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1.
Ecotoxicology ; 29(8): 1128-1137, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32827288

RESUMO

Mercury exposure can disrupt development of the cerebellum, part of the brain essential for coordination of movement through a complex environment, including flight. In precocial birds, such as fowl, the cerebellum develops embryonically, and the chick is capable of leaving the nest within hours of hatching. However, most birds, including all songbirds, are altricial, and spend weeks in the nest between hatching and fledging. The objective of this study was to describe the normal development of the cerebellum in a model altricial songbird so as to determine the effect of exposure to mercury on cerebellar maturation. Adult zebra finch (Taeniopygia guttata) pairs were fed either a control diet, or a diet augmented with one of four treatment-levels of methylmercury (0.3-2.4 µg/g wet weight), and their offspring, the subjects of this study, were fed the same diet by parents. We documented, for the first time, the schedule of cerebellar development in an altricial bird, and compared stages of development among methylmercury-exposed groups. For all treatments of methylmercury, the age of completion of cellular migration was later than for control zebra finches, indicating a delay in cerebellar maturation. Displaced (heterotopic) Purkinje neurons, a pathology typical of methylmercury exposure in developing vertebrate brains, were more numerous in methylmercury-exposed birds, and persisted at least until the age of independence. Delays in maturation of the cerebellum could delay fledging in altricial bird species, with potential serious implications for the fitness of exposed individuals, as predation rates in the nest are often very high.


Assuntos
Cerebelo/crescimento & desenvolvimento , Poluentes Ambientais/toxicidade , Tentilhões , Mercúrio/toxicidade , Animais , Cerebelo/efeitos dos fármacos , Feminino , Masculino
2.
Sci Rep ; 10(1): 9420, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32523011

RESUMO

We investigated the role of nitric oxide synthase (NOS) in mediating blood-brain barrier (BBB) disruption and peripheral immune cell infiltration in the cerebellum following blast exposure. Repetitive, but not single blast exposure, induced delayed-onset BBB disruption (72 hours post-blast) in cerebellum. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) administered after blast blocked BBB disruption and prevented CD4+ T-cell infiltration into cerebellum. L-NAME also blocked blast-induced increases in intercellular adhesion molecule-1 (ICAM-1), a molecule that plays a critical role in regulating blood-to-brain immune cell trafficking. Blocking NOS-mediated BBB dysfunction during this acute/subacute post-blast interval (24-71 hours after the last blast) also prevented sensorimotor impairment on a rotarod task 30 days later, long after L-NAME cleared the body. In postmortem brains from Veterans/military Servicemembers with blast-related TBI, we found marked Purkinje cell dendritic arbor structural abnormalities, which were comparable to neuropathologic findings in the blast-exposed mice. Taken collectively, these results indicate that blast provokes delayed-onset of NOS-dependent pathogenic cascades that can later emerge as behavioral dysfunction. These results also further implicate the cerebellum as a brain region vulnerable to blast-induced mTBI.


Assuntos
Traumatismos por Explosões/metabolismo , Traumatismos por Explosões/fisiopatologia , Concussão Encefálica/fisiopatologia , Doenças Cerebelares/metabolismo , Doenças Cerebelares/fisiopatologia , Cerebelo/fisiopatologia , Óxido Nítrico Sintase/metabolismo , Animais , Traumatismos por Explosões/tratamento farmacológico , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Concussão Encefálica/tratamento farmacológico , Concussão Encefálica/metabolismo , Doenças Cerebelares/tratamento farmacológico , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Modelos Animais de Doenças , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NG-Nitroarginina Metil Éster/farmacologia , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/metabolismo , Células de Purkinje/patologia
3.
Toxicon ; 183: 44-50, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32464148

RESUMO

3-nitropropionic acid (3-NP) is a mycotoxin widely used to produce a rat model of Huntington's disease. While there are numerous studies on the effect of this neurotoxin, still further investigation is required to understand the influence of this toxin on different regions of the brain. In the present study, there are two groups of rats of which one is treated with 3-NP. Behavioral, stereological and immunohistochemical analyses were conducted. The results show that locomotor activity is largely affected and anxiety is induced up to a certain level, but there is no gross manifestation of deficit in memory. Microscopic observations illustrate damages in the hippocampus and other parts of the brain. Astrogliosis and glial scars were another finding of this study. In conclusion, although 3-NP can be used as a model of Huntington's disease, it exerts a disseminated effect on different regions of the brain.


Assuntos
Micotoxinas/toxicidade , Nitrocompostos/toxicidade , Propionatos/toxicidade , Animais , Encéfalo , Cerebelo/efeitos dos fármacos , Gliose , Hipocampo/efeitos dos fármacos , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar
4.
Toxicology ; 440: 152492, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32407874

RESUMO

Neurotoxicity induced by exposure to heavy metal lead (Pb) is a concern of utmost importance particularly for countries with industrial-based economies. The developing brain is especially sensitive to exposure to even minute quantities of Pb which can alter neurodevelopmental trajectory with irreversible effects on motor, emotive-social and cognitive attributes even into later adulthood. Chemical synapses form the major pathway of inter-neuronal communications and are prime candidates for higher order brain (motor, memory and behavior) functions and determine the resistance/susceptibility for neurological disorders, including neuropsychopathologies. The synaptic pathways and mechanisms underlying Pb-mediated alterations in neuronal signaling and plasticity are not completely understood. Employing a biochemically isolated synaptosomal fraction which is enriched in synaptic terminals and synaptic mitochondria, this study aimed to analyze the alterations in bioenergetic and redox/antioxidant status of cerebellar synapses induced by developmental exposure to Pb (0.2 %). Moreover, we test the efficacy of vitamin C (ascorbate; 500 mg/kg body weight), a neuroprotective and neuromodulatory antioxidant, in mitigation of Pb-induced neuronal deficits. Our results implicate redox and bioenergetic disruptions as an underlying feature of the synaptic dysfunction observed in developmental Pb neurotoxicity, potentially contributing to consequent deficits in motor, behavioral and psychological attributes of the organisms. In addition, we establish ascorbate as a key ingredient for therapeutic approach against Pb induced neurotoxicity, particularly for early-life exposures.


Assuntos
Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Cerebelo/metabolismo , Metabolismo Energético/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo/patologia , Sinapses/metabolismo , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Cerebelo/efeitos dos fármacos , Feminino , Glutationa/metabolismo , Chumbo/sangue , Intoxicação do Sistema Nervoso por Chumbo/psicologia , Masculino , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo
5.
Toxicology ; 440: 152500, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32428529

RESUMO

Autism spectrum disorders (ASD) include neurodevelopmental disorders in which behavioral deficits can result from neuronal imbalance of excitation to inhibition (E/I) in the brain. Here we used RT-qPCR to screen for the expression of 99 genes associated with excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission in the cerebral cortex, hippocampus and cerebellum of rats in an established VPA model of ASD. The largest changes in the expression of glutamatergic genes were found in the cerebral cortex, where 12 genes including these encoding some of the subunits of the ionotropic glutamate receptors, were upregulated, while 2 genes were downregulated. The expression of genes encoding the presynaptic glutamatergic proteins vGluT1 and mGluR7 and PKA, involved in downstream glutamatergic signaling, was elevated more than 100-fold. Changes in GABAergic gene expression were found in the cortex, cerebellum and hippocampus; 3 genes were upregulated, and 3 were downregulated. In conclusion, these results revealed that, in the ASD model, several glutamatergic genes in the rat cerebral cortex were upregulated, which contrasts with small and balanced changes in the expression of GABAergic genes. The VPA rat model, useful in studying the molecular basis of ASD, may be suitable for testing experimental therapies in these disabilities.


Assuntos
Transtorno Autístico/induzido quimicamente , Transtorno Autístico/genética , Ácido Glutâmico/genética , Ácido Valproico , Ácido gama-Aminobutírico/genética , Animais , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Feminino , GABAérgicos , Perfilação da Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/biossíntese , Receptores de Glutamato Metabotrópico/genética , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/biossíntese , Proteína Vesicular 1 de Transporte de Glutamato/genética
6.
PLoS One ; 15(4): e0230774, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240226

RESUMO

Oxidative stress is considered to be involved in the pathogenesis of primary blast-related traumatic brain injury (bTBI). We evaluated the effects of ascorbic acid 2-glucoside (AA2G), a well-known antioxidant, to control oxidative stress in rat brain exposed to laser-induced shock waves (LISWs). The design consisted of a controlled animal study using male 10-week-old Sprague-Dawley rats. The study was conducted at the University research laboratory. Low-impulse (54 Pa•s) LISWs were transcranially applied to rat brain. Rats were randomized to control group (anesthesia and head shaving, n = 10), LISW group (anesthesia, head shaving and LISW application, n = 10) or LISW + post AA2G group (AA2G administration after LISW application, n = 10) in the first study. In another study, rats were randomized to control group (n = 10), LISW group (n = 10) or LISW + pre and post AA2G group (AA2G administration before and after LISW application, n = 10). The measured outcomes were as follows: (i) motor function assessed by accelerating rotarod test; (ii) levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative stress marker; (iii) ascorbic acid in each group of rats. Ascorbic acid levels were significantly decreased and 8-OHdG levels were significantly increased in the cerebellum of the LISW group. Motor coordination disorder was also observed in the group. Prophylactic AA2G administration significantly increased the ascorbic acid levels, reduced oxidative stress and mitigated the motor dysfunction. In contrast, the effects of therapeutic AA2G administration alone were limited. The results suggest that the prophylactic administration of ascorbic acid can reduce shock wave-related oxidative stress and prevented motor dysfunction in rats.


Assuntos
Ácido Ascórbico/análogos & derivados , Ataxia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Ácido Ascórbico/farmacologia , Encéfalo/efeitos dos fármacos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Cerebelo/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
7.
J Neurosci ; 40(17): 3348-3359, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32169968

RESUMO

Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviors such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABAA receptor-mediated transmission in molecular layer interneurons of the mouse cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) following Ca2+ entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G with the subsequent production of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABAARs synapses through a GΑΒΑ receptor-associated protein-dependent mechanism. Given the widespread but cell type-specific expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these cells through a novel NO-mediated pathway.SIGNIFICANCE STATEMENT Long-term changes in the efficacy of GABAergic transmission is mediated by multiple presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk between excitatory and inhibitory synapses whereby Ca2+-entering through postsynaptic NMDARs promotes the recruitment and strengthening of GABAA receptor synapses via Ca2+/calmodulin-dependent protein kinase II. Although Ca2+ transport by NMDARs is also tightly coupled to nNOS activity and NO production, it has yet to be determined whether this pathway affects inhibitory synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway that strengthens inhibitory GABAergic synapses of cerebellar molecular layer interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Cerebelo/metabolismo , Interneurônios/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais/fisiologia , Animais , Cerebelo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Interneurônios/efeitos dos fármacos , Masculino , Camundongos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Técnicas de Patch-Clamp , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
8.
Int J Mol Sci ; 21(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041252

RESUMO

Lead (Pb) is a heavy metal with a proven neurotoxic effect. Exposure is particularly dangerous to the developing brain in the pre- and neonatal periods. One postulated mechanism of its neurotoxicity is induction of inflammation. This study analyzed the effect of exposure of rat pups to Pb during periods of brain development on the concentrations of selected cytokines and prostanoids in the forebrain cortex, hippocampus and cerebellum. METHODS: Administration of 0.1% lead acetate (PbAc) in drinking water ad libitum, from the first day of gestation to postnatal day 21, resulted in blood Pb in rat pups reaching levels below the threshold considered safe for humans by the Centers for Disease Control and Prevention (10 µg/dL). Enzyme-linked immunosorbent assay (ELISA) method was used to determine the levels of interleukins IL-1ß, IL-6, transforming growth factor-ß (TGF-ß), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2). Western blot and quantitative real-time PCR were used to determine the expression levels of cyclooxygenases COX-1 and COX-2. Finally, Western blot was used to determine the level of nuclear factor kappa B (NF-κB). RESULTS: In all studied brain structures (forebrain cortex, hippocampus and cerebellum), the administration of Pb caused a significant increase in all studied cytokines and prostanoids (IL-1ß, IL-6, TGF-ß, PGE2 and TXB2). The protein and mRNA expression of COX-1 and COX-2 increased in all studied brain structures, as did NF-κB expression. CONCLUSIONS: Chronic pre- and neonatal exposure to Pb induces neuroinflammation in the forebrain cortex, hippocampus and cerebellum of rat pups.


Assuntos
Cerebelo/imunologia , Encefalite/induzido quimicamente , Hipocampo/imunologia , Chumbo/toxicidade , Efeitos Tardios da Exposição Pré-Natal/imunologia , Prosencéfalo/imunologia , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Cerebelo/efeitos dos fármacos , Dinoprostona/metabolismo , Modelos Animais de Doenças , Encefalite/imunologia , Feminino , Hipocampo/efeitos dos fármacos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Gravidez , Prosencéfalo/efeitos dos fármacos , Ratos , Tromboxano B2/metabolismo , Fator de Crescimento Transformador beta/metabolismo
9.
Toxicol Lett ; 322: 87-97, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31935479

RESUMO

1,2-Dichloroethane (1,2-DCE) is a widely used chlorinated organic toxicant, but little is known about the cerebellar dysfunction induced by excessive exposure to it. To uncover 1,2-DCE-induced neurotoxicity in cerebellar granular cells (CGCs), and to investigate the underlying mechanisms, we explored this, both in vitro and in vivo. Our findings showed significant cell viability inhibition in human CGCs (HCGCs) treated with 1,2-DCE. Flow cytometry and mitochondrial membrane potential analyses discovered an increase in apoptotic-mediated cell death in HCGCs after 1,2-DCE treatment. This HCGC apoptosis was involved in the increases of protein expression in Cytochrome c, Caspase-3, Bad, Bim, transformation related protein 53, Caspase-8, tumor necrosis factor-α, and Survivin. Quantitative real-time PCR (qPCR) and western blot confirmed the increases in Cytochrome c, Caspase-3, cleaved Caspase-3, and Bad in HCGCs after 1,2-DCE treatment. Bax inhibitor peptide V5 rescued 1,2-DCE-induced HCGC apoptosis. Furthermore, 80 CD-1 male mice were exposed to 1,2-DCE by inhalation at 0, 100, 350, and 700 mg/m3 for 6 h/day for 4 weeks. An open field test found abnormal neurobehavioral changes in the mice exposed to 1,2-DCE. Histopathological examination showed significantly shrunken and hypereosinophilic cytoplasm with nuclear pyknosis in mouse CGCs from the 700 mg/m3 1,2-DCE group. TdT-mediated dUTP nick-end labeling assay verified significant increases in apoptotic positive cells in the mouse CGCs after 1,2-DCE exposure. We confirmed the increases in the expressions of Cytochrome c, Caspase-3, cleaved Caspase-3 and Bad in the mice exposed to 1,2-DCE. These findings suggest that 1,2-DCE exposure can induce CGC apoptosis and cerebellar dysfunction, at least in part, through mitochondrial pathway.


Assuntos
Apoptose/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Dicloretos de Etileno/toxicidade , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Cerebelo/metabolismo , Cerebelo/patologia , Cerebelo/fisiopatologia , Humanos , Locomoção/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Medição de Risco , Transdução de Sinais
10.
J Oncol Pharm Pract ; 26(6): 1492-1494, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31948347

RESUMO

Cytarabine is a pyrimidine analogue that is used for the treatment of acute myeloid leukemia at different doses. Standard doses of cytarabine are used for induction therapy, while high doses are used for post-remission (consolidation) and relapsed/refractory treatment. One of the major side effects of its high doses is acute cerebellar toxicity occurring in 10 to 25% of patients. We report a case that developed this side effect after receiving two doses of high-dose cytarabine. The patient's symptoms improved after withholding the drug. Thereafter, the patient tolerated treatment continuation with lower doses.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cerebelo/efeitos dos fármacos , Citarabina/efeitos adversos , Citarabina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão , Adulto Jovem
11.
Psychopharmacology (Berl) ; 237(5): 1305-1315, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31984446

RESUMO

RATIONALE: To demonstrate that repeated episodes of binge drinking during the adolescent period can lead to long-term deficits in motor function and memory in adulthood, and increase proteins in the brain involved with inflammation and apoptotic cell death. METHODS: Groups of early adolescent (PND 26) and periadolescent (PND 34) Sprague-Dawley rats were exposed to either ethanol or plain air through a vapor chamber apparatus for five consecutive days (2 h per day), achieving a blood ethanol concentration equivalent to 6-8 drinks in the treatment group. Subjects then underwent a series of behavioral tests designed to assess memory, anxiety regulation, and motor function. Brains were collected on PND 94 for subsequent western blot analysis. RESULTS: Behavioral testing using the rota-rod, cage-hang, novel object recognition, light-dark box, and elevated plus maze apparatuses showed significant differences between groups; several of which persisted for up to 60 days after treatment. Western blot testing indicated elevated levels of caspase-3/cleaved caspase-3, NF-kB, and PKC/pPKC proteins in the cerebella of ethanol-treated animals. CONCLUSIONS: Differences on anxiety tests indicate a possible failure of behavioral inhibition in the treatment group leading to riskier behavior. Binge drinking also impairs motor coordination and object memory, which involve the cerebellar and hippocampal brain regions, respectively. These experiments indicate the potential dangers of binge drinking while the brain is still developing and indicate the need for future studies in this area.


Assuntos
Apoptose/fisiologia , Bebedeira/metabolismo , Bebedeira/psicologia , Cerebelo/metabolismo , Etanol/administração & dosagem , Mediadores da Inflamação/metabolismo , Administração por Inalação , Fatores Etários , Animais , Apoptose/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Etanol/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia
12.
J Biochem Mol Toxicol ; 34(1): e22416, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31714633

RESUMO

The present study investigated the protective effect of curcumin and mitochondrial-targeted curcumin (MTC) in rotenone-induced cerebellar toxicity in mice. Treatment of rotenone in mice significantly shortened the stride length for both forelimb and hind-limb and increased fore-paws and hind-limb base width. Co-treatment of curcumin and MTC with rotenone improved the walking pattern. A significant increase in lipid peroxidation, nitric oxide and decreased activity of AChE, reduced glutathione, superoxide dismutase and catalase were observed in rotenone-treated mice while co-treatment of curcumin and MTC with rotenone significantly increased AChE activity and protected against rotenone-induced oxidative damage. Rotenone exposed mice showed irregular, damaged Purkinje cells and perineuronal vacuolation while co-treatment of curcumin and MTC with rotenone protected against rotenone-induced cellular damage in these cells. The result exhibits that both curcumin and MTC showed protective effects against rotenone-induced cerebellar toxicity in mice and MTC is more effective than curcumin.


Assuntos
Cerebelo/efeitos dos fármacos , Curcumina/farmacologia , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Rotenona/farmacologia , Animais , Cerebelo/metabolismo , Glutationa/metabolismo , Masculino , Camundongos , Superóxido Dismutase/metabolismo
13.
Arch Physiol Biochem ; 126(1): 1-6, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30269600

RESUMO

Aim: This study tested the hypothesis that folic acid (FA) modulates biogenic amines and protects the brain against oxidative stress induced by 3-nitropropionic acid (3NPA).Methods: Male Wistar rats received (groups of six) for 5 d: FA (50 mg/kg); 3NPA (10 mg/kg); or FA +3NPA. At last day, rats were sacrificed, and their brain was obtained to measure the levels of dopamine, 5-hydroxiindol acetic acid (5-HIAA). Reduced glutathione (GSH), total ATPase, H2O2 and lipid peroxidation were measured.Results: GSH increased significantly in cortex of rats treated with FA. ATPase increased significantly in cerebellum/medulla oblongata and decreased in cortex of animal treated with 3NPA. 5-HIAA increased in striatum of rats that received 3NPA alone or combined with FA.Conclusion: 3NPA generates free radicals such effect can be counteracted with FA administration since this folate increases antioxidant capacity and modulates biogenic amines.


Assuntos
Antioxidantes/farmacologia , Cerebelo/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Ácido Fólico/farmacologia , Fármacos Neuroprotetores/farmacologia , Nitrocompostos/antagonistas & inibidores , Propionatos/antagonistas & inibidores , Adenosina Trifosfatases/metabolismo , Animais , Cerebelo/metabolismo , Córtex Cerebral/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Glutationa/agonistas , Glutationa/metabolismo , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/metabolismo , Ácido Hidroxi-Indolacético/agonistas , Ácido Hidroxi-Indolacético/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Bulbo/efeitos dos fármacos , Bulbo/metabolismo , Nitrocompostos/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Propionatos/administração & dosagem , Ratos , Ratos Wistar
14.
J Nutr ; 150(5): 1031-1040, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31883016

RESUMO

BACKGROUND: Vitamin E (α-tocopherol; α-T) deficiency causes spinocerebellar ataxia. α-T supplementation improves neurological symptoms, but little is known about the differential bioactivities of natural versus synthetic α-T during early life. OBJECTIVE: We assessed the effects of dietary α-T dose and source on tissue α-T accumulation and gene expression in adolescent α-tocopherol transfer protein-null (Ttpa-/-) mice. METHODS: Three-week-old male Ttpa-/- mice (n  = 7/group) were fed 1 of 4 AIN-93G-based diets for 4 wk: vitamin E deficient (VED; below α-T limit of detection); natural α-T, 600 mg/kg diet (NAT); synthetic α-T, 816 mg/kg diet (SYN); or high synthetic α-T, 1200 mg/kg diet (HSYN). Male Ttpa+/+ littermates fed AIN-93G [75 mg synthetic α-T (CON)] served as controls (n  = 7). At 7 wk of age, tissue α-T concentrations and stereoisomer profiles were measured for all groups. RNA-sequencing was performed on cerebella of Ttpa-/- groups. RESULTS: Ttpa-/- mice fed VED had undetectable brain α-T concentrations. Cerebral cortex α-T concentrations were greater in Ttpa-/- mice fed NAT (9.1 ± 0.7 nmol/g), SYN (10.8 ± 1.0 nmol/g), and HSYN (13.9 ± 1.6 nmol/g) compared with the VED group but were significantly lower than in Ttpa+/+ mice fed CON (24.6 ± 1.2 nmol/g) (P < 0.001). RRR-α-T was the predominant stereoisomer in brains of Ttpa+/+ mice (∼40%) and Ttpa-/- mice fed NAT (∼94%). α-T stereoisomer composition was similar in brains of Ttpa-/- mice fed SYN and HSYN (2R: ∼53%; 2S: ∼47%). Very few of the 16,774 genes measured were differentially expressed. However, compared with the NAT diet, HSYN significantly downregulated 20 myelin genes, including 2 transcription factors: SRY-box transcription factor 10 (Sox10) and myelin regulatory factor (Myrf), and several downstream target genes (false discovery rate <0.05). CONCLUSIONS: High-dose synthetic α-T compared with natural α-T alters myelin gene expression in the adolescent mouse cerebellum, which could lead to morphological and functional abnormalities later in life.


Assuntos
Proteínas de Transporte/metabolismo , Cerebelo/metabolismo , Bainha de Mielina/metabolismo , alfa-Tocoferol/síntese química , alfa-Tocoferol/farmacologia , Ração Animal/análise , Animais , Peso Corporal , Proteínas de Transporte/genética , Cerebelo/efeitos dos fármacos , Dieta , Ingestão de Alimentos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout
15.
Biomed Res Int ; 2019: 1767203, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815123

RESUMO

Neurological diseases particularly Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and epilepsy are on the rise all around the world causing morbidity and mortality globally with a common symptom of gradual loss or impairment of motor behaviour. Striatum, which is a component of the basal ganglia, is involved in facilitating voluntary movement while the cerebellum is involved in the maintenance of balance and coordination of voluntary movements. Dopamine, serotonin, gamma-aminobutyric acid (GABA), and glutamate, to name a few, interact in regulating the excitation and inhibition of motor neurons. In another hand, interestingly, the motor loss associated with neurological diseases is possibly resulted from neuroinflammation induced by the neuroimmune system. Toll-like receptors (TLRs) are present in the central nervous system (CNS), specifically and primarily expressed in microglia and are also found on neurons and astrocytes, functioning mainly in the regulation of proinflammatory cytokine production. TLRs are always found to be associated or involved in the induction of neuroinflammation in neurodegenerative diseases. Activation of toll-like receptor 4 (TLR4) through TLR4 agonist, lipopolysaccharide (LPS), stimulation initiate a signaling cascade whereby the TLR4-LPS interaction has been found to result in physiological and behavioural changes including retardation of motor activity in the mouse model. TLR4 inhibitor TAK-242 was reflected in the reduction of the spinal cord pathology along with the motor improvement in ALS mouse. There is cross talk with neuroinflammation and neurochemicals. For example, TLR4 activation by LPS is noted to release proinflammatory cytokines, IL-1ß, from microglia that subsequently suppresses GABA receptor activities at the postsynaptic site and reduces GABA synthesis at the presynaptic site. Glial glutamate transporter activities are also found to be suppressed, showing the association between TLR4 activation and the related neurotransmitters and corresponding receptors and transporters in the event of neuroinflammation. This review is helpful to understand the connection between neurotransmitter and neuroinflammation in striatum- and cerebellum-mediated motor behaviour.


Assuntos
Cerebelo/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Inflamação , Neurônios Motores/efeitos dos fármacos , Neurotransmissores/farmacologia , Animais , Astrócitos/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Dopamina/farmacologia , Ácido Glutâmico/farmacologia , Humanos , Interleucina-1beta , Lipopolissacarídeos/efeitos adversos , Camundongos , Microglia/metabolismo , Serotonina/farmacologia , Receptor 4 Toll-Like , Receptores Toll-Like , Ácido gama-Aminobutírico/farmacologia
16.
BMC Neurosci ; 20(1): 65, 2019 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-31883511

RESUMO

BACKGROUND: Histone deacetylase-3 (HDAC3) promotes neurodegeneration in various cell culture and in vivo models of neurodegeneration but the mechanism by which HDAC3 exerts neurotoxicity is not known. HDAC3 is known to be a transcriptional co-repressor. The goal of this study was to identify transcriptional targets of HDAC3 in an attempt to understand how it promotes neurodegeneration. RESULTS: We used chromatin immunoprecipitation analysis coupled with deep sequencing (ChIP-Seq) to identify potential targets of HDAC3 in cerebellar granule neurons. One of the genes identified was the activity-dependent and neuroprotective transcription factor, Neuronal PAS Domain Protein 4 (Npas4). We confirmed using ChIP that in healthy neurons HDAC3 associates weakly with the Npas4 promoter, however, this association is robustly increased in neurons primed to die. We find that HDAC3 also associates differentially with the brain-derived neurotrophic factor (Bdnf) gene promoter, with higher association in dying neurons. In contrast, association of HDAC3 with the promoters of other neuroprotective genes, including those encoding c-Fos, FoxP1 and Stat3, was barely detectable in both healthy and dying neurons. Overexpression of HDAC3 leads to a suppression of Npas4 and Bdnf expression in cortical neurons and treatment with RGFP966, a chemical inhibitor of HDAC3, resulted in upregulation of their expression. Expression of HDAC3 also repressed Npas4 and Bdnf promoter activity. CONCLUSION: Our results suggest that Bdnf and Npas4 are transcriptional targets of Hdac3-mediated repression. HDAC3 inhibitors have been shown to protect against behavioral deficits and neuronal loss in mouse models of neurodegeneration and it is possible that these inhibitors work by upregulating neuroprotective genes like Bdnf and Npas4.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cerebelo/metabolismo , Histona Desacetilases/metabolismo , Neurônios/metabolismo , Acrilamidas/farmacologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Células Cultivadas , Cerebelo/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Neurônios/efeitos dos fármacos , Fenilenodiaminas/farmacologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Proteínas Repressoras/metabolismo , Fator de Transcrição STAT3/metabolismo , Transcrição Genética/fisiologia
17.
Molecules ; 24(21)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694174

RESUMO

Administration of subanesthetic doses of ketamine during brain maturation represents a tool to mimic an early insult to the central nervous system (CNS). The cerebellum is a key player in psychosis pathogenesis, to which oxidative stress also contributes. Here, we investigated the impact of early celastrol administration on behavioral dysfunctions in adult mice that had received ketamine (30 mg/kg i.p.) at postnatal days (PNDs) 7, 9, and 11. Cerebellar levels of 8-hydroxydeoxyguanosine (8-OHdG), NADPH oxidase (NOX) 1 and NOX2, as well as of the calcium-binding protein parvalbumin (PV), were also assessed. Furthermore, celastrol effects on ketamine-induced alterations of proinflammatory (TNF-α, IL-6 and IL-1ß) and anti-inflammatory (IL-10) cytokines in this brain region were evaluated. Early celastrol administration prevented ketamine-induced discrimination index decrease at adulthood. The same was found for locomotor activity elevations and increased close following and allogrooming, whereas no beneficial effects on sniffing impairment were detected. Ketamine increased 8-OHdG in the cerebellum of adult mice, which was also prevented by early celastrol injection. Cerebellar NOX1 levels were enhanced at adulthood following postnatal ketamine exposure. Celastrol per se induced NOX1 decrease in the cerebellum. This effect was more significant in animals that were early administered with ketamine. NOX2 levels did not change. Ketamine administration did not affect PV amount in the cerebellum. TNF-α levels were enhanced in ketamine-treated animals; however, this was not prevented by early celastrol administration. While no changes were observed for IL-6 and IL-1ß levels, ketamine determined a reduction of cerebellar IL-10 expression, which was prevented by early celastrol treatment. Our results suggest that NOX inhibition during brain maturation prevents the development of psychotic-like behavioral dysfunctions, as well as the increased cerebellar oxidative stress and the reduction of IL-10 in the same brain region following ketamine exposure in postnatal life. This opens novel neuroprotective opportunities against early detrimental insults occurring during brain development.


Assuntos
Cerebelo/efeitos dos fármacos , Interleucina-10/metabolismo , Ketamina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transtornos Psicóticos/tratamento farmacológico , Triterpenos/farmacologia , Animais , Cerebelo/metabolismo , Modelos Animais de Doenças , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 2/metabolismo , NADPH Oxidases/metabolismo , Parvalbuminas/metabolismo , Transtornos Psicóticos/metabolismo , Espécies Reativas de Oxigênio/metabolismo
18.
J Toxicol Sci ; 44(11): 799-809, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31708536

RESUMO

In the present study, we investigated the effects of lead (Pb) and ascorbic acid co-administration on rat cerebellar development. Female rats were randomly divided into the following groups: control, Pb, and Pb plus ascorbic acid (PA) groups. From one week prior to mating, female rats were administered Pb (0.3% Pb acetate in drinking water) and ascorbic acid (100 mg/kg, oral intubation). The chemical administration was stopped on postnatal day 21 when the morphology of the offspring's cerebellum is similar to that of the adult brain. The blood Pb level was significantly increased following long-term Pb exposure. Ascorbic acid reduced Pb levels in the dams and offspring. Nissl staining demonstrated that the number of Purkinje cells was significantly reduced following Pb exposure, while ascorbic acid ameliorated this effect in the cerebellum of the offspring. Calcium-binding proteins, such as calbindin, calretinin, and parvalbumin were commonly expressed in Purkinje cells, and Pb exposure and ascorbic acid treatment resulted in similar patterns of change, namely Pb-induced impairment and ascorbic acid-mediated amelioration. The gamma-aminobutyric acid transporter 1 (GABAT1) is expressed in the pinceau structure where the somata of Purkinje cells are entwined in inhibitory synapses. The number of GABAT1-immunoreactive synapses was reduced following Pb exposure, and ascorbic acid co-treatment prevented this effect in the cerebellar cortex. Therefore, it can be concluded that ascorbic acid supplementation to mothers during gestation and lactation may have potential preventive effects against Pb-induced impairments in the developing cerebellum via protection of inhibitory neurons and synapses.


Assuntos
Ácido Ascórbico/farmacologia , Proteínas de Ligação ao Cálcio/metabolismo , Cerebelo/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Chumbo/toxicidade , Troca Materno-Fetal , Fármacos Neuroprotetores/farmacologia , Animais , Cerebelo/metabolismo , Cerebelo/patologia , Feminino , Lactação/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos Sprague-Dawley
19.
J Integr Neurosci ; 18(3): 277-283, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31601076

RESUMO

Rats were divided into six groups: sham/control , Dl-3-n-butylphthalide, P1 (low phenytoin, 100 mg/kg), P2 (high phenytoin, 200 mg/kg), NP1 (Dl-3-n-butylphthalide 80 mg/kg, phenytoin 100 mg/kg), NP2 (Dl-3-n-butylphthalide 80 mg/kg, phenytoin 200 mg/kg). Hematoxylin/eosin and Nissl staining showed that, compared to the sham/control group, the Dl-3-n-butylphthalide group had no obvious hippocampal and cerebellar neuron loss, but there was a significant neuron loss in the P1 and P2 groups (P < 0.05), which was more obvious in the P2 group (P < 0.05). The positive expression of Bax and Bcl-2 proteins in hippocampal and cerebellar neurons was not significantly different between sham and Dl-3-n-butylphthalide groups; however, compared to sham, Bax expression was significantly increased and Bcl-2 was significantly decreased in the hippocampal and cerebellar neurons of rats in both P1 and P2 groups (P < 0.05), being more obvious in the P2 group (P < 0.05). Furthermore, the administration of Dl-3-n-butylphthalide attenuated the deleterious effects of phenytoin (P < 0.05). Our results indicate that phenytoin causes apoptosis of hippocampal and cerebellar neurons in rats in a dose-dependent manner, with the effect of a higher dose being more obvious, whereas, Dl-3-n-butylphthalide inhibits the phenytoin-induced apoptosis of neurons and has a neuroprotective role.


Assuntos
Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fenitoína/toxicidade , Animais , Anticonvulsivantes/toxicidade , Cerebelo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
20.
Artigo em Inglês | MEDLINE | ID: mdl-31492429

RESUMO

The sex- and age-specific effects of omega (n)-3 polyunsaturated fatty acids (PUFA) enriched diets on brainstem and cerebellar fatty acid composition, and the expression of stearoyl-CoA desaturase (SCD)-1 and myelin basic protein (MBP) were investigated in C57BL/6 mice. Female mice were fed diets (20% fat, w/w) high or low in n-3 PUFA before mating, during pregnancy and lactation; and offspring (both males and females) were weaned onto their mother's designated diet for 16 weeks. A diet high in n-3 PUFA caused an accretion of docosahexaenoic acid in the cerebellum. Monounsaturated fatty acids increased from weaning to 16 weeks in the cerebellum. The changes in the cerebellar fatty acids were more pronounced in females, with a significant effect of diet. A diet high in n-3 PUFA increased cerebellar SCD-1 and MBP mRNA expression. These findings are novel and demonstrate that the effects of n-3 PUFA are brain region, age- and sex-specific.


Assuntos
Tronco Encefálico/química , Cerebelo/química , Gorduras na Dieta/administração & dosagem , Ácidos Docosa-Hexaenoicos/análise , Ácidos Graxos Monoinsaturados/análise , Ácidos Graxos Ômega-3/administração & dosagem , Fatores Etários , Animais , Tronco Encefálico/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Gorduras na Dieta/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Feminino , Lactação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Proteína Básica da Mielina/genética , Gravidez , Caracteres Sexuais , Comportamento Sexual Animal , Estearoil-CoA Dessaturase/genética , Regulação para Cima , Desmame
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