Acrylamide acute neurotoxicity in adult zebrafish

Un articulo indexadoAcute exposure to acrylamide (ACR), a type-2 alkene, may lead to a ataxia, skeletal muscles weakness and numbness of the extremities in human and laboratory animals. In the present manuscript, ACR acute neurotoxicity has been characterized in adult zebrafish, a vertebrate model increasingly used in human neuropharmacology and toxicology research. At behavioral level, ACR-treated animals exhibited “depression-like” phenotype comorbid with anxiety behavior. At transcriptional level, ACR induced down-regulation of regeneration-associated genes and up-regulation of oligodendrocytes and reactive astrocytes markers, altering also the expression of genes involved in the presynaptic vesicle cycling. ACR induced also significant changes in zebrafish brain proteome and formed adducts with selected cysteine residues of specific proteins, some of them essential for the presynaptic function. Finally, the metabolomics analysis shows a depletion in the monoamine neurotransmitters, consistent with the comorbid depression and anxiety disorder, in the brain of the exposed fish.Conacy

A Zebrafish Model of Neurotoxicity by Binge-Like Methamphetamine Exposure

Hyperthermia is a common confounding factor for assessing the neurotoxic effects of methamphetamine (METH) in mammalian models. The development of new models of methamphetamine neurotoxicity using vertebrate poikilothermic animals should allow to overcome this problem. The aim of the present study was to develop a zebrafish model of neurotoxicity by binge-like methamphetamine exposure. After an initial testing, zebrafish was exposed to 40 mg/L of METH for 48h, and the effects on the brain monoaminergic profile, locomotor, anxiety-like and social behaviors as well as on the expression of key genes of the catecholaminergic system were determined. A concentration- and time-dependent decrease in the brain levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) was found in METH-exposed fish. A significant hyperactivity was found during the first hour of exposure followed 3h after by a positive geotaxis and negative scototaxis in the novel tank and in the light/dark paradigm, respectively. Moreover, the behavioral phenotype in the treated fish was consistent with social isolation. At transcriptional level, th1 and slc18a2 (vmat2) exhibited a significant increase after 3h of exposure, whereas the expression of gfap, a marker of astroglial response to neuronal injury, was strongly increased after 48h exposure. However, no evidences of oxidative stress were found in the brain of the treated fish. Altogether, this study demonstrates the suitability of the adult zebrafish as a model of METH-induced neurotoxicity and provides more information about the biochemical and behavioral consequences of METH abuse

Zwitterionic self-assembled nanoparticles as carriers for Plasmodium targeting in malaria oral treatment

© 2021 Elsevier B.V. The current decline in antimalarial drug efficacy due to the evolution of resistant Plasmodium strains calls for new strategies capable of improving the bioavailability of antimalarials, especially of those whose lipophilic character imparts them a low solubility in biological fluids. Here we have designed, synthesized and characterized amphiphilic zwitterionic block copolymers forming nanoparticles capable of penetrating the intestinal epithelium that can be used for oral administration. Poly(butyl methacrylate-co-morpholinoethyl sulfobetaine methacrylate) (PBMA-MESBMA)-based nanoparticles exhibited a specific targeting to Plasmodium falciparum-infected vs. parasite-free red blood cells (74.8%/0.8% respectively), which was maintained upon encapsulation of the lipophilic antimalarial drug curcumin (82.6%/0.3%). The in vitro efficacy of curcumin upon encapsulation was maintained relative to the free compound, with an IC50 around 5 μM. In vivo assays indicated a significantly increased curcumin concentration in the blood of mice one hour after being orally fed PBMA-MESBMA-curcumin in comparison to the administration of free drug (18.7 vs. 2.1 ng/ml, respectively). At longer times, however, plasma curcumin concentration equaled between free and encapsulated drug, which was reflected in similar in vivo antimalarial activities in Plasmodium yoelii yoelii-infected mice. Microscopic analysis in blood samples of fluorescently labeled PBMA-MESBMA revealed the presence of the polymer inside P. yoelii yoelii-parasitized erythrocytes one hour after oral administration to infected animals

Repeated administration of N-ethyl-pentedrone induces increased aggression and impairs social exploration after withdrawal in mice

N-ethyl-pentedrone (NEPD, 2-(ethylamino)-1-phenyl-1-pentanone) is one of the latest synthetic cathinone derivatives that emerged into the illicit drug market. This drug has psychostimulant properties and has been related with several intoxications and even fatalities. However, information about the consequences of its acute and repeated consumption is lacking. Thus, the aim of our study was to investigate the behavioral effects after both acute and repeated NEPD exposure as well as the neurochemical changes. Male OF1 mice were treated with an acute dose (1, 3 or 10 mg/kg, i.p.) or received repeated injections of these doses (twice/day, 5 days) of NEPD. Shortly after drug-exposure or during drug-withdrawal, anxiety-like behavior, aggressiveness, social interaction, depressive-like symptoms, body weight and temperature were assessed. Also, monoamine synthesis enzymes, levels of neurotransmitters and their precursors and main metabolites, as well as ΔFosB, were determined in striatum and prefrontal cortex from post-mortem tissue. Acute administration of NEPD induced anxiolytic effects and reduced social exploration whereas during withdrawal after repeated administration the anxiolytic effect had vanished, and the reduced social exploration was still present and accompanied with increased aggressive behavior. Moreover, NEPD (10 mg/kg) induced slight hyperthermia and reduced weight gain during the repeated administration, whereas increased locomotor activity and lack of depressive symptoms were found during withdrawal. This was accompanied by increased plasma corticosterone and decrease in striatal dopamine. Finally, the long-lasting and robust increase in ΔFosB levels found in striatum after NEPD chronic exposure suggests a high risk of dependence. The increased aggressivity and locomotor activity, together with this potential of inducing dependence justify a warning about the risks of consumption of NEPD if translated to humans. Keywords: Addiction; Aggressive behavior; Monoamine levels; N-ethyl-pentedrone; Synthetic cathinones

Androgenic activation, impairment of the monoaminergic system and altered behavior in zebra!sh larvae exposed to environmental concentrations of fenitrothion

Artículo indizadoFenitrothion is an organophosphorus insecticide usually found in aquatic ecosystems at concentrations in the range of low ng/L. In this manuscript we show that 24 h exposure to environmental concentrations of fenitro- thion, from ng/L to low !g/L, altered basal locomotor activity, visual-motor response and acoustic/vibrational es- cape response of zebra!sh larvae. Furthermore, fenitrothion and expression of gap43a, gfap, atp2b1a, and mbp exhibited a signi!cant non-monotonic concentration-response relationship. Once determined that environmen- tal concentrations of fenitrothion were neurotoxic for zebra!sh larvae, a computational analysis identi!ed poten- tial protein targets of this compound. Some of the predictions, including interactions with acetylcholinesterase, monoamine-oxidases and androgen receptor (AR), were experimentally validated. Binding to AR was the most suitable candidate for molecular initiating event, as indicated by both the up-regulation of cyp19a1b and sult2st3 and the non-monotonic relationship found between fenitrothion and the observed responses. Finally, when the integrity of the monoaminergic system was evaluated, altered levels of L-DOPA, DOPAC, HVA and 5-HIAA were found, as well as a signi!cant up-regulation of slc18a2 expression at the lowest concentrations of fenitrothion. These data strongly suggest that concentrations of fenitrothion commonly found in aquatic ecosystems present a signi!cant environmental risk for !sh communities.This work was supported by the Spanish Government with FEDER Funds (CTM2017-83242-R; D.R.) and the net- work of recognized research groups by the Catalan Government (2017 SGR_902)

Therapeutic potential of N-acetylcysteine in acrylamide acute neurotoxicity in adult zebrafish

Two essential key events in acrylamide (ACR) acute neurotoxicity are the formation of adducts with nucleophilic sulfhydryl groups on cysteine residues of selected proteins in the synaptic terminals and the depletion of the glutathione (GSx) stores in neural tissue. The use of N-acetylcysteine (NAC) has been recently proposed as a potential antidote against ACR neurotoxicity, as this chemical is not only a well-known precursor of the reduced form of glutathione (GSH), but also is an scavenger of soft electrophiles such as ACR. In this study, the suitability of 0.3 and 0.75 mM NAC to protect against the neurotoxic effect of 0.75 mM ACR has been tested in vivo in adult zebrafish. NAC provided only a mild to negligible protection against the changes induced by ACR in the motor function, behavior, transcriptome and proteome. The permeability of NAC to cross blood-brain barrier (BBB) was assessed, as well as the ACR-scavenging activity and the gamma-glutamyl-cysteine ligase (γ-GCL) and acylase I activities. The results show that ACR not only depletes GSx levels but also inhibits it synthesis from NAC/cysteine, having a dramatic effect over the glutathione system. Moreover, results indicate a very low NAC uptake to the brain, probably by a combination of low BBB permeability and high deacylation of NAC during the intestinal absorption. These results strongly suggest that the use of NAC is not indicated in ACR acute neurotoxicity treatment.This work was supported by the NATO SfP project MD.SFPP 984777 (D.R.) and the Spanish Government (CTM2017-83242-R; D.R.). M.F acknowledges financial support from the Beatriu de Pinós programme (Grant No. 2016 BP 00233) provided by the Secretariat of Universities and Research department of the Ministry for Business and Knowledge, Catalonia Government. Mention of specific products or trade names does not indicate endorsement by the US federal government.Peer reviewe

Pharmaceuticals released from senior residences: occurrence and risk evaluation

One of the main pursuits, yet most difficult, in monitoring studies is to identify the sources of environmental pollution. In this study, we have identified health-care facilities from south European countries as an important source of pharmaceuticals in the environment. We have estimated that compounds consumed in by the elderly and released from effluents of senior residences can reach river waters at a concentration higher than 0.01 μg/L, which is the European Medicines Agency (EMA) threshold for risk evaluation of pharmaceuticals in surface waters. This study has been based on five health institutions in Portugal, Spain, and France, with 52 to 130 beds. We have compiled the pharmaceuticals dispensed on a daily base and calculated the consumption rates. From 54.9 to 1801 g of pharmaceuticals are consumed daily, with laxatives, analgesics, antiepileptics, antibiotics, and antidiabetic agents being the main drug families administered. According to excretion rates, dilution in the sewerage system, and elimination in wastewater treatment plants, macrogol, metformin, paracetamol, acetylcysteine, amoxicillin, and gabapentin, among others, are expected to reach river waters. Finally, we discuss the risk management actions related to the discharge of pharmaceuticals from senior residences to surface waters

Residues of Deltamethrin in Pine Needles and Pine Nuts of Catalonia (Spain)

In recent years, recurrent droughts have weakened stone pine (Pinus pinea) forests and facilitated the emergence of harmful pests and diseases, including the Leptoglossus occidentalis. The production of stone pine nuts has declined over the past five years. To control this hemipteran pest, a synthetic pyrethroid insecticide called deltamethrin is being tested. However, it is necessary to estimate the residue left by these treatments in forest stands. Therefore, a fast and robust analytical procedure was developed based on QuEChERS clean-up extraction, followed by gas chromatography coupled with an electron capture detector. This optimized method can detect residual concentrations of deltamethrin in pine nuts and pine needles up to 0.1 and 6 μg kg−1, respectively, with a limit of quantification of 0.4 and 20 μg kg−1. Great recoveries (between 84 and 102%) were obtained for both matrices, and no matrix effect was observed. The results showed that two weeks after spraying, the deltamethrin content in the needles of stone pines decreased by up to 75%, and after nine months, its presence was like that of nontreated trees. Keywords: pine needle; nut; deltamethrin; gas chromatographyThis work was supported by the grants PID2020-113371RA-C22 (C. Gómez) by Science and Innovation Ministry from Spanish Government and PID2019-107483GB-100 (N. Aletà) ‘Making sustainable the Stone pine (Pinus pinea L.) production by its management as nut tree’ (2020–2024) and by the Spanish GOPinea ‘Mejora e Innovación en la Producción del piñón nacional’ (2021–2023) by MICIN.info:eu-repo/semantics/publishedVersio

The role of serotonergic signaling on phototactic and locomotor behavior in Daphnia magna

The role of serotonin in Daphnia magna phototactic and locomotor behavior was assessed using reverse genetics and pharmacological treatments with serotonin and fluoxetine. The study was conducted with four clones: the wild type clone and three CRISPR D. magna ones with mutations in the tryptophan hydrolase gene (TRH) that is involved in serotonin synthesis. These included clones TRHA- and TRHB- with mutations in both alleles that lack serotonin and the mono-allelic mutant TRH+, that has serotonin. Obtained results indicated that animals lacking serotonin showed an increased negative phototactism and locomotor activity upon light stimuli and a reduced response to fish kairomones relative to the wild type and TRH+ individuals. Exposure to exogenous serotonin re-established the phototactism and locomotor activity of TRH- individuals to those of the wild type but did not affect phototactic responses to fish kairomones. Unexpectedly, fluoxetine was able to modify locomotor activity and phototactic behavior against fish kairomones in TRH- individuals lacking serotonin, and also it increased the concentrations of acethylcholine and GABA in exposed animals, which support the argument that fluoxetine may also affect other neurological pathways.This work was supported by the grants PID2020-113371RB-C21, PID2020-113371RA-C22, funded by MCIN/AEI/10.13039/501100011033.Peer reviewe

Aqueous stability and degradation of psychiatric and neuroactive compounds and its biological activity in Daphnia magna

Pharmaceuticals and other emerging contaminants are continuously released into the aquatic environment, considered as 'pseudo-persistent' pollutants. Many compounds degrade fast in the environment, but sometimes their transformation products (TPs) are equally or even more toxic than the parental compounds, raising concern about the potential risks to the environment. In this way, the crustacean Daphnia magna (D. magna) is one of the most widely used organisms in aquatic toxicology studies, since it is an interesting non-vertebrate model to study via neurotransmitters the toxicological consequences of contaminants. In this study, the stability in water of 17 neuroactive compounds using ultra-high-performance liquid chromatography (UHPLC) coupled to a MS/MS detector was evaluated. In order to assess the stability of the compounds, samples of 1 ng μL-1 were analyzed at different times (0, 24 and 48 h). No degradation was observed for most of the studied compounds, except for apomorphine and 6-hydroxydopamine that were degraded completely in the first 24 h. The behavioral assay was based in the automatized delivery of visible light stimuli. Most of the tested compounds altered motile responses to light significantly. The pharmaceuticals memantine, imidacloprid, fluoxetine, deprenyl, diazepam, apomorphine and 6-hydroxydopamine decreased motile responses to light. Conversely, pilocarpine, scopolamine, nicotine and p-chlorophenylalanine increased motile responses. Despite the observed degradation of apomorphine and 6-hydroxydopamine, their degradation products (APO-TP1 and 6OH-TP1) were stable and so their effects on behavior. This study shows that a degradation or transformation of the main pollutant is not always linked to a decrease in its toxicity.The authors thank Ms. Anna Muñoz and Dr. Gemma Gotor, of the Analytical and Applied Chemistry Department in IQS, for their great support in the laboratory.Peer reviewe