The Cyanotoxin 2,4-DAB Reduces Viability and Causes Behavioral and Molecular Dysfunctions Associated with Neurodegeneration in Larval Zebrafish

Exposure to cyanotoxins has been linked to neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer’s, and Parkinson’s disease. While the cyanotoxin β-methylamino-L-alanine (BMAA) has received much attention, cyanobacteria produce many cyanotoxic compounds, several of which have been detected in nature alongside BMAA, including 2,4-diaminobutyric acid (2,4-DAB) and N-(2-aminoethyl)glycine (AEG). Thus, the question of whether 2,4-DAB and AEG also cause neurotoxic effects in vivo is of great interest, as is the question of whether they interact to enhance toxicity. Here, we evaluate the toxic and neurotoxic effects of these cyanotoxins alone or in combination by measuring zebrafish larval viability and behavior after exposure. 2,4-DAB was the most potent cyanotoxin as it decreased larval viability by approximately 50% at 6 days post fertilization, while BMAA and AEG decreased viability by just 16% and 8%, respectively. Although we only observed minor neurotoxic effects on spontaneous locomotion, BMAA and AEG enhanced acoustic startle sensitivity, and they interacted in an additive manner to exert their effects. 2,4-DAB; however, only modulated startle kinematics, an indication of motor dysfunction. To investigate the mechanisms of 2,4-DAB’s effects, we analyzed the protein profile of larval zebrafish exposed to 500 µM 2,4-DAB at two time points and identified molecular signatures consistent with neurodegeneration, including disruption of metabolic pathways and downregulation of the ALS-associated genes SOD1 and UBQLN4. Together, our data demonstrate that BMAA and its isomers AEG and 2,4-DAB cause neurotoxic effects in vivo, with 2,4-DAB as the most potent of the three in the zebrafish model.

TRAIL-R Deficient Mice Are Protected From Neurotoxic Effects of Amyloid-β

TRAIL, a member of TNF superfamily, is a potent inducer of neuronal death. Neurotoxic effects of TRAIL appear mediated by its death receptor TRAIL-R2/DR5. To assess the role of TRAIL/TRAIL-R2 pathway in AD-related neurodegeneration, we studied the impact of the treatment with amyloid-β (Aβ) upon cell viability and inflammation in TRAIL-R-deficient mice (TRAIL-R-/-). Here, we demonstrate that the lack of TRAIL-R2 protects from death cultured TRAIL-R-/- mouse embryonic hippocampal cells undergone treatment with either Aβ1-42 or TRAIL. Consistently, stereotaxic injection of Aβ1-42 resulted in blunted caspase activation, as well as in reduction of JNK phosphorylation and increased AKT phosphorylation in TRAIL-R-/- mice. Moreover, the lack of TRAIL-R2 was associated with blunted constitutive p53 expression in mice undergone Aβ1-42 treatment, as well as in decrease of phosphorylated forms of tau and GSK3β protein. Likewise, TRAIL-R2 appears essential to both TRAIL-Aβ mediated neurotoxicity and inflammation. Indeed, hippocampi of TRAIL-R-/- mice, challenged with Aβ1-42, showed a scanty expression of microglial (Iba-1) and astrocytic (GFAP) markers along with attenuated levels of IL-1β, TNF-a, iNOS and COX2. In conclusion, the bulk of these results demonstrate that the constitutive lack of TRAIL-R2 is associated with a substantial reduction of noxious effects of Aβ1-42, providing further evidence on the prominent role played by TRAIL in course of Aβ-related neurodegeneration and confirming that the TRAIL system represents a potential target for innovative AD therapy.

Impacts of Fluoride Neurotoxicity and Mitochondrial Dysfunction on Cognition and Mental Health: A Literature Review

This review focuses on the synthesis of current experimental and observational data regarding the effect of fluoride exposure on childhood mental health and the role of mitochondrial function as a mechanism of action. We aggregated data on the relationships between fluoride neurotoxicity, mitochondrial function, and cognitive and mental health using PubMed. Current animal and human research suggest that prenatal and perinatal fluoride exposure might have neurotoxic effects. These studies observed physical changes (fur loss and delayed reflex development in animals), intelligence loss, increased hyperactivity, and irregular moods associated with fluoride exposure. Two gaps in the literature were identified: (1) there is limited research on the mental and emotional impacts of fluoride exposure compared to research on cognitive outcomes, and (2) human studies primarily focus on prenatal and perinatal exposure, with little research conducted at other time points (e.g., adolescence). Furthermore, there is no agreed-upon mechanism for the neurotoxic effects of fluoride; however, fluoride can induce mitochondrial damage, including decreasing circulating mitochondrial DNA content, dysregulating biogenesis, and circular structure loss. Additionally, many neurodevelopmental conditions have mitochondrial underpinnings. More work is needed to elucidate the impact and timing of fluoride exposure on mental health and the role of mitochondrial function as a biological mechanism

Propofol effects in rodent models of traumatic brain injury: a systematic review

Background Traumatic brain injury (TBI) causes high mortality and disability worldwide. Animal models have been developed to explore the complex processes in TBI. Propofol is used to manage head injuries during surgical intervention and mechanical ventilation in patients with TBI. Many studies have investigated the neuroprotective effect of propofol on TBI. However, other studies have shown neurotoxic effects. Objectives To review systematically the literature regarding the neuroprotective and neurotoxic effects of propofol in rodent models of TBI. Methods Data from rodents as models of TBI with propofol as one of the intervention agents, and/or comparing the neuroprotective effects of propofol with the other substances in rodent models of TBI, were obtained from PubMed, EBSCO Host, and ProQuest databases. The PRISMA 2020 statement recommendations were followed and research questions were developed based on PICOS guidelines. Data was extracted from the literature using a standardized Cochrane method. Results We analyzed data from 12 articles on physiological changes of experimental animals before and after trauma, the effects of propofol administration, and the observed neurotoxic effects. The effects of propofol administration were observed in terms of changes in traumatic lesion volume, the release of antioxidants and inflammatory factors, and the neurological function of rodent models of TBI. Conclusion Propofol has neuroprotective and neurotoxic effects via several mechanisms, and various doses have been used in research to determine its effects. The timing of administration, the dose administered, and the duration of administration contribute to determine the effect of propofol in rodent models of TBI. However, the doses that produce neuroprotective and neurotoxic effects are not yet clear and further research is needed to determine them.

GABAA Receptor Subunit Composition Drives Its Sensitivity to the Insecticide Fipronil

Fipronil (FPN) is a worldwide-used neurotoxic insecticide, targeting, and blocking GABAA receptors (GABAARs). Beyond its efficiency on insect GABAARs, FPN causes neurotoxic effects in humans and mammals. Here, we investigated the mode of action of FPN on mammalian α6-containing GABAARs to understand its inhibitory effects on GABA-induced currents, as a function of the synaptic or extrasynaptic localization of GABAARs. We characterized the effects of FPN by electrophysiology using Xenopus oocytes which were microtransplanted with cerebellum membranes or injected with α6β3, α6β3γ2S (synaptic), and α6β3δ (extrasynaptic) cDNAs. At micromolar concentrations, FPN dose-dependently inhibited cerebellar GABA currents. FPN acts as a non-competitive antagonist on ternary receptors. Surprisingly, the inhibition of GABA-induced currents was partial for extra-synaptic (α6β3δ) and binary (α6β3) receptors, while synaptic α6β3γ2S receptors were fully blocked, indicating that the complementary γ or δ subunit participates in FPN-GABAAR interaction. FPN unexpectedly behaved as a positive modulator on β3 homopentamers. These data show that FPN action is driven by the subunit composition of GABAARs—highlighting the role of the complementary subunit—and thus their localization within a physiological synapse. We built a docking model of FPN on GABAARs, which reveals two putative binding sites. This is consistent with a double binding mode of FPN on GABAARs, possibly one being of high affinity and the other of low affinity. Physiologically, the γ/δ subunit incorporation drives its inhibitory level and has important significance for its toxicity on the mammalian nervous system, especially in acute exposure.

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 at 20 and 40 mg/L for 48 h, the later METH concentration was selected for developing the model 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 3 h 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 3 h of exposure, whereas the expression of gfap, a marker of astroglial response to neuronal injury, was strongly increased after 48 h 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.

Histone Methyltransferases SUV39H1 and G9a and DNA Methyltransferase DNMT1 in Penumbra Neurons and Astrocytes after Photothrombotic Stroke

Background: Cerebral ischemia, a common cerebrovascular disease, is one of the great threats to human health and new targets for stroke therapy are needed. The transcriptional activity in the cell is regulated by epigenetic processes such as DNA methylation/demethylation, acetylation/deacetylation, histone methylation, etc. Changes in DNA methylation after ischemia can have both neuroprotective and neurotoxic effects depending on the degree of ischemia damage, the time elapsed after injury, and the site of methylation. Methods: In this study, we investigated the changes in the expression and intracellular localization of DNA methyltransferase DNMT1, histone methyltransferases SUV39H1, and G9a in penumbra neurons and astrocytes at 4 and 24 h after stroke in the rat cerebral cortex using photothrombotic stroke (PTS) model. Methods of immunofluorescence microscopy analysis, apoptosis analysis, and immunoblotting were used. Additionally, we have studied the effect of DNMT1 and G9a inhibitors on the volume of PTS-induced infarction and apoptosis of penumbra cells in the cortex of mice after PTS. Results: This study has shown that the level of DNMT1 increased in the nuclear and cytoplasmic fractions of the penumbra tissue at 24 h after PTS. Inhibition of DNMT1 by 5-aza-2′-deoxycytidine protected cells of PTS-induced penumbra from apoptosis. An increase in the level of SUV39H1 in the penumbra was found at 24 h after PTS and G9a was overexpressed at 4 and 24 h after PTS. G9a inhibitors A-366 and BIX01294 protected penumbra cells from apoptosis and reduced the volume of PTS-induced cerebral infarction. Conclusion: Thus, the data obtained show that DNA methyltransferase DNMT1 and histone methyltransferase G9a can be potential protein targets in ischemic penumbra cells, and their inhibitors are potential neuroprotective agents capable of protecting penumbra cells from postischemic damage to the cerebral cortex.

Brominated flame retardant TBPH induced oxidative damage and reduced the expression of memory-related proteins in mice, with no discernable impairment of learning and memory

Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH) is one of the new brominated flame retardants with adverse neurobehavioral potential. These flame retardants are often added to household furnishings where children would come into contact with them. This study explores whether oral exposure to TBPH for 28 days would impair neurobehavioral function in mice and the role of curcumin (CUR) in this process. CUR is a natural antioxidant and is thought to be of use in the treatment of neurological toxicity due to its neuroprotective effects. Learning and memory of mice exposed to TBPH was investigated using the Morris water maze. Levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were determined to assess oxidative damage. Western blot was used to detect the expression of glucose-regulated protein 78-kDa (GRP78), PKR-like ER kinase (PERK), and C/EBP homologous protein (CHOP) in the hippocampus. End-point effects were evaluated through observing post-synaptic density protein-95 (PSD-95), brain-derived neurotrophic factor (BDNF), and phosphorylated cAMP response element binding protein (p-CREB). Although TBPH exposure alone does not impair learning and memory, oxidative stress markers and endoplasmic reticulum stress–associated proteins were adversely affected in exposed mice. TBPH could significantly decrease the levels of BDNF, p-CREB, and PSD-95 in the hippocampus, and these TBPH-induced neurotoxic effects were attenuated by CUR. These findings provide further understanding of the neurotoxic effects of TBPH and the protective effect of CUR on TBPH exposure.