Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.866
Filtrar
1.
Int. arch. otorhinolaryngol. (Impr.) ; 23(3): 267-275, July-Sept. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1040018

RESUMO

Abstract Introduction Riluzole (2-amino-6-trifluoromethoxy benzothiazole) is known as a neuroprotective, antioxidant, antiapoptotic agent. It may have beneficial effects on neuronal cell death due to cisplatin-induced ototoxicity. Objective To evaluate the effect of riluzole on cisplatin-induced ototoxicity in guinea pigs. Methods Twenty-four guinea pigs, studied in three groups, underwent auditory brainstem response evaluation using click and 8 kHz tone burst stimuli. Subsequently, 5 mg/kg of cisplatin were administered to all animals for 3 days intraperitoneally (i.p.) to induce ototoxicity. Half an hour prior to cisplatin, groups 1, 2 and 3 received 2 ml of saline i.p., 6 mg/kg of riluzole hydrochloride i.p., and 8 mg/kg of riluzole hydrochloride i.p., respectively, for 3 days. The auditory brainstem responses were repeated 24 hours after the last drug administration. The cochleae were analyzed by transmission electron microscopy (TEM). Results After drug administiration, for 8,000 Hz stimulus, group 1 had significantly higher threshold shifts when compared with groups 2 (p < 0.05) and 3 (p < 0.05), and there was no significant difference in threshold shifts between groups 2 and 3 (p > 0.05). Transmission electron microscopy findings demonstrated the protective effect of riluzole on the hair cells and the stria vascularis, especially in the group treated with 8 mg/kg of riluzole hydrochloride. Conclusion We can say that riluzolemay have a protective effect on cisplatin- induced ototoxicity. However, additional studies are needed to confirm these results and the mechanisms of action of riluzole.


Assuntos
Animais , Masculino , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Cisplatino/efeitos adversos , Riluzol/farmacologia , Perda Auditiva Neurossensorial/induzido quimicamente , Limiar Auditivo/efeitos dos fármacos , Estria Vascular/efeitos dos fármacos , Estria Vascular/patologia , Nervo Coclear/efeitos dos fármacos , Nervo Coclear/patologia , Riluzol/uso terapêutico , Modelos Animais , Microscopia Eletrônica de Transmissão , Cobaias , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/patologia , Degeneração Neural/induzido quimicamente
2.
Neurochem Res ; 44(7): 1726-1735, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31087207

RESUMO

Tacrolimus, a calcineurin (CaN) inhibitor, has been used for treatment of refractory allergic ocular disease, although its role in optic nerve degeneration remains to be elucidated. In this study, we investigated whether tacrolimus modulates tumor necrosis factor (TNF)-mediated axonal degeneration and whether it alters nuclear factor of activated T cells (NFATc), a downstream effector of CaN signaling. Immunoblot analysis showed no significant difference in CaNAα protein levels in optic nerve on day 3, 7, or 14 after TNF injection compared with PBS injection. However, a significant increase in NFATc1 protein level was observed in optic nerve 7 days after TNF injection. This increase was negated by simultaneous administration of tacrolimus. Administration of tacrolimus alone did not change the NFATc1 protein level in comparison to that observed after PBS injection. A significant increase in TNF protein level was observed in optic nerve 14 days after TNF injection and this increase was prevented by tacrolimus. Immunohistochemical analysis showed the immunoreactivity of NFATc1 to be increased in optic nerve after TNF injection. This increased immunoreactivity was colocalized with glial fibrillary acidic protein and was suppressed by tacrolimus. Treatment of tacrolimus significantly ameliorated the TNF-mediated axonal loss. These results suggest that tacrolimus is neuroprotective against axon loss in TNF-induced optic neuropathy and that the effect arises from suppression of the CaN/NFATc1 pathway.


Assuntos
Axônios/efeitos dos fármacos , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Doenças do Nervo Óptico/prevenção & controle , Tacrolimo/uso terapêutico , Fatores de Transcrição/antagonistas & inibidores , Animais , Axônios/patologia , Inibidores de Calcineurina/uso terapêutico , Masculino , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Nervo Óptico/patologia , Doenças do Nervo Óptico/induzido quimicamente , Doenças do Nervo Óptico/patologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
3.
Int J Dev Neurosci ; 75: 19-26, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30959098

RESUMO

Exposure to sevoflurane and other inhalational anesthetics can induce neurodegeneration in the developing brain. Although dexmedetomidine (DEX) has provided neuroprotection against hypoxic ischemic injury, relatively little is known about whether it has the neuroprotective effects against anesthetic-induced neurodegeneration. This study examined whether DEX improves the long-term cognitive dysfunction observed after exposure of neonatal rats to 3% sevoflurane. Seven-day-old rats received intraperitoneal saline (DEX 0) or DEX (6.6, 12.5, 25 µg/kg) 30 min before exposure to 3% sevoflurane with 21% oxygen for 4 h (n = 10 per group). The pups in the control group received only DEX 25 µg/kg without anesthesia. The escape latency in the Morris water maze was significantly increased in the DEX 0 group compared with the sham and control group, and the escape latency, but not the swimming path length, was significantly shorter at post-natal day 47 in the DEX 25 than in the DEX 0 group. The percent time spent in the quadrant was significantly decreased in the DEX 0 group compared with the sham and control group, and the percent time spent in the quadrant was significantly increased in the DEX 25 group compared with the DEX 0 groups. The freezing times of the DEX 0 and 6.6 groups were significantly decreased compared with those in the sham, control and DEX 25 groups. The number of NeuN-positive cells in the CA1 region was significantly decreased in the DEX 0 and 6.6 groups compared with the sham, control and DEX 25 groups. These findings indicate pre-treatment with DEX may improve long-term cognitive function and ameliorate the neuronal degeneration induced by sevoflurane exposure in neonatal rats.


Assuntos
Anestésicos Inalatórios/efeitos adversos , Dexmedetomidina/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Sevoflurano/efeitos adversos , Animais , Animais Recém-Nascidos , Cognição/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Dexmedetomidina/farmacologia , Medo , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/patologia , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar
4.
J Toxicol Sci ; 44(3): 191-199, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30842371

RESUMO

Exposure to organic mercury, especially methylmercury (MeHg), causes Minamata disease, a severe chronic neurological disorder. Minamata disease predominantly affects the central nervous system, and therefore, studies on the mechanisms of MeHg neurotoxicity have focused primarily on the brain. Although the peripheral nervous system is also affected by the organometallic compound and shows signs of neural degeneration, the mechanisms of peripheral MeHg neurotoxicity remain unclear. In the present study, we performed quantitative immunohistochemical analyses of the dorsal root ganglion (DRG) and associated sensory and motor fibers to clarify the mechanisms of MeHg-induced peripheral neurotoxicity in Wistar rats. Methylmercury chloride (6.7 mg/kg/day) was orally administrated for 5 days, followed by 2 days without administration, and this cycle was repeated once again. Seven and 14 days after the beginning of MeHg exposure, rats were anesthetized, and their DRGs and sensory and motor nerve fibers were removed and processed for immunohistochemical analyses. The frozen sections were immunostained for neuronal, Schwann cell, microglial and macrophage markers. DRG sensory neuron somata and axons showed significant degeneration on day 14. At the same time, an accumulation of microglia and the infiltration of macrophages were observed in the DRGs and sensory nerve fibers. In addition, MeHg caused significant Schwann cell proliferation in the sensory nerve fibers. In comparison, there was no noticeable change in the motor fibers. Our findings suggest that in the peripheral nervous system, MeHg toxicity is associated with neurodegenerative changes to DRG sensory neurons and the induction of a neuroprotective and/or enhancement of neurodegenerative host response.


Assuntos
Gânglios Espinais/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Compostos de Metilmercúrio/toxicidade , Microglia/efeitos dos fármacos , Degeneração Neural/induzido quimicamente , Células de Schwann/efeitos dos fármacos , Animais , Proliferação de Células , Masculino , Ratos Wistar
5.
Tissue Cell ; 56: 31-40, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30736902

RESUMO

After injury of the nervous system glial cells react according to the stimuli by modifying their morphology and function. Glia activation was reported in different kainic acid (KA)-induced neurodegeneration models. Here, we describe glial morphometric changes occurring in an excitotoxic KA-induced cervical spinal cord injury model. Concomitant degenerative and apoptotic processes are also reported. Male rats injected at the spinal cord C5 segment either with KA or saline were euthanized at post-injection (PI) days 1, 2, 3 or 7. Anti-IBA-1 and anti-GFAP antibodies were used to identify microglia and activated astrocytes, respectively, and to morphometrically characterized them. Fluoro-Jade B staining and TUNEL reaction were used to determine neuronal and glial degeneration and apoptosis. KA-injected group showed a significant increase in microglia number at the ipsilateral side by PI day 3. Different microglia reactive phenotypes were observed. Reactive microglia was still present by PI day 7. Astrocytes in KA-injected group showed a biphasic increase in number at PI days 1 and 3. Degenerative and apoptotic events were only observed in KA-injected animals, increasing mainly by PI day 1. Understanding the compromise of glia in different neurodegenerative processes may help to define possible common or specific therapeutic approaches directed towards neurorestorative strategies.


Assuntos
Anticorpos Anti-Idiotípicos/administração & dosagem , Proteína Glial Fibrilar Ácida/imunologia , Degeneração Neural/tratamento farmacológico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Anticorpos Anti-Idiotípicos/imunologia , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Proteína Glial Fibrilar Ácida/antagonistas & inibidores , Ácido Caínico/toxicidade , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/patologia , Degeneração Neural/induzido quimicamente , Degeneração Neural/imunologia , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/patologia , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/induzido quimicamente , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia
6.
Neurochem Int ; 125: 25-34, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30739037

RESUMO

Vitamin A (retinol) is involved in signaling pathways regulating gene expression and was postulated to be a major antioxidant and anti-inflammatory compound of the diet. Parkinson's disease (PD) is a progressive neurodegenerative disorder, characterized by loss of nigral dopaminergic neurons, involving oxidative stress and pro-inflammatory activation. The aim of the present study was to evaluate the neuroprotective effects of retinol oral supplementation against 6-hydroxydopamine (6-OHDA, 12 µg per rat) nigrostriatal dopaminergic denervation in Wistar rats. Animals supplemented with retinol (retinyl palmitate, 3000 IU/kg/day) during 28 days exhibited increased retinol content in liver, although circulating retinol levels (serum) were unaltered. Retinol supplementation did not protect against the loss of dopaminergic neurons (assessed through tyrosine hydroxylase immunofluorescence and Western blot). Retinol supplementation prevented the effect of 6-OHDA on Iba-1 levels but had no effect on 6-OHDA-induced GFAP increase. Moreover, GFAP levels were increased by retinol supplementation alone. Rats pre-treated with retinol did not present oxidative damage or thiol redox modifications in liver, and the circulating levels of TNF-α, IL-1ß, IL-6 and IL-10 were unaltered by retinol supplementation, demonstrating that the protocol used here did not cause systemic toxicity to animals. Our results indicate that oral retinol supplementation is not able to protect against 6-OHDA-induced dopaminergic denervation, and it may actually stimulate astrocyte reactivity without altering parameters of systemic toxicity.


Assuntos
Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Degeneração Neural/induzido quimicamente , Degeneração Neural/tratamento farmacológico , Simpatectomia Química/métodos , Vitamina A/administração & dosagem , Administração Oral , Animais , Neurônios Dopaminérgicos/metabolismo , Masculino , Degeneração Neural/metabolismo , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Resultado do Tratamento
7.
Toxicology ; 417: 64-73, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30797899

RESUMO

The activation of NADPH oxidase contributes to dopaminergic neurodegeneration induced by paraquat and maneb, two concurrently used pesticides in agriculture. However, the mechanisms remain unclear. Ferroptosis, a recently recognized form of regulated cell death, has been implicated in the pathogenesis of multiple neurodegenerative diseases. This study is designed to investigate whether ferroptosis is involved in NADPH oxidase-regulated dopaminergic neurotoxicity. In vitro study showed that paraquat and maneb exposure induced ferroptosis in SHSY5Y dopaminergic cells, which was associated with activation of NADPH oxidase. Inhibition of NADPH oxidase by apocynin or diphenyleneiodonium (DPI), two widely used NADPH oxidase inhibitors mitigated paraquat and maneb-induced ferroptotic cell death. Consistently, stimulating activation of NADPH oxidase by phorbol myristate acetate (PMA) or supplementation of H2O2 exacerbated ferroptosis in paraquat and maneb-treated SHSY5Y cells. Mechanistic inquiry revealed that NADPH oxidase activation elicited lipid peroxidation, a main driving force for ferroptosis, since both apocynin and DPI greatly reduced MDA contents and simultaneously recovered levels of glutathione and glutathione peroxidase 4 (GPX4) in paraquat and maneb-treated SHSY5Y cells. The contribution of NADPH oxidase on ferroptosis of dopaminergic neurons was further verified in vivo by showing reduced iron content, lipid peroxidation, neuroinflammation and dopaminergic neurodegeneration, which are all involved in ferroptosis, in combined apocynin and paraquat and maneb-treated mice compared with paraquat and maneb alone group. Altogether, our findings showed that NADPH oxidase contributed to paraquat and maneb-induced dopaminergic neurodegeneration through ferroptosis, providing a novel mechanism for pesticide-induced dopaminergic neurotoxicity.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Maneb/toxicidade , NADPH Oxidases/fisiologia , Degeneração Neural/induzido quimicamente , Paraquat/toxicidade , Animais , Linhagem Celular Tumoral , Neurônios Dopaminérgicos/enzimologia , Fungicidas Industriais/toxicidade , Herbicidas/toxicidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Neural/enzimologia , Distribuição Aleatória
8.
Neuropharmacology ; 148: 189-198, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30633929

RESUMO

A significant proportion of neonatal and childhood seizures are poorly controlled by existing anti-seizure drugs (ASDs), likely due to prominent differences in ionic homeostasis and network connectivity between the immature and mature brain. In addition to the poor efficacy of current ASDs, many induce apoptosis, impair synaptic development, and produce behavioral deficits when given during early postnatal development. There is growing interest in new targets, such as cannabidiol (CBD) and its propyl analog cannabidivarin (CBDV) for early life indications. While CBD was recently approved for treatment of refractory childhood epilepsies, little is known about the efficacy or safety of CBDV. Here, we addressed this gap through a systematic evaluation of CBDV against multiple seizure models in postnatal day (P) 10 and 20 animals. We also evaluated the impact of CBDV on acute neurotoxicity in immature rats. CBDV (50-200 mg/kg) displayed an age and model-specific profile of anticonvulsant action. In P10 rats, CBDV suppressed seizures only in the pentylenetetrazole model. In P20 rats, CBDV suppressed seizures in the pentylenetetrazole, DMCM, and maximal electroshock models. Between P10 and P20, we identified significant increases in mRNA expression of TRPV1 in multiple brain regions; when CBDV was tested in P20 TRPV1 knockout mice, anticonvulsant effects were attenuated. Finally, CBDV treatment generally avoided induction of neuronal degeneration in immature rats. Together, the efficacy and safety profile of CBDV suggest it may have therapeutic value for early life seizures.


Assuntos
Canabinoides/efeitos adversos , Canabinoides/uso terapêutico , Convulsões/tratamento farmacológico , Fatores Etários , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Knockout , Degeneração Neural/induzido quimicamente , Ratos , Convulsões/induzido quimicamente , Convulsões/genética , Canais de Cátion TRPV/biossíntese , Canais de Cátion TRPV/genética
9.
Neuroimage ; 189: 180-191, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30630081

RESUMO

White matter abnormalities, revealed by Diffusion Tensor Imaging (DTI), are observed in patients with Alzheimer's Disease (AD), representing neural network deficits that underlie gradual cognitive decline in patients. However, how DTI changes related to the development of Amyloid beta (Aß) and tau pathology, two key hallmarks of AD, remain elusive. We hypothesized that tauopathy induced by Aß could initiate an axonal degeneration, leading to DTI-detectable white matter abnormalities. We utilized the visual system of the transgenic p301L tau mice as a model system. Aß was injected in Lateral Geniculate Nucleus (LGN), where the Retinal Ganglion Cell (RGC) axons terminate. Longitudinal DTI was conducted to detect changes in the optic tract (OT) and optic nerve (ON), containing the distal and proximal segments of RGC axons, respectively. Our results showed DTI changes in OT (significant 13.2% reduction in axial diffusion, AxD vs. vehicle controls) followed by significant alterations in ON AxD and fractional anisotropy, FA. Histology data revealed loss of synapses, RGC axons and cell bodies resulting from the Aß injection. We further tested whether microtubule-stabilizing compound Epothilone D (EpoD) could ameliorate the damage. EpoD co-treatment with Aß was sufficient to prevent Aß-induced axon and cell loss. Using an acute injection paradigm, our data suggest that EpoD may mediate its protective effect by blocking localized, acute Aß-induced tau phosphorylation. This study demonstrates white matter disruption resulting from localized Aß, the importance of tau pathology induction to changes in white matter connectivity, and the use of EpoD as a potential therapeutic avenue to prevent the axon loss in AD.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Epotilonas/farmacologia , Corpos Geniculados/efeitos dos fármacos , Degeneração Neural , Fragmentos de Peptídeos/farmacologia , Células Ganglionares da Retina/efeitos dos fármacos , Tauopatias , Moduladores de Tubulina/farmacologia , Substância Branca , Peptídeos beta-Amiloides/administração & dosagem , Animais , Imagem de Tensor de Difusão , Modelos Animais de Doenças , Epotilonas/administração & dosagem , Camundongos , Degeneração Neural/induzido quimicamente , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/tratamento farmacológico , Degeneração Neural/prevenção & controle , Fragmentos de Peptídeos/administração & dosagem , Tauopatias/induzido quimicamente , Tauopatias/diagnóstico por imagem , Tauopatias/tratamento farmacológico , Tauopatias/patologia , Moduladores de Tubulina/administração & dosagem , Substância Branca/diagnóstico por imagem , Substância Branca/efeitos dos fármacos
10.
PLoS One ; 14(1): e0210995, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30677061

RESUMO

Chemotherapy-induced peripheral neuropathy (CiPN) is a serious adverse effect in the clinic, but nonclinical assessment methods in animal studies are limited to labor intensive behavioral tests or semi-quantitative microscopic evaluation. Hence, microRNA (miRNA) biomarkers and automated in-life behavioral tracking were assessed for their utility as non-invasive methods. To address the lack of diagnostic biomarkers, we explored miR-124, miR-183 and miR-338 in a CiPN model induced by paclitaxel, a well-known neurotoxic agent. In addition, conventional and Vium's innovative Digital Vivarium technology-based in-life behavioral tests and postmortem microscopic examination of the dorsal root ganglion (DRG) and the sciatic nerve were performed. Terminal blood was collected on days 8 or 16, after 20 mg/kg paclitaxel was administered every other day for total of 4 or 7 doses, respectively, for plasma miRNA quantification by RT-qPCR. DRG and sciatic nerve samples were collected from mice sacrificed on day 16 for miRNA quantification. Among the three miRNAs analyzed, only miR-124 was statistically significantly increased (5 fold and 10 fold on day 8 and day 16, respectively). The increase in circulating miR-124 correlated with cold allodynia and axonal degeneration in both DRG and sciatic nerve. Automated home cage motion analysis revealed for the first time that nighttime motion was significantly decreased (P < 0.05) in paclitaxel-dosed animals. Although both increase in circulating miR-124 and decrease in nighttime motion are compelling, our results provide positive evidence warranting further testing using additional peripheral nerve toxicants and diverse experimental CiPN models.


Assuntos
Antineoplásicos/toxicidade , MicroRNA Circulante/sangue , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Animais , Antineoplásicos Fitogênicos/toxicidade , Automação , Comportamento Animal/efeitos dos fármacos , Biomarcadores/sangue , MicroRNA Circulante/genética , MicroRNA Circulante/metabolismo , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Hiperalgesia/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/sangue , MicroRNAs/genética , MicroRNAs/metabolismo , Movimento , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Paclitaxel/toxicidade , Doenças do Sistema Nervoso Periférico/fisiopatologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia
11.
Neurotox Res ; 35(3): 711-723, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30666559

RESUMO

The link between neonatal BMAA exposure and neurodegeneration has recently been demonstrated in rodents. We therefore investigated the behavioral and histopathological dose response to BMAA administered as a single dose. We report here that exposure to a BMAA dose as low as 50 mg/kg on PND 3 caused mild short-term behavioral alterations as well as beta-amyloid deposition together with neuronal loss in the hippocampus of adult rats. Additionally, all histopathological abnormalities and behavioral deficits that had been observed in a previous study in the brain and spinal cord tissue of rats exposed to 400 mg/kg BMAA on PND 3 were also observed here in the brain and spinal cord tissue of male and female rats exposed to 100 mg/kg BMAA at the same age, although the proteinopathy burdens and volume losses were lower. Both behavioral deficits and histopathology increased with increasing dose, and a single neonatal BMAA exposure at a dose of 100 mg/kg was the lowest dose able to cause clinical signs of toxicity, behavioral deficits, and neuropathology that are typically observed in AD, PD, and/or ALS patients.


Assuntos
Diamino Aminoácidos/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Doenças Neurodegenerativas/induzido quimicamente , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Animais , Animais Recém-Nascidos , Animais não Endogâmicos , Encéfalo/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Doenças Neurodegenerativas/patologia , Distribuição Aleatória , Ratos Sprague-Dawley , Fatores Sexuais , Medula Espinal/crescimento & desenvolvimento
12.
Eur. j. anat ; 23(1): 65-76, ene. 2019. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-181632

RESUMO

The level of heavy metals in Nigeria waterways is grossly influenced by the irrepressible disposal and recycling of electronic waste. The impact of heavy metals obtained from waterways on the prefrontal cortex of experimental rats was investigated in this study. Thirty (30) adult male Wistar rats weighing about 150-180 g were used in this study. Ten rats apiece were assigned randomly into three groups. Pooled sampled water and water containing the highest average concentration of combined heavy metals recorded in the waterways was given to the Wistar rats within the treatment groups ad libitum for 65 days. Blood sera were obtained for analysis of oxidative stress markers. The prefrontal cortex was processed for paraffin embedding, and sections stained for histological, histochemical and immunochemical evaluations. P < 0.05 was regarded as significant for data using one-way analysis of variance. Oxidative damage was observed in animals from the treatment groups when compared to the control. The analysed levels of oxidative stress markers showed statistically significant differences, except between groups given pooled sampled water and combined metals. Neurodegeneration was attested from the histological and histochemical evaluations, and the immunohistochemical evaluation revealed marked astrocytosis with induced oxidative stress while comparing the experimental groups


No disponible


Assuntos
Animais , Ratos , Metais Pesados/efeitos adversos , Doenças Neurodegenerativas/induzido quimicamente , Córtex Pré-Frontal/química , Córtex Pré-Frontal/lesões , Cérebro/anatomia & histologia , Degeneração Neural/induzido quimicamente , Ratos Wistar , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Lobo Frontal/metabolismo , Doenças Neurodegenerativas/veterinária , Degeneração Neural/veterinária
13.
Neurotoxicology ; 70: 48-61, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30399392

RESUMO

Huntington's disease (HD) is functionally linked to environmental factors including cigarette use and dyshomeostasis in the levels of metals. Interestingly, one of the most abundant heavy metals in cigarettes is cadmium (Cd), which also accumulates in the striatum and causes neurotoxicity upon exposure. Thus, we hypothesized that heterozygous huntingtin (HTT), responsible for the majority of cases of HD in patients, in combination with Cd exposure would cause neurotoxicity and neurodegeneration via increased intracellular accumulation of Cd and activation of oxidative stress signaling mechanisms in a mouse striatal cell line model of HD. We report that heterozygous HTT striatal cells are significantly more susceptible to Cd-induced cytotoxicity as compared to wild-type HTT cells upon exposure for 48 h. The heterozygous HTT and Cd-induced cytotoxicity led to a NADPH oxidase (NOX) mediated oxidative stress that was attenuated by exogenous antioxidants and a NOX inhibitor, apocynin. Heterozygous HTT coupled with Cd exposure caused increased expression of protein kinase C δ (PKCδ) and other key oxidative stress proteins levels, enhanced the activation of caspase-9 and caspase-3 mediated apoptosis, and blocked the overexpression of extracellular signal-regulated kinase (ERK). We observed significantly greater intracellular accumulation of Cd and reduced expression of divalent metal transporter 1 (DMT1) protein in the heterozygous HTT striatal cells upon Cd exposure. Treatment with zinc, manganese, and iron as well as exogenous antioxidants significantly attenuated the Cd-induced cytotoxicity. Collectively, these results demonstrate that heterozygous HTT exhibits greater neurotoxic properties when coupled with Cd exposure to cause cell death via caspase mediated apoptosis, altered metal transport, and modulation of ERK and PKCδ dependent oxidative signaling mechanisms.


Assuntos
Cádmio/toxicidade , Corpo Estriado/metabolismo , Proteína Huntingtina/metabolismo , Degeneração Neural/metabolismo , Estresse Oxidativo/fisiologia , Proteína Quinase C-delta/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Linhagem Celular Transformada , Corpo Estriado/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteína Huntingtina/genética , Metais Pesados/metabolismo , Camundongos , Camundongos Transgênicos , Degeneração Neural/induzido quimicamente , Degeneração Neural/genética , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
14.
Neurotox Res ; 35(2): 421-431, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30328585

RESUMO

A single injection of LPS produced low-grade neuroinflammation leading to Parkinson's disease (PD) in mice several months later. Whether such a phenomenon occurs in rats and whether such low-grade neuroinflammation would aggravate rotenone (ROT) neurotoxicity and disrupts circadian clock gene/protein expressions were examined in this study. Male rats were given two injections of LPS (2.5-7.5 mg/kg), and neuroinflammation and dopamine neuron loss were evident 3 months later. Seven months after a single LPS (5 mg/kg) injection, rats received low doses of ROT (0.5 mg/kg, sc, 5 times/week for 4 weeks) to examine low-grade neuroinflammation on ROT toxicity. LPS plus ROT produced more pronounced non-motor and motor dysfunctions than LPS or ROT alone in behavioral tests, and decreased mitochondrial complex 1 activity, together with aggravated neuroinflammation and neuron loss. The expressions of clock core genes brain and muscle Arnt-like protein-1 (Bmal1), locomotor output cycles kaput (Clock), and neuronal PAS domain protein-2 (Npas2) were decreased in LPS, ROT, and LPS plus ROT groups. The expressions of circadian feedback genes Periods (Per1 and Per2) were also decreased, but Cryptochromes (Cry1 and Cry2) were unaltered. The circadian clock target genes nuclear receptor Rev-Erbα (Nr1d1), and D-box-binding protein (Dbp) expressions were also decreased. Consistent with the transcript levels, circadian clock protein BMAL1, CLOCK, NR1D1, and DBP were also decreased. Thus, LPS-induced chronic low-grade neuroinflammation potentiated ROT neurotoxicity and disrupted circadian clock gene/protein expression, suggesting a role of disrupted circadian in PD development and progression. Graphical Abstract ᅟ.


Assuntos
Relógios Circadianos/fisiologia , Mediadores da Inflamação/metabolismo , Degeneração Neural/metabolismo , Proteínas Circadianas Period/biossíntese , Rotenona/toxicidade , Animais , Relógios Circadianos/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Expressão Gênica , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inseticidas/toxicidade , Lipopolissacarídeos/toxicidade , Masculino , Degeneração Neural/induzido quimicamente , Proteínas Circadianas Period/genética , Ratos , Ratos Sprague-Dawley
15.
Toxicology ; 411: 154-162, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30336192

RESUMO

Humans are exposed simultaneously to a variety of neurotoxic agents, including manganese (Mn) and methylmercury (MeHg). Therefore, the study of combined exposures to toxicants is timely. This work aimed to study changes in cholinergic system focusing on acetylcholinesterase (ace-2), monoaminergic system focusing on vesicular monoamine transporter (VMAT, cat-1) expression, to address changes in antioxidant enzymatic systems, namely, the expression of superoxide dismutase (sod-3 and sod-4) and catalase (ctl-3), as well as worm reproduction and locomotion. C. elegans in the L1 larval stage were exposed to Mn, MeHg or both. All analyses were done 24 h after the end of exposure, except for behavior and reproduction tests that were assessed in L4 larval stage worms. The values obtained for lethal dose 50% (LD50) were 17.78 mM for Mn and 30.63 µM for MeHg. It was observed that body bends, pharyngeal pumping and brood size decreased in worms exposed to metals when undergoing combined exposures. Relative mRNA content of ace-2, cat-1, sod-3, sod-4 and ctl-3 was increased at the highest concentration of the interaction (50 mM Mn + 50 µM MeHg). Cholinergic degeneration was observed in all groups co-exposed to both metals. Notably, combined exposure to metals was more toxic to the worms than when exposed to a single metal.


Assuntos
Monoaminas Biogênicas/biossíntese , Caenorhabditis elegans , Manganês/toxicidade , Compostos de Metilmercúrio/toxicidade , Transtornos dos Movimentos , Estresse Oxidativo/efeitos dos fármacos , Sistema Nervoso Parassimpático/efeitos dos fármacos , Animais , Proteínas de Caenorhabditis elegans/biossíntese , Proteínas de Caenorhabditis elegans/genética , Feminino , Larva/efeitos dos fármacos , Dose Letal Mediana , Masculino , Manganês/farmacocinética , Compostos de Metilmercúrio/farmacocinética , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Reprodução , Regulação para Cima/efeitos dos fármacos
16.
Neurotox Res ; 35(2): 410-420, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30276717

RESUMO

Proteostasis and oxidative stress were evaluated in motor cortex and spinal cord of aged Lewis rats exposed to 1 mg/kg/day of rotenone during 4 or 8 weeks, prior or after practicing three protocols of mild treadmill running. Results demonstrated that exercise done after the beginning of neurodegeneration reverted the increased oxidative stress (measured by H2O2 levels and SOD activity), increased neuron strength, and improved proteostasis in motor cortex. Spinal cord was not affected. Treadmill running practiced before neurodegeneration protected cortical motor neurons of the rotenone-exposed rats; but in this case, oxidative stress was not altered, whereas proteasome activity was increased and autophagy decreased. Spinal cord was not protected when exercise was practiced before neurodegeneration. Prolonged treadmill running (10 weeks) increased oxidative stress, autophagy, and proteasome activity, whereas neuron viability was decreased in motor cortex. In spinal cord, this protocol decreased oxidative stress and increased proteasome activity. Major conclusions were that treadmill running practiced before or after the beginning of neurodegeneration may protect motor cortex neurons, whereas prolonged mild running seems to be beneficial for spinal cord.


Assuntos
Teste de Esforço/métodos , Córtex Motor/metabolismo , Degeneração Neural/metabolismo , Estresse Oxidativo/fisiologia , Condicionamento Físico Animal/fisiologia , Proteostase/fisiologia , Animais , Inseticidas/toxicidade , Masculino , Córtex Motor/efeitos dos fármacos , Degeneração Neural/induzido quimicamente , Degeneração Neural/terapia , Estresse Oxidativo/efeitos dos fármacos , Condicionamento Físico Animal/métodos , Proteostase/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Rotenona/toxicidade
17.
J Cell Physiol ; 234(3): 3007-3019, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30206943

RESUMO

An elevated level of homocysteine (Hcy) leads to hyperhomocysteinemia (HHcy), which results in vascular dysfunction and pathological conditions identical to stroke symptoms. Hcy increases oxidative stress and leads to increase in blood-brain barrier permeability and leakage. Hydrogen sulfide (H2 S) production during the metabolism of Hcy has a cerebroprotective effect, although its effectiveness in Hcy-induced neurodegeneration and neurovascular permeability is less explored. Therefore, the current study was designed to perceive the neuroprotective effect of exogenous H 2 S against HHcy, a cause of neurodegeneration. To test this hypothesis, we used four groups of mice: control, Hcy, control + sodium hydrosulfide hydrate (NaHS), and Hcy + NaHS, and an HHcy mice model in Swiss albino mice by giving a dose of 1.8 g of dl-Hcy/L in drinking for 8-10 weeks. Mice that have 30 µmol/L Hcy were taken for the study, and a H 2 S supplementation of 20 µmol/L was given for 8 weeks to all groups of mice. HHcy results in the rise of the levels of superoxide and nitrite, although a concomitant decrease in the level of superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, and arginase in oxidative stress and a concomitant decrease in the endogenous level of H 2 S. Although H 2 S supplementation ameliorated, the effect of HHcy and the levels of H 2 S returned to the average level in HHcy animals supplemented with H 2 S. Interestingly, H 2 S supplementation ameliorated neurovascular remodeling and neurodegeneration. Thus, our study suggested that H 2 S could be a beneficial therapeutic candidate for the treatment of Hcy-associated neurodegeneration, such as stroke and neurovascular disorders.


Assuntos
Transtornos Cerebrovasculares/tratamento farmacológico , Sulfeto de Hidrogênio/farmacologia , Hiper-Homocisteinemia/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Transtornos Cerebrovasculares/induzido quimicamente , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/patologia , Modelos Animais de Doenças , Homocisteína/toxicidade , Humanos , Hiper-Homocisteinemia/genética , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Metaloproteinase 9 da Matriz/genética , Camundongos , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
18.
J Trace Elem Med Biol ; 51: 19-27, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30466930

RESUMO

Despite the vast distribution among tissues, the central nervous system (CNS) represents the main target of methylmercury (MeHg) toxicity. However, few studies have evaluated the effects of MeHg exposure on the CNS at equivalent doses to human environmental exposure. In our study, we evaluated the motor cortex, an important area of motor control, in adult rats chronically exposed to MeHg in a concentration equivalent to those found in fish-eating populations exposed to mercury (Hg). The parameters evaluated were total Hg accumulation, oxidative stress, tissue damage, and behavioral assessment in functional actions that involved this cortical region. Our results show in exposed animals a significantly greater level of Hg in the motor cortex; increase of nitrite levels and lipid peroxidation, associated with decreased antioxidant capacity against peroxyl radicals; reduction of neuronal and astrocyte density; and poor coordination and motor learning impairment. Our data showed that chronic exposure at low doses to MeHg is capable of promoting damages to the motor cortex of adult animals, with changes in oxidative biochemistry misbalance, neurodegeneration, and motor function impairment.


Assuntos
Compostos de Metilmercúrio/farmacologia , Córtex Motor/efeitos dos fármacos , Córtex Motor/fisiopatologia , Destreza Motora/efeitos dos fármacos , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Compostos de Metilmercúrio/administração & dosagem , Córtex Motor/patologia , Ratos , Ratos Wistar
19.
Sci Rep ; 8(1): 16584, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30410110

RESUMO

The tetanus toxin C-fragment is a non-toxic peptide that can be transported from peripheral axons into spinal motoneurons. In in vitro experiments it has been shown that this peptide activates signaling pathways associated with Trk receptors, leading to cellular survival. Because motoneuron degeneration is the main pathological hallmark in motoneuron diseases, and excitotoxicity is an important mechanism of neuronal death in this type of disorders, in this work we tested whether the tetanus toxin C-fragment is able to protect MN in the spinal cord in vivo. For this purpose, we administered the peptide to rats subjected to excitotoxic motoneuron degeneration induced by the chronic infusion of AMPA in the rat lumbar spinal cord, a well-established model developed in our laboratory. Because the intraspinal infusion of the fragment was only weakly effective, whereas the i.m. administration was remarkably neuroprotective, and because the i.m. injection of an inhibitor of Trk receptors diminished the protection, we conclude that such effects require a retrograde signaling from the neuromuscular junction to the spinal motoneurons. The protection after a simple peripheral route of administration of the fragment suggests a potential therapeutic use of this peptide to target spinal MNs exposed to excitotoxic conditions in vivo.


Assuntos
Doença dos Neurônios Motores/prevenção & controle , Degeneração Neural/prevenção & controle , Fragmentos de Peptídeos/administração & dosagem , Medula Espinal/patologia , Toxina Tetânica/administração & dosagem , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/efeitos adversos , Animais , Modelos Animais de Doenças , Injeções Intramusculares , Injeções Espinhais , Masculino , Doença dos Neurônios Motores/induzido quimicamente , Doença dos Neurônios Motores/metabolismo , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , Fragmentos de Peptídeos/farmacologia , Fosforilação , Ratos , Receptor trkA/metabolismo , Medula Espinal/metabolismo , Toxina Tetânica/farmacologia
20.
Glia ; 66(11): 2366-2384, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30375063

RESUMO

Excitotoxicity is well known in the neuronal death in the brain and is also linked to neuronal damages in the retina. Recent accumulating evidence show that microglia greatly affect excitotoxicity in the brain, but their roles in retina have received only limited attention. Here, we report that retinal excitotoxicity is mediated by microglia. To this end, we employed three discrete methods, that is, pharmacological inhibition of microglia by minocycline, pharmacological ablation by an antagonist for colony stimulating factor 1 receptor (PLX5622), and genetic ablation of microglia using Iba1-tTA::DTAtetO/tetO mice. Intravitreal injection of NMDA increased the number of apoptotic retinal ganglion cells (RGCs) followed by reduction in the number of RGCs. Although microglia did not respond to NMDA directly, they became reactive earlier than RGC damages. Inhibition or ablation of microglia protected RGCs against NMDA. We found up-regulation of proinflammatory cytokine genes including Il1b, Il6 and Tnfa, among which Tnfa was selectively blocked by minocycline. PLX5622 also suppressed Tnfa expression. Tumor necrosis factor α (TNFα) signals were restricted in microglia at very early followed by spreading into other cell types. TNFα up-regulation in microglia and other cells were significantly attenuated by minocycline and PLX5622, suggesting a central role of microglia for TNFα induction. Both inhibition of TNFα and knockdown of TNF receptor type 1 by siRNA protected RGCs against NMDA. Taken together, our data demonstrate that a phenotypic change of microglia into a neurotoxic one is a critical event for the NMDA-induced degeneration of RGCs, suggesting an importance of non-cell-autonomous mechanism in the retinal neuronal excitotoxicity.


Assuntos
Morte Celular/fisiologia , Citocinas/metabolismo , Microglia/fisiologia , Células Ganglionares da Retina/fisiologia , Aminopiridinas/farmacologia , Animais , Animais Recém-Nascidos , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/genética , Agonistas de Aminoácidos Excitatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/ultraestrutura , N-Metilaspartato/farmacologia , Degeneração Neural/induzido quimicamente , Traumatismos do Nervo Óptico/induzido quimicamente , Compostos Orgânicos/farmacologia , Pirróis/farmacologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/ultraestrutura , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição Brn-3A/genética , Fator de Transcrição Brn-3A/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA