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2.
Sci Rep ; 10(1): 11130, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636435

RESUMO

Tramadol is an opioid used as an analgesic for treating moderate or severe pain. The long-term use of tramadol can induce several adverse effects. The toxicological mechanism of tramadol abuse is unclear. Metabolomics is a very useful method for investigating the toxicology of drug abuse. We investigated the impact of chronic tramadol administration on the cerebrum of mice, focusing on the metabolites after tramadol administration. The mice received 20 or 50 mg/kg body weight tramadol dissolved in physiological saline daily for 5 weeks via oral gavage. Compared with the control group, the low dose tramadol group showed seven potential biomarkers, including gamma-hydroxybutyric acid, succinate semialdehyde, and methylmalonic acid, which were either up- or down-regulated. Compared with the control group, the high dose tramadol group showed ten potential biomarkers, including gamma-hydroxybutyric acid, glutamine, and O-phosphorylethanolamine, which were either up- or down-regulated. The up-regulated gamma-hydroxybutyric acid and the down-regulated succinate semialdehyde revealed that the neurotransmitter system was disrupted after tramadol abuse. Compared with the low dose tramadol group, there were twenty-nine potential biomarkers in the high dose tramadol group, mainly related to the pentose phosphate pathway and glycerophospholipid metabolism. In conclusion, metabolomics in the tramadol abuse group demonstrated that long-term tramadol abuse can result in oxidative damage, inflammation, and disruption of the GABA neurotransmitter system, which will help to elucidate the toxicology of tramadol abuse.


Assuntos
Analgésicos Opioides/toxicidade , Cérebro/efeitos dos fármacos , Tramadol/toxicidade , Analgésicos Opioides/administração & dosagem , Animais , Biomarcadores/análise , Cérebro/química , Cérebro/metabolismo , Masculino , Malondialdeído/análise , Metabolômica , Camundongos , Superóxido Dismutase/metabolismo , Tramadol/administração & dosagem
3.
Artigo em Inglês | MEDLINE | ID: mdl-32062416

RESUMO

Our objective was to determine whether consumption of a single meal has the potential to alter brain oxylipin content. We examined the cerebrum of mice fed a single high-fat/high-sucrose Western meal or a low-fat/low-sucrose control meal, as well as fasted mice. We found no changes in fatty acid composition of cerebrum across the groups. The cerebral oxylipin profile of mice fed a Western meal is distinct from the profile of mice fed a low-fat/low-sucrose meal. Cerebral gene expression of cyclooxygenase 1, cyclooxygenase 2, and epoxide hydrolase 1 were elevated in Western meal-fed mice compared to low-fat/low-sucrose meal-fed mice. Mice that consumed either meal had lower gene expression of cytochrome P450, family 2, subfamily j, polypeptide 12 than fasted mice. Our data in this hypothesis-generating study indicates that the composition of a single meal has the potential to alter brain oxylipins and the gene expression of the enzymes responsible for their production.


Assuntos
Cérebro/química , Dieta Ocidental/efeitos adversos , Oxilipinas/química , Animais , Cérebro/efeitos dos fármacos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Epóxido Hidrolases/metabolismo , Jejum , Regulação da Expressão Gênica , Masculino , Refeições , Proteínas de Membrana/metabolismo , Camundongos
4.
Microsc Res Tech ; 83(4): 436-445, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31916363

RESUMO

Nowadays, apoptosis is mostly evaluated visually in histological studies. By using the quantitative digital image analysis, this study aimed to investigate the effect of acrylamide-based monomers (acrylamide [AAm], methacrylamide [MAAm], N-isopropylacrylamide [NIPAm]) on the cerebrum tissues in rats, which are the most common water-soluble monomers in the production of polymeric hydrogels used as biomaterials. The Wistar albino rats weighing ~220-240 g were divided into control and three test groups. The control group received 1 mL of saline, and the test groups received 1 mL of aqueous 50 mg/kg/day intramuscular injection of AAm, MAAm, and NIPAm, respectively. At the end of the experiments, brain tissues of all rats euthanized by intramuscular injection of sodium pentobarbital were removed. Terminal deoxynucleotide transferase dUTP nick and labeling (TUNEL) method was applied to brain tissue sections. The monomers have been shown to cause apoptosis due to oxidative stress in cerebrum tissue. Based on apoptosis by tunneling method, quantitative digital image analysis of cell fragments was performed with Olympus cellSens Dimension 1.15 software, and the number, total count area, selected area, average area, and ROI% values of the fragments were found. In addition, the total area and ROI% values of the fragments increased linearly with increasing the molar mass of monomers from the digital image analysis data. Quantitative digital image analysis can facilitate the monitoring of apoptosis caused by the oxidative stress of monomers used in the production of the biomaterials.


Assuntos
Acrilamidas/administração & dosagem , Apoptose/efeitos dos fármacos , Cérebro/patologia , Processamento de Imagem Assistida por Computador/métodos , Acrilamidas/química , Animais , Cérebro/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
5.
J Neurochem ; 154(3): 330-348, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31957020

RESUMO

Angiopoietin-1, an angiogenic factor, stabilizes brain microvessels through Tie-2 receptor tyrosine kinase. In traumatic brain injury, blood-brain barrier (BBB) disruption is an aggravating factor that induces brain edema and neuroinflammation. We previously showed that BQ788, an endothelin ETB receptor antagonist, promoted recovery of BBB function after lateral fluid percussion injury (FPI) in mice. To clarify the mechanisms underlying BBB recovery mediated by BQ788, we examined the involvements of the angiopoietin-1/Tie-2 signal. When angiopoietin-1 production and Tie-2 phosphorylation were assayed by quantitative reverse transcription polymerase chain reaction and western blotting, increased angiopoietin-1 production and Tie-2 phosphorylation were observed in 7-10 days after FPI in the mouse cerebrum, whereas no significant effects were obtained at 5 days. When BQ788 (15 nmol/day, i.c.v.) were administered in 2-5 days after FPI, increased angiopoietin-1 production and Tie-2 phosphorylation were observed. Immunohistochemical observations showed that brain microvessels and astrocytes contained angiopoietin-1 after FPI, and brain microvessels also contained phosphorylated Tie-2. Treatment with endothelin-1 (100 nM) decreased angiopoietin-1 production in cultured astrocytes and the effect was inhibited by BQ788 (1 µM). Five days after FPI, increased extravasation of Evans blue dye accompanied by reduction in claudin-5, occludin, and zonula occludens-1 proteins were observed in mouse cerebrum while these effects of FPI were reduced by BQ788 and exogenous angiopoietin-1 (1 µg/day, i.c.v.). The effects of BQ788 were inhibited by co-administration of a Tie-2 kinase inhibitor (40 nmol/day, i.c.v.). These results suggest that BQ788 administration after traumatic brain injury promotes recovery of BBB function through activation of the angiopoietin-1/Tie-2 signal.


Assuntos
Angiopoietina-1/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Lesões Encefálicas Traumáticas/metabolismo , Antagonistas do Receptor de Endotelina B/farmacologia , Oligopeptídeos/farmacologia , Piperidinas/farmacologia , Receptor TIE-2/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Cérebro/efeitos dos fármacos , Cérebro/lesões , Cérebro/metabolismo , Masculino , Camundongos
6.
Environ Toxicol Pharmacol ; 71: 103216, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31260942

RESUMO

Methylmercury is an environmental pollutant that shows selective toxicity to the central nervous system. We previously reported that brain-specific expression of chemokine CCL3 increases in mice administered methylmercury. However, the relationship between CCL3 and methylmercury toxicity has not been elucidated. Here, we confirmed that induction of CCL3 expression occurs before pathological change by methylmercury treatment was observed in the mouse brain. This induction was also observed in C17.2 mouse neural stem cells before methylmercury-induced cytotoxicity. In addition, cells in which CCL3 was knocked-down showed higher methylmercury sensitivity than did control cells. Moreover, activation of transcription factor NF-κB was observed following methylmercury treatment, and methylmercury-mediated induction of CCL3 expression was partially suppressed by knockdown of p65, an NF-κB subunit. Our results suggest that NF-κB plays a role in the induction of methylmercury-mediated CCL3 expression and that this action may be a cellular response to methylmercury toxicity.


Assuntos
Quimiocina CCL3/biossíntese , Poluentes Ambientais/toxicidade , Compostos de Metilmercúrio/toxicidade , NF-kappa B/biossíntese , Células-Tronco Neurais/efeitos dos fármacos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/patologia , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Cérebro/patologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia
7.
Eur. j. anat ; 23(4): 243-251, jul. 2019. ilus, graf
Artigo em Inglês | IBECS | ID: ibc-182997

RESUMO

Atomoxetine (ATX) is a noradrenaline reuptake inhibitor used to treat Attention deficit hyperactive syndrome (ADHD), or improve cognition in normal subjects. The cognitive effects of ATX require inputs from the hippocampus. Moreover, proliferation is said to be located in the dentate gyrus (DG) of the hippocampus.In the present study, we hypothesised that ATX improves memory and proliferation of the adult rat hippocampus. To test this hypothesis, 5 intraperitoneal injections of ATX (30 mg/kg/day) over 5 consecutive days were delivered to rats. 30 minutes after the last injection, spatial memory was tested using the Novel location recognition (NLR) test. Proliferation of hippocampal cells was quantified using immunohistochemistry for the proliferative marker Ki67. ATX-treated rats showed cognitive enhancement in the NLR task and increase in cell proliferation in the Subgranular zone (SGZ) of the DG, compared to saline-treated controls. The results demonstrate that ATX is able to enhance cognition through increasing the levels of proliferation in the adult rat brains


No disponible


Assuntos
Animais , Adulto , Ratos , Cloridrato de Atomoxetina/farmacologia , Cérebro/efeitos dos fármacos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/farmacologia , Hipocampo/anatomia & histologia , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Imuno-Histoquímica , Habituação Psicofisiológica/efeitos dos fármacos , Modelos Animais de Doenças , Neurogênese/efeitos dos fármacos
8.
Transl Psychiatry ; 9(1): 172, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253763

RESUMO

Ketamine acts as a rapid clinical antidepressant at 25 min after injection with effects sustained for 7 days. As dissociative effects emerging acutely after injection are not entirely discernible from therapeutic action, we aimed to dissect the differences between short-term and long-term response to ketamine to elucidate potential imaging biomarkers of ketamine's antidepressant effect. We used a genetical model of depression, in which we bred depressed negative cognitive state (NC) and non-depressed positive cognitive state (PC) rat strains. Four parallel rat groups underwent stress-escape testing and a week later received either S-ketamine (12 NC, 13 PC) or saline (12 NC, 12 PC). We acquired resting-state functional magnetic resonance imaging time series before injection and at 30 min and 48 h after injection. Graph analysis was used to calculate brain network properties. We identified ketamine's distinct action over time in a qualitative manner. The rapid response entailed robust and strain-independent topological modifications in cognitive, sensory, emotion, and reward-related circuitry, including regions that exhibited correlation of connectivity metrics with depressive behavior, and which could explain ketamine's dissociative and antidepressant properties. At 48 h ketamine had mainly strain-specific action normalizing habenula, midline thalamus, and hippocampal connectivity measures in depressed rats. As these nodes mediate cognitive flexibility impaired in depression, action within this circuitry presumably reflects ketamine's procognitive effects induced only in depressed patients. This finding is especially valid, as our model represents cognitive aspects of depression. These empirically defined circuits explain ketamine's distinct action over time and might serve as translational imaging correlates of antidepressant response in preclinical testing.


Assuntos
Antidepressivos/farmacologia , Cérebro/efeitos dos fármacos , Conectoma , Depressão/tratamento farmacológico , Ketamina/farmacologia , Rede Nervosa/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Cérebro/diagnóstico por imagem , Cérebro/fisiopatologia , Modelos Animais de Doenças , Habenula/diagnóstico por imagem , Habenula/efeitos dos fármacos , Habenula/fisiopatologia , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiopatologia , Ratos , Ratos Sprague-Dawley , Tálamo/diagnóstico por imagem , Tálamo/efeitos dos fármacos , Tálamo/fisiopatologia
10.
Bull Exp Biol Med ; 166(3): 317-320, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30627909

RESUMO

The in vitro and in vivo models of ethanol-induced neurodegeneration were used to evaluate the content and functional activity of various types of regeneration-competent cells in subventricular zone of the cerebral hemispheres in C57Bl/6JY mice. In nervous tissue culture, ethanol (65 mM) produced no effect on formation of neurospheres. When administered per os in a daily dose of 3 g/kg for 8 weeks, ethanol produced no effect on the number of neural CFU in situ. In both cases, ethanol reduced proliferative activity of neural CFU. Long-term administration of ethanol in vivo suppressed differentiation of neural stem cells and decreased the number of committed precursors (neural cluster-forming units) in the subventricular zone of cerebral hemispheres. In vitro application of ethanol stimulated secretion of humoral growth factors by the cluster-forming neural glial cells. In contrast, in vivo administration of ethanol suppressed this secretion.


Assuntos
Alcoolismo/patologia , Cérebro/efeitos dos fármacos , Etanol/farmacologia , Ventrículos Laterais/efeitos dos fármacos , Doenças Neurodegenerativas/patologia , Neurônios/efeitos dos fármacos , Alcoolismo/metabolismo , Animais , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cérebro/metabolismo , Cérebro/patologia , Cérebro/fisiopatologia , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intercelular/agonistas , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Ventrículos Laterais/metabolismo , Ventrículos Laterais/patologia , Ventrículos Laterais/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Doenças Neurodegenerativas/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/patologia , Cultura Primária de Células , Esferoides Celulares/efeitos dos fármacos
11.
Neuropharmacology ; 149: 1-12, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30695710

RESUMO

Limited information exists on the link between purinergic class P2X7 receptors (P2X7Rs) and calcium ion channels in epilepsy; no data has been reported regarding the interaction between P2X7Rs and T-type calcium ion channels in epilepsy. Thus, this study is an evaluation of the role that T-type calcium ion channels play in the effect of P2X7Rs on penicillin-induced epileptiform activity. In the first set of experiments, P2X7R agonist BzATP (at 25-, 50-, 100- and 200-µg doses), P2X7R antagonist A-438079 (at 5-, 10-, 20- and 40-µg doses) and T-type calcium ion channel antagonist, NNC-550396 were administered for electrophysiological analyses 30 min after penicillin injection (2.5 µl, 500 IU). In the second set of experiments, the effective doses of these substances were used for biochemical analyses. Malondialdehyde (MDA), advanced oxidation protein product (AOPP), glutathione (GSH), glutathione reductase (GR), glutathione peroxide (GPx), catalase (CAT) and superoxide dismutase (SOD) levels were measured in the cerebrum, cerebellum and brainstem of rats. BzATP (100 µg, icv) increased the mean frequency of epileptiform activity, whereas A-438079 (40 µg, icv) and NNC-550396 (30 µg, ic) reduced it. Both A-438079 and NNC-550396 reversed BzATP's proconvulsant action. BzATP increased lipid peroxidation and protein oxidation; it also altered other antioxidant enzymes measured in this study, which were all then reversed via A-438079 and NNC-550396, at least in the cerebrum. The electrophysiological and biochemical analysis of present study suggest that P2X7Rs and its interaction with T-type calcium ion channels play an important role in the experimental model of epilepsy.


Assuntos
Canais de Cálcio Tipo T/efeitos dos fármacos , Canais de Cálcio Tipo T/metabolismo , Epilepsia/metabolismo , Receptores Purinérgicos P2X7/efeitos dos fármacos , Receptores Purinérgicos P2X7/metabolismo , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Animais , Antioxidantes/metabolismo , Benzimidazóis/farmacologia , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/metabolismo , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Ciclopropanos/farmacologia , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Naftalenos/farmacologia , Penicilinas/farmacologia , Agonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/farmacologia , Ratos , Ratos Wistar , Tetrazóis/farmacologia
12.
BMC Neurosci ; 19(1): 55, 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30208879

RESUMO

BACKGROUND: The long-term effects of psychotropic drugs are associated with the reversal of disease-related alterations through the reorganization and normalization of neuronal connections. Molecular factors that trigger drug-induced brain plasticity remain only partly understood. Doublecortin-like kinase 1 (Dclk1) possesses microtubule-polymerizing activity during synaptic plasticity and neurogenesis. However, the Dclk1 gene shows a complex profile of transcriptional regulation, with two alternative promoters and exon splicing patterns that suggest the expression of multiple isoforms with different kinase activities. RESULTS: Here, we applied next-generation sequencing to analyze changes in the expression of Dclk1 gene isoforms in the brain in response to several psychoactive drugs with diverse pharmacological mechanisms of action. We used bioinformatics tools to define the range and levels of Dclk1 transcriptional regulation in the mouse nucleus accumbens and prefrontal cortex. We also sought to investigate the presence of DCLK1-derived peptides using mass spectrometry. We detected 15 transcripts expressed from the Dclk1 locus (FPKM > 1), including 2 drug-regulated variants (fold change > 2). Drugs that act on serotonin receptors (5-HT2A/C) regulate a subset of Dclk1 isoforms in a brain-region-specific manner. The strongest influence was observed for the mianserin-induced expression of an isoform with intron retention. The drug-activated expression of novel alternative Dclk1 isoforms was validated using qPCR. The drug-regulated isoform contains genetic variants of DCLK1 that have been previously associated with schizophrenia and hyperactivity disorder in humans. We identified a short peptide that might originate from the novel DCLK1 protein product. Moreover, protein domains encoded by the regulated variant indicate their potential involvement in the negative regulation of the canonical DCLK1 protein. CONCLUSIONS: In summary, we identified novel isoforms of the neuroplasticity-related gene Dclk1 that are expressed in the brain in response to psychotropic drug treatments.


Assuntos
Processamento Alternativo/efeitos dos fármacos , Cérebro/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Psicotrópicos/farmacologia , Transcrição Genética/efeitos dos fármacos , Animais , Cérebro/metabolismo , Biologia Computacional , Masculino , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Isoformas de Proteínas/efeitos dos fármacos , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Saccharomyces cerevisiae
13.
Vascul Pharmacol ; 111: 26-35, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30114508

RESUMO

We assessed the ability of poststroke losartan and captopril treatment to attenuate hematoma expansion and plasma extravasation after intracerebral hemorrhagic stroke in Kyoto-Wistar stroke-prone hypertensive rats (SHRsp). Cerebrum volume, herniation and surface areas exhibiting new and old hemorrhages and albumin extravasation were measured prior to and after stroke and following 30 and 60 days of post-stroke losartan or captopril treatment in Evans Blue dye perfused brains. Lesion morphology was studied in serial sections. Losartan or captopril treatment initiated at stroke prevented death for 60 days without lowering BP. Stroke onset was associated with the development and subsequent expansion of cerebrum volume, herniation, hematoma and plasma albumin extravasation. Losartan arrested cerebral volume expansion and herniation, and produced the virtual disappearance of hematoma and plasma albumin extravasation after 60 days. Captopril treatment equally attenuated cerebral herniation and hematoma expansion but was less effective in stopping albumin extravasation and allowed cerebrum volume to increase to post-stroke levels after 60 days of treatment. Both treatments resolved hematomas into cortical fluid filled spaces and prevented new hemorrhage formation. We believe that the treatments attenuated death after stroke by inhibiting hemorrhagic expansion through non-pressure related physiological changes mediated by the inhibition of the renin-angiotensin system.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Captopril/farmacologia , Hemorragia Cerebral/tratamento farmacológico , Cérebro/efeitos dos fármacos , Losartan/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Edema Encefálico/prevenção & controle , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Cérebro/metabolismo , Cérebro/patologia , Cérebro/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Masculino , Ratos Endogâmicos WKY , Albumina Sérica/metabolismo , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo
14.
J Agric Food Chem ; 66(25): 6402-6413, 2018 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-29865786

RESUMO

The residues from the widely used broad-spectrum environmental herbicide, atrazine (ATR), result in the exposure of nontarget organisms and persist as a global major public health hazard. ATR is neurotoxic and may cause adverse health effects in mammals, birds, and fishes. Nevertheless, the molecular mechanism of ATR induced neurotoxicity remains unclear. To assess the molecular mechanisms of ATR-induced cerebral toxicity through potential oxidative damage, quail were treated with ATR by oral gavage administration at doses of 0, 50, 250, and 500 mg/kg body weight daily for 45 days. Markedly, increases in the amount of swelling of neuronal cells, the percentage of mean damaged mitochondria, mitochondrial malformation, and mitochondrial vacuolar degeneration as well as decreases in the mitochondrial cristae and mitochondrial volume density were observed by light and electron microscopy in the cerebrum of quail. ATR induced toxicities in the expression of mitochondrial function-related genes and promoted oxidative damage, as indicated by effects on oxidative stress indices. These results indicated that ATR exposure can cause neurological disorders and cerebral injury. ATR may initiate apoptosis by activating Bcl-2, Bax, and Caspase3 protein expression but failed to induce autophagy (LC3B has not cleaved to LC3BI/II). Furthermore, ATR induced CYP-related enzymes metabolism disorders by activating the nuclear xenobiotic receptors response (NXRs including AHR, CAR, and PXR) and increased expression of several CYP isoforms (including CYP1B1 and CYP2C18) and thereby producing mitochondrial dysfunction. In this study, we observed ATR exposure resulted in oxidative stress and mitochondrial dysfunction by activating the NXR response and interfering the CYP450s homeostasis in quail cerebrum that supported the molecular mechanism of ATR induced cerebrum toxicity. In conclusion, these results provided new evidence on molecular mechanism of ATR induced neurotoxicity.


Assuntos
Atrazina/toxicidade , Proteínas Aviárias/metabolismo , Cérebro/efeitos dos fármacos , Coturnix/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Herbicidas/toxicidade , Receptores Citoplasmáticos e Nucleares/metabolismo , Xenobióticos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Proteínas Aviárias/genética , Cérebro/metabolismo , Coturnix/genética , Sistema Enzimático do Citocromo P-450/genética , Homeostase/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/genética
15.
Toxicol Ind Health ; 34(6): 397-407, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29656705

RESUMO

The aim of this study was to assess the effects of neonatal bisphenol A (BPA) administration on neuroendocrine features (the thyroid-brain axis). BPA (20 or 40 µg/kg) was orally administered to juvenile male albino rats ( Rattus norvegicus) from postnatal days (PNDs) 15 to 30. Both doses resulted in lower serum thyroxine (T4), triiodothyronine (T3), and growth hormone levels and higher thyrotropin level than the control levels at PND 30. In the neonatal cerebellum and cerebrum, vacuolation, pyknosis, edema, degenerative changes, and reductions in the size and number of the cells were observed in both treated groups. Alternatively, elevations in oxidative markers (lipid peroxidation, nitric oxide, and hydrogen peroxide [H2O2]) at both dose levels were recorded at PND 30, along with decreased activities of antioxidant markers (ascorbic acid, total thiol [t-SH], glutathione, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, and catalase) with respect to control levels. Thus, the BPA-induced hypothyroid state may disturb the neonatal thyroid-brain axis via production of free radicals, and this could damage the plasma membrane and cellular components, delaying cerebrum and cerebellum development.


Assuntos
Compostos Benzidrílicos/toxicidade , Cerebelo/efeitos dos fármacos , Cérebro/efeitos dos fármacos , Sistemas Neurossecretores/efeitos dos fármacos , Fenóis/toxicidade , Glândula Tireoide/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antioxidantes/análise , Biomarcadores/análise , Cerebelo/química , Cerebelo/metabolismo , Cérebro/química , Cérebro/metabolismo , Masculino , Ratos , Glândula Tireoide/química , Glândula Tireoide/metabolismo , Hormônios Tireóideos/análise
16.
Biomed Pharmacother ; 102: 392-402, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29573618

RESUMO

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication that occurs as a result of liver failure. Umbelliferone (UMB; 7-hydroxycoumarin) is a natural product with proven hepatoprotective activity; however, nothing has yet been reported on its protective effect against hyperammonemia, the main culprit behind the symptoms of HE. Here, we evaluated the effect of UMB against ammonium chloride (NH4Cl)-induced hyperammonemia, oxidative stress, inflammation and hematological alterations in rats. We demonstrated the modulatory role of UMB on the glutamate-nitric oxide (NO)-cGMP pathways in the cerebrum of rats. Rats received intraperitoneal injections of NH4Cl (3 times/week) for 8 weeks and concomitantly received 50 mg/kg UMB. NH4Cl-induced rats showed significantly elevated blood ammonia and liver function markers. Lipid peroxidation and NO were increased in the liver and cerebrum of rats while the antioxidant defenses were declined. UMB significantly reduced blood ammonia, liver function markers, lipid peroxidation and NO, and enhanced the antioxidant defenses in NH4Cl-induced rats. UMB significantly prevented anemia, leukocytosis, thrombocytopenia and prolongation of PT and aPTT. Hyperammonemic rats showed elevated levels of cerebral TNF-α, IL-1ß and glutamine as well as increased activity and expression of Na+/K+-ATPase, effects that were significantly reversed by UMB. In addition, UMB down-regulated nitric oxide synthase and soluble guanylate cyclase in the cerebrum of hyperammonemic rats. In conclusion, this study provides evidence that UMB protects against hyperammonemia via attenuation of oxidative stress and inflammation. UMB prevents hyperammonemia associated hematological alterations and therefore represents a promising protective agent against the deleterious effects of excess ammonia.


Assuntos
GMP Cíclico/metabolismo , Ácido Glutâmico/metabolismo , Hiperamonemia/tratamento farmacológico , Inflamação/tratamento farmacológico , Óxido Nítrico/metabolismo , Estresse Oxidativo , Transdução de Sinais , Umbeliferonas/uso terapêutico , Amônia/sangue , Cloreto de Amônio , Anemia/sangue , Anemia/complicações , Anemia/tratamento farmacológico , Anemia/prevenção & controle , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Coagulação Sanguínea/efeitos dos fármacos , Cérebro/efeitos dos fármacos , Cérebro/enzimologia , Cérebro/patologia , Regulação para Baixo/efeitos dos fármacos , Glutamina/biossíntese , Hiperamonemia/sangue , Hiperamonemia/complicações , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Leucocitose/sangue , Leucocitose/complicações , Leucocitose/tratamento farmacológico , Leucocitose/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Testes de Função Hepática , Masculino , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Umbeliferonas/farmacologia
17.
Nutrients ; 10(3)2018 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-29495376

RESUMO

A negative association between blood lead and vitamin D concentrations has been reported, however, experimental data on the effect of lead (Pb) on vitamin D metabolism is scarce. We investigated the effects of Pb on serum vitamin D metabolites, vitamin D activating enzymes and vitamin D receptor (VDR) in rats. Newborn Wistar rat pups were exposed to 0.2% Pb-acetate via their dams' drinking water from post-natal day (PND) 1 to 21 and directly in drinking water until PND30. Serum 25-hydroxyvitamin D was analyzed with LC-MS/MS and 1,25-dihydroxyvitamin D with an immunoassay. Tissue expression of vitamin D activating enzymes and VDR were measured by Western blot and immunohistochemistry. Serum 25-hydroxyvitamin D was significantly decreased at both PND21 and PND30, whereas 1,25-dihydroxyvitamin D was decreased (p < 0.05) only at PND21 in the Pb-exposed rats. Expression of renal 1-α-hydroxylase was decreased by Pb only at PND21 (p < 0.05) but the brain 1-α-hydroxylase was not affected. Hepatic 25-hydroxylase expression was significantly decreased at PND21 but significantly increased at PND30 by Pb exposure. VDR expression in the brain was increased at both PND21 and PND30 (p < 0.05). These results suggest that Pb interferes with vitamin D metabolism by affecting the expression of its metabolizing enzymes.


Assuntos
Chumbo/toxicidade , Vitamina D/sangue , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Animais , Animais Recém-Nascidos , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Colestanotriol 26-Mono-Oxigenase/genética , Colestanotriol 26-Mono-Oxigenase/metabolismo , Cromatografia Líquida , Rim/efeitos dos fármacos , Rim/metabolismo , Chumbo/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Ratos , Ratos Wistar , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Espectrometria de Massas em Tandem , Vitamina D/metabolismo
18.
Naunyn Schmiedebergs Arch Pharmacol ; 391(5): 489-499, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29453527

RESUMO

Molecular investigations were performed in order to determine the major characteristics of voltage-gated Na+ channel ß-subunits in mouse vas deferens. The use of real-time quantitative PCR showed that the expression of Scn1b was significantly higher than that of other ß-subunit genes (Scn2b - Scn4b). Immunoreactivity of Scn1b proteins was also detected in the inner circular and outer longitudinal smooth muscle of mouse vas deferens. In whole-cell recordings, the actions of 4,9-anhydroTTX on voltage-gated Na+ current peak amplitude in myocytes (i.e., native INa) were compared with its inhibitory potency on recombinant NaV1.6 channels (expressed in HEK293 cells). A depolarizing rectangular voltage-pulse elicited a fast and transient inward native INa and recombinant NaV1.6 expressed in HEK293 cells (i.e., recombinant INa). The current decay of native INa was similar to the recombinant NaV1.6 current co-expressed with ß1-subunits. The current-voltage (I-V) relationships of native INa were similar to those of recombinant NaV1.6 currents co-expressed with ß1-subunits. Application of 4,9-anhydroTTX inhibited the peak amplitude of native INa (K i = 510 nM), recombinant INa (K i = 112 nM), and recombinant INa co-expressed with ß1-subunits (K i = 92 nM). The half-maximal (Vhalf) activation and inactivation of native INa values were similar to those observed in recombinant INa co-expressed with ß1-subunits. These results suggest that ß1-subunit proteins are likely to be expressed mainly in the smooth muscle layers of murine vas deferens and that 4,9-anhydroTTX inhibited not only native INa but also recombinant INa and recombinant INa co-expressed with ß1-subunits in a concentration-dependent manner.


Assuntos
Miócitos de Músculo Liso/efeitos dos fármacos , Subunidades Proteicas/fisiologia , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/análogos & derivados , Ducto Deferente/citologia , Canais de Sódio Disparados por Voltagem/fisiologia , Animais , Cérebro/efeitos dos fármacos , Cérebro/fisiologia , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Miócitos de Músculo Liso/fisiologia , Proteínas Recombinantes , Tetrodotoxina/farmacologia
19.
J Leukoc Biol ; 103(1): 107-118, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29345065

RESUMO

Fingolimod (FTY720), an immunomodulator, is approved as an oral treatment for patients with relapsing forms of multiple sclerosis. Its effects are largely attributed to its mechanism of selectively retaining lymphocytes in the lymph nodes to reduce autoreactive T-cell recruitment in the CNS. In this study, we investigated the therapeutic effect of FTY720 on an animal model of CNS inflammation induced by intracerebral ventricle LPS injection. We found that FTY720 treatment significantly prevented LPS-induced neutrophil recruitment in the CNS by inhibiting leukocyte recruitment in cerebral microvessels. Furthermore, FTY720 also inhibited the expressions of adhesion molecules on the cerebral endothelium, but did not affect the expression levels of pro-inflammatory cytokines (TNF-α and IL-6) and chemokines (CXCL1 and CXCL2) in the CNS parenchyma. The inhibition of endothelial activation was accompanied by reduced phosphorylation of signaling molecules, including serine/threonine-specific protein kinase (Akt), STAT6, and nuclear factor-κB. This FTY720-attenuated inhibition of leukocyte recruitment and endothelial activation was reversed by blocking the functions of sphingosine kinase 2 or sphingosine-1-phosphate receptor 1. Our study demonstrated, for the first time, that FTY720 directly inhibits the phosphorylation of multiple signaling molecules in endothelial cells, thereby effectively blocking leukocyte recruitment in the CNS.


Assuntos
Sistema Nervoso Central/imunologia , Cérebro/imunologia , Endotélio Vascular/imunologia , Cloridrato de Fingolimode/farmacologia , Inflamação/imunologia , Leucócitos/imunologia , Microvasos/imunologia , Animais , Células Cultivadas , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Circulação Cerebrovascular , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Citocinas/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
20.
Environ Res ; 160: 449-461, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29073573

RESUMO

Air pollution-exposure is associated with detrimental outcomes in the central nervous system (CNS) such as cerebrovascular disorders, including stroke, and neurodegenerative diseases. While the mechanisms of these CNS-related outcomes involved have not been fully elucidated, exposure to traffic-generated air pollutants has been associated with altered blood brain barrier (BBB) integrity and permeability. The current study investigated whether inhalation exposure to mixed vehicle emissions (MVE) alters cerebral microvascular integrity in healthy 3 mo old C57BL/6 mice, as well as whether exposure-mediated effects were exacerbated by a high-fat (HF) vs. low-fat (LF) diet. Mice on each diet were randomly assigned to be exposed to either filtered air (FA) or MVE [100PM/m3 vehicle emissions mixture: 30µg PM/m3 gasoline engine + 70µg PM/m3 diesel engine emissions; median size ~ 60nm; particle mass size distribution median of ~ 1µm (range: < 0.5-20µm)] for 6h/d, 7d/wk, for 30d. Using sodium fluorescein as a tracer, we observed a significant increase in BBB permeability in both HF + MVE exposed and HF + FA animals, compared to LF + FA controls. Exposure to HF + MVE also led to a significant increase plasma ox-LDL and ox-LDL scavenger receptors (LOX-1 and CD-36) expression in the cerebral vasculature. Histological analysis revealed decreased expression of TJ protein, claudin-5, associated with increased matrix metalloproteinase (MMP)-9 activity and oxidative stress in the cerebral vasculature of HF + MVE mice, compared to LF + MVE. Such findings indicate that inhalation exposure to traffic-generated pollutants, coupled with a HF diet, results in altered BBB integrity and increased ox-LDL signaling in the cerebral vasculature in a wildtype animal model.


Assuntos
Poluentes Atmosféricos/toxicidade , Cérebro/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Emissões de Veículos/toxicidade , Animais , Cérebro/irrigação sanguínea , Cérebro/patologia , Dieta Hiperlipídica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
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