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1.
Brain Res ; 1835: 148908, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38582416

RESUMO

BDNF, a neurotrophic factor, and its receptors have been implicated in the pathophysiology of mild traumatic brain injury (mTBI). The brainstem houses many vital functions, that are also associated with signs and symptoms of mTBI, but has been understudied in mTBI animal models. We determined the extent to which neurotrophic protein and associated receptor expression is affected within the brainstem of adult rats following mTBI. Their behavioral function was assessed and temporal expression of the 'negative' regulators of neuronal function (p75, t-TrkB, and pro-BDNF) and 'positive' neuroprotective (FL-TrkB and m-BDNF) protein isoforms were determined via western blot and immunohistochemistry at 1, 3, 7, and 14 post-injury days (PID) following mTBI or sham (control) procedure. Within the brainstem, p75 expression increased at PID 1 vs. sham animals. t-TrkB and pro-BDNF expression increased at PID 7 and 14. The 'positive' protein isoforms of FL-TrkB and m-BDNF expression were increased only at PID 7. The ratio of t-TrkB:FL-TrkB (negative:positive) was substantial across groups and time points, suggesting a negative impact of neurotrophic signaling on neuronal function. Additional NeuN experiments revealed cell death occurring within a subset of neurons within the medulla. While behavioral measures improved by PID 7-14, negative neurotrophic biochemical responses persisted. Despite the assertion that mTBI produces "mild" injury, evidence of cell death was observed in the medulla. Ratios of TrkB and BDNF isoforms with conflicting functions suggest that future work should specifically measure each subtype since they induce opposing downstream effects on neuronal function.


Assuntos
Tronco Encefálico , Fator Neurotrófico Derivado do Encéfalo , Ratos Sprague-Dawley , Receptor trkB , Animais , Masculino , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Receptor trkB/metabolismo , Tronco Encefálico/metabolismo , Ratos , Concussão Encefálica/metabolismo , Modelos Animais de Doenças , Neurônios/metabolismo , Isoformas de Proteínas/metabolismo , Fatores de Tempo , Proteínas do Tecido Nervoso/metabolismo , Lesões Encefálicas Traumáticas/metabolismo
2.
Environ Toxicol ; 32(3): 956-969, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27296064

RESUMO

Carbaryl, a widely used carbamate-based insecticide, is a potent anticholinesterase known to induce delayed neurotoxicity following chronic exposure. However, its potential toxic effects on the cochlea, the sensory organ for hearing that contains cholinergic efferent neurons and acetylcholine receptors on the hair cells (HC) and spiral ganglion neurons has heretofore not been evaluated. To assess ototoxic potential of carbaryl, cochlear organotypic cultures from postnatal day 3 rats were treated with doses of carbaryl ranging from 50 to 500 µM for 48 h up to 96 h. Carbaryl damaged both the sensory HC and spiral ganglion neurons in a dose- and duration-dependent manner. HC and neuronal damage was observed at carbaryl concentrations as low as 50 µM after 96-h treatment and 100 µM after 48-h treatment. Hair cell was greatest in the high frequency basal region of the cochlea and progressively decreased towards the apex consistent with the majority of ototoxic drugs. In contrast, damage to the spiral ganglion neurons was of similar magnitude in the basal and apical regions of the cochlea. Carbaryl damage was characterized by soma shrinkage, nuclear condensation and fragmentation, and blebbing, morphological features of programmed cell death. Carbaryl upregulated the expression of executioner caspase-3 in HC and spiral ganglion neurons indicating that cellular damage occurred primarily by caspase-mediated apoptosis. These results suggest that chronic exposure to carbaryl and other carbamate anticholinesterases may be ototoxic. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 956-969, 2017.


Assuntos
Apoptose/efeitos dos fármacos , Carbaril/toxicidade , Cóclea/efeitos dos fármacos , Animais , Caspase 3/metabolismo , Células Cultivadas , Cóclea/metabolismo , Cóclea/patologia , Células Ciliadas Auditivas/citologia , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Microscopia Confocal , Ratos , Ratos Sprague-Dawley , Gânglio Espiral da Cóclea/efeitos dos fármacos , Gânglio Espiral da Cóclea/metabolismo , Gânglio Espiral da Cóclea/patologia
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