioral assessment and brain acetylcholinesterase levels in rats subchronically exposed to fipronil

O fipronil é um inseticida de toxicidade seletiva amplamente empregado na agricultura e na medicina veterinária. Porém, há relatos de efeitos neurotóxicos dessa substância, que geram prejuízos para vertebrados. Avaliou-se a atividade locomotora, a coordenação motora e a atividade da enzima acetilcolinesterase cerebral em ratos expostos ao fipronil. Ratos Wistar machos adultos (n=15) receberam fipronil em dose de 30mg/kg, por via oral, durante 15 dias; o grupo controle (n=15) foi tratado com solução fisiológica, por via oral, no mesmo período. No 16° dia de experimentação, os animais foram submetidos aos testes de arena de campo aberto e hole board. No 17° dia, foram anestesiados e eutanasiados, procedendo-se à coleta de órgãos, e posteriormente foi feita a avaliação da AChE cerebral. A exposição ao fipronil não provocou alterações significativas sobre a coordenação motora e a atividade locomotora, porém gerou inibição significativa da atividade da acetilcolinesterase cerebral. Esses achados sugerem que o fipronil pode provocar efeitos neurotóxicos em curto prazo, os quais podem ser exacerbados caso a exposição seja prolongada.(AU)

Fipronil is a selective-toxicity insecticide widely used in agriculture and veterinary medicine. However, there are reports of neurotoxic effects of this substance, causing damages to vertebrates. We evaluated the locomotor activity, motor coordination and the activity of brain acetylcholinesterase in rats exposed to fipronil. Adult male Wistar rats (n= 15) received fipronil at a dose of 30mg/kg orally for 15 days; the Control group (n= 15) was treated with oral solution in the same period. On the 16th day of experimentation, the animals were submitted to the open field arena test and hole-board test. On the 17th day, they were anesthetized and euthanized, and organs were collected, and subsequently brain AChE was evaluated. Exposure to fipronil yielded no significant changes on motor coordination and locomotor activity but caused significant inhibition of brain acetylcholinesterase activity. These findings suggest that fipronil may cause short-term neurotoxic effects, which may be exacerbated if exposure is prolonged.(AU)

Neurotoxicity, Behavior, and Lethal Effects of Cadmium, Microplastics, and Their Mixtures on Pomatoschistus microps Juveniles from Two Wild Populations Exposed under Laboratory Conditions-Implications to Environmental and Human Risk Assessment.

Microplastics (MPs) were found to modulate the toxicity of other pollutants but the knowledge on the topic is still limited. The goals of this study were to investigate the short-term toxicity of cadmium (Cd) to wild Pomatochistus microps juveniles, the potential modulation of acute Cd toxicity by 1-5 µm polyethylene MPs in this species, and possible differences of sensitivity to Cd and MPs-Cd mixtures between juveniles from two distinct wild populations. Juveniles were collected in the estuaries of Minho (M-est) and Lima (L-est) Rivers (NW Portugal). One 96 h bioassay with M-est juveniles and another one with L-est juveniles were carried out in laboratory conditions. Each bioassay had 12 treatments: control, 5 Cd concentrations, 1 MPs concentration, and 5 MPs-Cd mixtures. No significant differences in Cd-induced mortality between juveniles from distinct estuaries or between juveniles exposed to Cd alone and those exposed to MPs-Cd mixtures were found. The total 96h LC10 and LC50 of Cd alone were 2 mg/L (95% CI: 0-4 mg/L) and 8 mg/L (95% CI: 2-17 mg/L), respectively. Cd alone significantly decreased the post-exposure predatory performance (PEPP) of M-est (≥6 mg/L) and L-est juveniles (≥3 mg/L), and acetylcholinesterase (AChE) activity of M-est juveniles (13 mg/L). MPs alone (0.14 mg/L) significantly reduced the PEPP and AChE activity of L-est juveniles but not of M-est juveniles. MPs-Cd mixtures (3-13 mg/L of Cd + 0.14 mg/L of MPs) significantly inhibited the PEPP of juveniles from both estuaries and AChE of L-est estuary juveniles but not of M-est juveniles. Evidences of toxicological interactions, namely antagonism, between MPs and Cd were found. Overall, the results indicate that MPs modulated the sub-lethal toxic effects of Cd in wild P. microps juveniles, especially neurotoxicity. Moreover, the environmental conditions of the natural habitats to which juveniles were exposed during pre-developmental phases influence the sub-lethal toxicity of Cd, MPs, and their mixtures. The implications to environmental and human risk assessment are discussed and further research is needed.

Differential role of dose and environment in initiating and intensifying neurotoxicity caused by MDMA in rats.

BACKGROUND: MDMA causes serotonin (5-HT) syndrome immediately after administration and serotonergic injury in a few days or weeks. However, a serotonin syndrome is not always followed by serotonergic injury, indicating different mechanisms responsible for two adverse effects. The goal of present study was to determine causes for two adverse events and further test that dose and environment have a differential role in initiating and intensifying MDMA neurotoxicity. METHODS: Initiation and intensification were examined by comparing neurotoxic effects of a high-dose (10 mg/kg × 3 at 2 h intervals) with a low-dose (2 mg/kg × 3) under controlled-environmental conditions. Initiation of a serotonin syndrome was estimated by measuring extracellular 5-HT, body-core temperature, electroencephalogram and MDMA concentrations in the cerebrospinal fluid, while intensification determined in rats examined under modified environment. Initiation and intensification of the serotonergic injury were assessed in rats by measuring tissue 5-HT content, SERT density and functional integrity of serotonergic retrograde transportation. RESULTS: Both low- and high-dose could cause increases in extracellular 5-HT to elicit a serotonin syndrome at the same intensity. Modification of environmental conditions, which had no impact on MDMA-elicited increases in 5-HT levels, markedly intensified the syndrome intensity. Although either dose would cause the severe syndrome under modified environments, only the high-dose that resulted in high MDMA concentrations in the brain could cause serotonergic injury. CONCLUSION: Our results reveal that extracellular 5-HT is the cause of a syndrome and activity of postsynaptic receptors critical for the course of syndrome intensification. Although the high-dose has the potential to initiate serotonergic injury due to high MDMA concentrations present in the brain, whether an injury is observed depends upon the drug environment via the levels of reactive oxygen species generated. This suggests that brain MDMA concentration is the determinant in the injury initiation while reactive oxygen species generation associated with the injury intensification. It is concluded that the two adverse events utilize distinctly different mediating molecules during the toxic initiation and intensification.

Dose-dependent neuroprotective effect of oriental phyto-derived glycyrrhizin on experimental neuroterminal norepinephrine depletion in a rat brain model.

The dose-dependent neuroprotective role of licorice-derived glycyrrhizin during subacute neuroterminal norepinephrine (NE) depletion was studied in rat brain. Experimental design included thirty 5-week-old male rats randomly divided into five groups. Compared to the saline-injected control group, the group receiving daily intraperitoneal injection of fusaric acid (FA; 5 mg/kg/b.w.) for 30 days showed pharmacological depletion of NE. The neuroprotective effects of three successively increasing oral doses of glycyrrhizin were examined in FA-treated rats. Neurochemical parameters and histo-/immunohistopathological changes in the hippocampus were examined. FA generated global hippocampal stress with altered neurobiochemical parameters, accompanied by immune-confirmed inflammatory tissue damage, and noticeable behavioral changes. Although glycyrrhizin after FA-induced intoxication did not correct the recorded drop in the NE level, it decreased the dopamine levels to control levels. Similarly, glycyrrhizin at a high dose restored the serotonin level to its normal value and blocked the FA-induced increase in the level of its metabolite, 5-hydroxyindoleacetic acid. The FA-induced rise in γ-aminobutyric acid (GABA) and histamine was alleviated after administration of a high dose of glycyrrhizin. This was accompanied by improvements in the bioenergetic status and neuronal regenerative capacity through recovery of ATP and brain-derived neurotrophic factor levels to the pre-intoxicated values. High doses of glycyrrhizin also ameliorated the FA-generated behavioral changes and oxidative damage, manifested by the reduction in the expression of cortical pro-apoptotic caspase 3 in the same group. This study suggests that glycyrrhizin can potentially mend most of the previously evoked neuronal damage induced by FA intoxication in the brain of an experimental rat model.

Lethality, neurotoxicity, morphological, histological and cellular alterations of Ni-Al nanoceramics on the embryo-larval development of Rhinella arenarum.

Alumina nanoparticles (NP-Al2O3) are widely used but their environmental effects are unknown, so they can become potentially dangerous. The aim of this study was to evaluate the toxicity of a nanoceramic catalyst Ni/γ-Al2O3 (NC) and NPs involved in their synthesis, γ-Al2O3 support (SPC) and NiO/γ-Al2O3 precursor (PC) on Rhinella arenarum embryo-larval development. The NPs toxicity significantly increased over time obtaining a similar sensitivity to PC and NC (336 h-LC50 = 4.03 and 5.11 mg/L respectively) and very low sensitivity to SPC (336 h-LC50 = 90.83 mg/L). Embryos exposed to SPC and PC exhibited general underdevelopment, axial flexures and behavioral alterations. Pharyngeal and intestinal epithelia alterations at the level of cell surface as dissociation, apoptosis and numerous lysosomes were observed at light and transmission electronic microscopy. Images of scanning electron microscope with backscattered electron detector revealed the presence of nickel in the intestinal epithelium. The increased toxicity of PC could be due to the presence of Ni as oxide which could interfere with vital functions such as breathing and feeding. Taking into account the exponential production and use of these NPs it is expected that their pollution levels will considerably increase and amphibians will be more exposed and at higher risk.

Toxic effects of lead exposure on bioaccumulation, oxidative stress, neurotoxicity, and immune responses in fish: A review.

Lead (Pb) is a highly toxic metal in aquatic environments. Fish are at the top of the food chain in most aquatic environments, and are the most susceptible to the toxic effects of Pb exposure. In addition, fish are one of the most abundant vertebrates, and they can directly affect humans through food intake; therefore, fish can be used to assess the extent of environmental pollution in an aquatic environment. Pb-induced toxicity in fish exposed to toxicants is primarily induced by bioaccumulation in specific tissues, and the accumulation mechanisms vary depending on water habitat (freshwater or seawater) and pathway (waterborne or dietary exposure). Pb accumulation in fish tissues causes oxidative stress due to excessive ROS production. Oxidative stress by Pb exposure induces synaptic damage and neurotransmitter malfunction in fish as neurotoxicity. Moreover, Pb exposure influences immune responses in fish as an immune-toxicant. Therefore, the purpose of this review was to examine the various toxic effects of Pb exposure, including bioaccumulation, oxidative stress, neurotoxicity, and immune responses, and to identify indicators to evaluate the extent of Pb toxicity by based on the level of Pb exposure.

Mechanisms of engineered nanoparticle induced neurotoxicity in Caenorhabditis elegans.

The wide-spread implementation of nanoparticles poses a major health concern. Unique biokinetics allow them to transfer to neurons throughout the body and inflict neurotoxicity, which is challenging to evaluate solely in mammalian experimental models due to logistics, financial and ethical limitations. In recent years, the nematode Caenorhabditis elegans has emerged as a promising nanotoxicology experimental surrogate due to characteristics such as ease of culture, short life cycle and high number of progeny. Most importantly, this model organism has a well conserved and fully described nervous system rendering it ideal for use in neurotoxicity assessment of nanoparticles. In that context, this mini review aims to summarize the main mechanistic findings on nanoparticle related neurotoxicity in the setting of Caenorhabditis elegans screening. The injury pathway primarily involves changes in intestinal permeability and defecation frequency both of which facilitate translocation at the site of neurons, where toxicity formation is linked partly to oxidative stress and perturbed neurotransmission.