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1.
Muscle Nerve ; 60(4): 367-375, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31107560

RESUMO

INTRODUCTION: Topical application of lidocaine-and-prilocaine (LP) cream attenuates the functionality of small cutaneous nerve fibers. The aim of this human study was to measure the underlying excitability modulation of small cutaneous nerve fibers using a novel and fast perception threshold tracking (PTT) technique. METHODS: Small sensory fibers were selectively blocked by 120-minute topical application of LP and confirmed by quantitative sensory testing. Excitability changes of small (activated by a specially designed pin electrode) and large (patch electrode) nerve fibers were assessed as the strength-duration relation and threshold electrotonus. RESULTS: The excitability assessed by the strength-duration relation and threshold electrotonus was significantly modulated for the small afferents (P < 0.05, Wilcoxon's test) but not the large afferents. DISCUSSION: This novel PTT technique was able to assess inhibition of membrane properties of small cutaneous fibers, suggesting the usefulness of the technique as a diagnostic method for assessing impairment of small fibers, as seen in many types of polyneuropathies.


Assuntos
Anestésicos Locais/farmacologia , Combinação Lidocaína e Prilocaína/farmacologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Limiar Sensorial/efeitos dos fármacos , Neuropatia de Pequenas Fibras/diagnóstico , Administração Cutânea , Adulto , Estudos Cross-Over , Método Duplo-Cego , Estimulação Elétrica , Eletrodiagnóstico , Feminino , Voluntários Saudáveis , Humanos , Masculino , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/efeitos dos fármacos , Fibras Nervosas Amielínicas/fisiologia , Limiar Sensorial/fisiologia , Adulto Jovem
2.
Artigo em Inglês | MEDLINE | ID: mdl-30893812

RESUMO

Osteopontin (OPN) is a multi-functional protein that binds to integrin and calcium-binding phosphoprotein. OPN is required for normal neuronal development and its axonal myelination. We studied the combined effect of lead (Pb) and ascorbic acid treatment on OPN expression in the developing cerebellum. We randomly divided pregnant female rats into three groups: control, Pb (lead acetate, 0.3%, drinking water), and Pb plus ascorbic acid (PA; ascorbic acid, 100 mg/kg, oral intubation) groups. The blood level of Pb was significantly increased, while ascorbic acid reduced Pb levels in the dams and pups. At postnatal day (PND) 21, results from Nissl staining and OPN immunohistochemistry demonstrated that OPN was detected in the Purkinje cell layer in the cerebellum. Ascorbic acid treatment mitigated Pb exposure-induced reduction in the number of intact Purkinje cells and OPN immunoreactive Purkinje cells in the cerebellum of pups. In addition, Pb-induced reduction in the number of oligodendrocytes and myelin-associated glycoprotein is associated with the malformation of the myelin sheath. Ascorbic acid provided protection from Pb-induced impairments. Pb-induced structural deficits in the cerebellum resulted in functional deterioration observed during locomotive tests (bar holding test and wire mesh ascending test), while ascorbic acid ameliorated these harmful effects. Present results suggest that the change of OPN is associated with myelination in the developing cerebellum. The results also demonstrated that exposure to Pb is harmful, while ascorbic acid treatment is beneficial.


Assuntos
Ácido Ascórbico/farmacologia , Cerebelo/efeitos dos fármacos , Cerebelo/crescimento & desenvolvimento , Chumbo/toxicidade , Osteopontina/metabolismo , Animais , Axônios/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Osteopontina/genética , Gravidez , Distribuição Aleatória , Ratos
3.
Neurotoxicology ; 70: 161-179, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30471306

RESUMO

During the mammalian brain development, oligodendrocyte progenitor cells (OPCs) are generated from neuroepithelium and migrate throughout the brain. Myelination is a tightly regulated process which involves time framed sequential events of OPCs proliferation, migration, differentiation and interaction with axons for functional insulated sheath formation. Myelin is essential for efficient and rapid conduction of electric impulses and its loss in the hippocampus of the brain may result in impaired memory and long-term neurological deficits. Carbofuran, a carbamate pesticide is known to cause inhibition of hippocampal neurogenesis and memory dysfunctions in rats. Nonetheless, the effects of carbofuran on OPCs proliferation, fate determination, maturation/differentiation and myelination potential in the hippocampus of the rat brain are still completely elusive. Herein, we investigated the effects of sub-chronic exposure of carbofuran during two different time periods including prenatal and adult brain development in rats. We observed carbofuran hampers OPCs proliferation (BrdU incorporation) and oligodendroglial differentiation in vitro. Similar effects of carbofuran were also observed in the hippocampus region of the brain at both the time points. Carbofuran exposure resulted in reduced expression of key genes and proteins involved in the regulation of oligodendrocyte development and functional myelination. It also affects the survival of oligodendrocytes by inducing apoptotic cell death. The ultrastructural analysis of myelin architecture clearly depicted carbofuran-mediated negative effects on myelin compaction and g-ratio alteration. Conclusively, our study demonstrated that carbofuran alters myelination potential in the hippocampus, which leads to cognitive deficits in rats.


Assuntos
Carbofurano/toxicidade , Hipocampo/efeitos dos fármacos , Inseticidas/toxicidade , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Fatores Etários , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Feminino , Hipocampo/patologia , Hipocampo/ultraestrutura , Masculino , Fibras Nervosas Mielinizadas/patologia , Fibras Nervosas Mielinizadas/ultraestrutura , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Oligodendroglia/patologia , Oligodendroglia/ultraestrutura , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar
4.
Neurosci Lett ; 694: 104-110, 2019 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-30423401

RESUMO

OBJECTIVE: To explore the pathogenesis of depression and the possible mechanism of the effects of selective serotonin reuptake inhibitors (SSRIs) on the myelinated fibers and myelin sheaths in the white matter during the antidepressant action of fluoxetine. METHODS: In this study, Sprague Dawley (SD) rats were divided into a Control group, a group treated with CUS and no drugs (CUS/Standard group) and a group treated with CUS and fluoxetine (CUS/FLX group). The CUS/FLX group was treated with fluoxetine at dose of 5 mg/kg for 21 days. The white matter volume, the myelinated fiber parameters and the myelin sheath volume in the white matter were calculated from transmission electron microscope images through unbiased stereological methods. RESULTS: The total volume and total length of myelinated fibers;and mean volume of white matter of the CUS/Standard group were significantly decreased compared to values from the control group (p = 0.025, p = 0.007, p = 0.000), whereas no significant differences in these stereological parameters were found between the CUS/Standard and CUS/FLX groups (p > 0.05). CONCLUSIONS: Fluoxetine successfully treated depression-like behavior but had no effects on the white matter or its component myelinated fibers in the CUS rat model of depression.


Assuntos
Antidepressivos de Segunda Geração/administração & dosagem , Depressão/tratamento farmacológico , Depressão/patologia , Fluoxetina/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , Substância Branca/efeitos dos fármacos , Substância Branca/ultraestrutura , Animais , Depressão/etiologia , Modelos Animais de Doenças , Masculino , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/ultraestrutura , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/ultraestrutura , Ratos Sprague-Dawley , Estresse Psicológico/complicações
5.
Neurosci Lett ; 685: 131-136, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30157448

RESUMO

Amisulpride is an effective antipsychotic for the treatment of schizophrenia with a lower propensity for extrapyramidal adverse effects than conventional antipsychotics. However, no study has investigated white matter (WM) integrity in patients with schizophrenia in relation to treatment response after amisulpride administration. Here, we investigated the associations of WM integrity with severity reductions in clinical symptoms in drug-free patients with schizophrenia at an early stage of amisulpride treatment. Nineteen patients with schizophrenia (SZ) and 15 healthy controls (HCs) participated in the present study. Diffusion tensor imaging data were acquired from all participants at baseline. All SZ participants began treatment with 200 mg of amisulpride per day. The dose was increased up to 1200 mg/day within 2 weeks depending on the severity of clinical symptoms, and maintained for the subsequent 6 weeks. Initially, and after 8 weeks of amisulpride treatment, SZ participants were assessed for the severity of overall illness, positive and negative symptoms, and motor side effects. SZ participants showed lower integrity in several WM regions, including the corpus callosum and fronto-temporal connections, when compared to HCs. Furthermore, lower WM integrity in fronto-temporo-limbic regions at baseline was found to be associated with severity reductions in positive symptoms after 8 weeks. Our findings suggest that WM integrity at the early stage of treatment may serve as a possible predictive marker for treatment response.


Assuntos
Amissulprida/farmacologia , Antipsicóticos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Substância Branca/efeitos dos fármacos , Adulto , Amissulprida/uso terapêutico , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas Mielinizadas/efeitos dos fármacos
6.
Toxicology ; 406-407: 92-103, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29894704

RESUMO

Organophosphates (OPs) are found in hundreds of valuable agricultural, industrial, and commercial compounds; however, they have also been associated with a variety of harmful effects in humans. The acute toxicity of OPs is attributed to the inhibition of the enzyme acetylcholinesterase (AChE); however, this mechanism may not account for all of the deleterious neurologic effects of OPs, especially at doses that produce no overt signs of acute toxicity. In this study, the effects of two weeks of daily subcutaneous exposure to the OP-nerve agent diisopropylfluorophosphate (DFP) in doses ranging from 0.125-0.500 mg/kg on whole brain volume, white matter, and gray matter integrity were evaluated in post mortem tissues using histology and magnetic resonance imaging (MRI) methods. The effects of DFP on axonal transport in the brains of living rats were evaluated using a manganese-enhanced MRI (MEMRI) method. DFP was associated with dose-dependent impairments in red blood cell and brain AChE (down to 29 and 18% of control, respectively at the highest dose), 24 h after the last injection. However, there were no visible signs of cholinergic toxicity noted in any portion of the study. Moreover, histological and MRI analysis of post mortem brains did not reveal any pronounced alterations of whole brain, white matter, or gray matter volumes associated with DFP. Electron microscopy did reveal a DFP-related increase in structural disruptions of myelinated axons (i.e., decompactions) in the fimbria region on the corpus callosum. MEMRI indicated that DFP was also associated with dose-dependent decreases in axonal transport in the brains of living rats, an effect that was also present after a 30-day (DFP-free) washout period, when AChE was not significantly inhibited. These results indicate that repeated exposures to the nerve agent, DFP at doses that are below the threshold for acute toxicity, can result in alterations in myelin structure and persistent decreases in axonal transport in the rodent brain. These observations could explain some of the long-term neurological deficits that have been observed in humans who have been repeatedly exposed to OPs.


Assuntos
Transporte Axonal/efeitos dos fármacos , Axônios/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Isoflurofato/toxicidade , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Animais , Transporte Axonal/fisiologia , Axônios/patologia , Axônios/ultraestrutura , Encéfalo/patologia , Encéfalo/ultraestrutura , Inibidores da Colinesterase/administração & dosagem , Relação Dose-Resposta a Droga , Isoflurofato/administração & dosagem , Masculino , Fibras Nervosas Mielinizadas/patologia , Fibras Nervosas Mielinizadas/ultraestrutura , Ratos , Ratos Wistar
7.
Neurobiol Dis ; 118: 22-39, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29940337

RESUMO

Intraventricular hemorrhage (IVH) in preterm infants results in reduced proliferation and maturation of oligodendrocyte progenitor cells (OPCs), and survivors exhibit reduced myelination and neurological deficits. Wnt signaling regulates OPC maturation and myelination in a context dependent manner. Herein, we hypothesized that the occurrence of IVH would downregulate Wnt signaling, and that activating Wnt signaling by GSK-3ß inhibition or Wnt3A recombinant human protein (rh-Wnt3A) treatment might promote maturation of OPCs, myelination of the white matter, and neurological recovery in premature rabbits with IVH. These hypotheses were tested in autopsy samples from preterm infants and in a rabbit model of IVH. Induction of IVH reduced expressions of activated ß-catenin, TCF-4, and Axin2 transcription factors in preterm newborns. Both AR-A014418 (ARA) and Wnt-3A treatment activated Wnt signaling. GSK-3ß inhibition by intramuscular ARA treatment accelerated maturation of OPCs, myelination, and neurological recovery in preterm rabbits with IVH compared to vehicle controls. In contrast, intracerebroventricular rh-Wnt3A treatment failed to enhance myelination and neurological function in rabbits with IVH. ARA treatment reduced microglia infiltration and IL1ß expression in rabbits with IVH relative to controls, whereas Wnt3A treatment elevated TNFα, IL1ß, and IL6 expression without affecting microglia density. GSK-3ß inhibition downregulated, while rh-Wnt3A treatment upregulated Notch signaling; and none of the two treatments affected the Sonic-Hedgehog pathway. The administration of ARA or rh-Wnt3A did not affect gliosis. The data suggest that GSK-3ß inhibition promoted myelination by suppressing inflammation and Notch signaling; and Wnt3A treatment failed to enhance myelination because of its pro-inflammatory activity and synergy with Notch signaling. GSK-3ß inhibitors might improve the neurological outcome of preterm infants with IVH.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/biossíntese , Recém-Nascido Prematuro/metabolismo , Fibras Nervosas Mielinizadas/metabolismo , Proteína Wnt3A/biossíntese , Animais , Encéfalo/efeitos dos fármacos , Feminino , Humanos , Recém-Nascido , Masculino , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Coelhos , Proteínas Recombinantes/biossíntese , Tiazóis/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia
8.
Neuroscience ; 385: 143-153, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-29908214

RESUMO

Estrogen replacement therapy (ERT) improves hippocampus-dependent cognition. This study investigated the impact of estrogen on hippocampal volume, CA1 subfield volume and myelinated fibers in the CA1 subfield of middle-aged ovariectomized rats. Ten-month-old bilaterally ovariectomized (OVX) female rats were randomly divided into OVX + E2 and OVX + Veh groups. After four weeks of subcutaneous injection with 17ß-estradiol or a placebo, the OVX + E2 rats exhibited significantly short mean escape latency in a spatial learning task than that in the OVX + Veh rats. Using stereological methods, we did not observe significant differences in the volumes of the hippocampus and CA1 subfields between the two groups. However, using stereological methods and electron microscopy techniques, the total length of myelinated fibers and the total volumes of myelinated fibers, myelin sheaths and myelinated axons in the CA1 subfields of OVX + E2 rats were significantly 38.1%, 34.2%, 36.1% and 32.5%, respectively, higher than those in the OVX + Veh rats. After the parameters were calculated according to different diameter ranges, the estrogen replacement-induced remodeling of myelinated fibers in CA1 was mainly manifested in the myelinated fibers with a diameter of <1.0 µm. Therefore, four weeks of continuous E2 replacement improved the spatial learning capabilities of middle-aged ovariectomized rats. The E2 replacement-induced protection of spatial learning abilities might be associated with the beneficial effects of estrogen on myelinated fibers, particularly those with the diameters less than 1.0 µm, in the hippocampal CA1 region of middle-aged ovariectomized rats.


Assuntos
Estradiol/farmacologia , Hipocampo/efeitos dos fármacos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Aprendizagem Espacial/efeitos dos fármacos , Animais , Região CA1 Hipocampal/anatomia & histologia , Região CA1 Hipocampal/efeitos dos fármacos , Terapia de Reposição de Estrogênios , Feminino , Hipocampo/anatomia & histologia , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Ratos , Ratos Sprague-Dawley
9.
Neurourol Urodyn ; 37(6): 1897-1903, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29508437

RESUMO

AIMS: We investigated the effects of silodosin, an α1A-adrenoceptor (AR) antagonist, on bladder function, especially on non-voiding contractions (NVCs), in a male rat model of bladder outlet obstruction (BOO) by evaluating cystometry (CMG) findings and bladder mechanosensitive single-unit afferent activities (SAAs), related with microcontractions, which may be similar with NVCs and to be of myogenic origin, in the rat model. METHODS: BOO was created by partial ligation of the posterior urethra. At 4 days after surgery for BOO, an osmotic pump filled with silodosin (0.12 mg/kg/day) or its vehicle was subcutaneously implanted. At 10 days after surgery, CMG and SAAs measurements were taken under conscious and urethane-anesthetized conditions, respectively. The SAAs of Aδ- and C-fibers, which were identified by electrical stimulation of the pelvic nerve and by bladder distention, and intravesical pressure were recorded during constant bladder-filling with saline. Microcontractions were divided into three phases: "ascending," "descending," and "stationary." RESULTS: The silodosin-treated group showed a smaller number of NVCs in CMG measurements and lower SAAs of both Aδ- and C-fibers than the vehicle-treated group during bladder-filling. Moreover, in the vehicle-treated groups, the SAAs of both fibers for the ascending phase of microcontractions were significantly higher than those for the other two phases. On the contrary, no significant change was found between any of these three phases in the silodosin-treated group. CONCLUSION: The present results suggest that silodosin inhibits the SAAs of mechanosensitive Aδ- and C-fibers at least partly due to suppressing myogenic bladder contractions in male BOO rats.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Indóis/farmacologia , Mecanorreceptores/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/inervação , Agentes Urológicos/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Animais , Implantes de Medicamento , Estimulação Elétrica , Indóis/administração & dosagem , Masculino , Contração Muscular/efeitos dos fármacos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Ratos , Ratos Wistar , Agentes Urológicos/administração & dosagem
10.
J Cell Biol ; 217(4): 1353-1368, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29434029

RESUMO

Myelination calls for a remarkable surge in cell metabolism to facilitate lipid and membrane production. Endogenous fatty acid (FA) synthesis represents a potentially critical process in myelinating glia. Using genetically modified mice, we show that Schwann cell (SC) intrinsic activity of the enzyme essential for de novo FA synthesis, fatty acid synthase (FASN), is crucial for precise lipid composition of peripheral nerves and fundamental for the correct onset of myelination and proper myelin growth. Upon FASN depletion in SCs, epineurial adipocytes undergo lipolysis, suggestive of a compensatory role. Mechanistically, we found that a lack of FASN in SCs leads to an impairment of the peroxisome proliferator-activated receptor (PPAR) γ-regulated transcriptional program. In agreement, defects in myelination of FASN-deficient SCs could be ameliorated by treatment with the PPARγ agonist rosiglitazone ex vivo and in vivo. Our results reveal that FASN-driven de novo FA synthesis in SCs is mandatory for myelination and identify lipogenic activation of the PPARγ transcriptional network as a putative downstream functional mediator.


Assuntos
Ácidos Graxos/biossíntese , Lipogênese , Bainha de Mielina/metabolismo , Fibras Nervosas Mielinizadas/metabolismo , Células de Schwann/metabolismo , Nervo Isquiático/metabolismo , Animais , Células Cultivadas , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Feminino , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Fibras Nervosas Mielinizadas/efeitos dos fármacos , PPAR gama/agonistas , PPAR gama/metabolismo , Rosiglitazona/farmacologia , Células de Schwann/efeitos dos fármacos , Nervo Isquiático/citologia , Nervo Isquiático/efeitos dos fármacos , Transdução de Sinais , Transcrição Genética
11.
Neuroscience ; 374: 236-249, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29421432

RESUMO

Direct current (DC) evokes long-lasting changes in neuronal networks both presynaptically and postsynaptically and different mechanisms were proposed to be involved in them. Different mechanisms were also suggested to account for the different dynamics of presynaptic DC actions on myelinated nerve fibers stimulated before they entered the spinal gray matter and on their terminal branches. The aim of the present study was to examine whether these different dynamics might be related to differences in the involvement of K+ channels. To this end, we compared effects of the K+ channel blocker 4-amino-pyridine (4-AP) on DC-evoked changes in the excitability of afferent fibers stimulated within the dorsal columns (epidurally) and within their projection areas in the dorsal horn and motor nuclei (intraspinally). 4-AP was applied systemically in deeply anesthetized rats. DC-evoked increases in the excitability of epidurally stimulated afferent nerve fibers, and increases in field potentials evoked by these fibers, were not affected by 4-AP. In contrast, sustained decreases rather than increases in the excitability of intraspinally stimulated terminal nerve branches were evoked by local application of DC in conjunction with 4-AP. The study leads to the conclusion that 4-AP-sensitive K+ channels contribute to the sustained DC-evoked post-polarization increases in the excitability at the level of terminal branches of nerve fibers but not of the nodes of Ranvier nor within the juxta-paranodal regions where other mechanisms would be involved in inducing the sustained DC-evoked changes.


Assuntos
Estimulação Elétrica , Fibras Nervosas Mielinizadas/fisiologia , Canais de Potássio/metabolismo , 4-Aminopiridina/farmacologia , Animais , Estimulação Elétrica/métodos , Feminino , Masculino , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/fisiologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/fisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiologia
12.
J Neurophysiol ; 119(5): 1993-2000, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29465329

RESUMO

Local nerve inflammation (neuritis) leads to ongoing activity and axonal mechanical sensitivity (AMS) along intact nociceptor axons and disrupts axonal transport. This phenomenon forms the most feasible cause of radiating pain, such as sciatica. We have previously shown that axonal transport disruption without inflammation or degeneration also leads to AMS but does not cause ongoing activity at the time point when AMS occurs, despite causing cutaneous hypersensitivity. However, there have been no systematic studies of ongoing activity during neuritis or noninflammatory axonal transport disruption. In this study, we present the time course of ongoing activity from primary sensory neurons following neuritis and vinblastine-induced axonal transport disruption. Whereas 24% of C/slow Aδ-fiber neurons had ongoing activity during neuritis, few (<10%) A- and C-fiber neurons showed ongoing activity 1-15 days following vinblastine treatment. In contrast, AMS increased transiently at the vinblastine treatment site, peaking on days 4-5 (28% of C/slow Aδ-fiber neurons) and resolved by day 15. Conduction velocities were slowed in all groups. In summary, the disruption of axonal transport without inflammation does not lead to ongoing activity in sensory neurons, including nociceptors, but does cause a rapid and transient development of AMS. Because it is proposed that AMS underlies mechanically induced radiating pain, and a transient disruption of axonal transport (as previously reported) leads to transient AMS, it follows that processes that disrupt axonal transport, such as neuritis, must persist to maintain AMS and the associated symptoms. NEW & NOTEWORTHY Many patients with radiating pain lack signs of nerve injury on clinical examination but may have neuritis, which disrupts axonal transport. We have shown that axonal transport disruption does not induce ongoing activity in primary sensory neurons but does cause transient axonal mechanical sensitivity. The present data complete a profile of key axonal sensitivities following axonal transport disruption. Collectively, this profile supports that an active peripheral process is necessary for maintained axonal sensitivities.


Assuntos
Transporte Axonal/fisiologia , Hiperalgesia/fisiopatologia , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Neuralgia/fisiopatologia , Neurite (Inflamação)/fisiopatologia , Nervo Isquiático/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Animais , Transporte Axonal/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos , Fatores de Tempo , Moduladores de Tubulina/farmacologia , Vimblastina/farmacologia
13.
Ann Anat ; 216: 135-141, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29305268

RESUMO

Elevated levels of endogenous estrogens in the course of pathological states of ovaries, as well as xenoestrogens, may lead to hyperestrogenism. It has previously been demonstrated that long-term estradiol-17ß (E2) administration in adult gilts affected the population of sympathetic intraovarian nerve fibers. The aim of this study has been to determine the effect of long-term E2 exposure on the cholinergic innervation pattern of porcine ovaries. Intraovarian distribution and the density of nerve fibers immunoreactive (IR) to vesicular acetylocholine transporter (VAChT) and/or neuronal isoform of nitric oxide synthase (nNOS), vasoactive intestinal polypeptide (VIP), somatostatin (SOM) were determined. From day 4 of the first estrous cycle to day 20 of the second studied cycle, experimental gilts were intramuscularly injected with E2, while control gilts received corn oil. The ovaries were then collected and processed for double-labelling immunofluorescence. After E2 administration, the total number of fibers IR to VAChT, nNOS and VIP decreased significantly. The numbers of VAChT-, nNOS- and VIP-IR fibers within the ground plexus were significantly lower, while they were significantly higher around small or medium tertiary follicles. In the E2-affected ovaries, the numbers of nNOS- and VIP-IR fibers were significantly higher near secondary follicles and VAChT-IR in the vicinity of medullar blood vessels. In turn, around the latter structures there were significantly lowered populations of nNOS- and VIP-IR nerve fibers. These results suggest that the elevated E2 levels that occur during pathological states may affect the cholinergic innervation pattern of ovaries and their function(s).


Assuntos
Estradiol/farmacologia , Ovário/efeitos dos fármacos , Ovário/inervação , Sistema Nervoso Parassimpático/efeitos dos fármacos , Animais , Feminino , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Óxido Nítrico Sintase Tipo I/metabolismo , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/inervação , Somatostatina/metabolismo , Sus scrofa , Suínos , Peptídeo Intestinal Vasoativo/metabolismo , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo
14.
J Comp Neurol ; 526(5): 790-802, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29205359

RESUMO

The effects of estrogen replacement therapy (ORT) on white matter and the myelin sheath ultrastructure in the white matter of middle-aged ovariectomized (OVX) rats were investigated in this study. Middle-aged rats were ovariectomized and divided into a placebo replacement (OVX + O) group and an estrogen replacement (OVX + E) group. Then, the Morris water maze, electron microscope techniques, and stereological methods were used to investigate the effects of ORT on spatial learning capacity, white matter volume and the myelin sheath ultrastructure in the white matter. We found that the spatial learning capacity of the OVX + E rats was significantly improved compared with that of the OVX + O rats. When compared with that of OVX + O rats, the total volume of the myelin sheaths in the white matter of the OVX + E rats was significantly increased by 27%, and the difference between the outer perimeter and inner perimeter of the myelin sheaths of the white matter in the OVX + E rats increased significantly by 12.6%. The myelinated fibers with mean diameters of 1.2-1.4 µm were significantly longer (46.1%) in the OVX + E rats; the difference between the mean diameter of myelinated fibers and the mean diameter of axons (0-0.4 µm) was significantly increased by 21.6% in the OVX + E rats. These results suggested that ORT had positive protective effects on the spatial learning ability and on the myelin sheath ultrastructure in the white matter of middle-aged OVX rats.


Assuntos
Estradiol/farmacologia , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/ultraestrutura , Fibras Nervosas Mielinizadas/ultraestrutura , Substância Branca/efeitos dos fármacos , Substância Branca/ultraestrutura , Animais , Terapia de Reposição de Estrogênios , Estrogênios/sangue , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Menopausa , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Ovariectomia/efeitos adversos , Ratos , Ratos Sprague-Dawley , Estatísticas não Paramétricas
15.
Eur J Pain ; 22(3): 511-526, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29082571

RESUMO

BACKGROUND: Vasopressin (AVP) seems to play a role as an antinociceptive neurohormone, but little is known about the peripheral site of action of its antinociceptive effects. Moreover, AVP can produce motor impairment that could be confused with behavioural antinociception. Finally, it is not clear which receptor is involved in the peripheral antinociceptive AVP effects. METHODS: In anaesthetized rats with end-tidal CO2 monitoring, extracellular unitary recordings were performed, measuring the evoked activity mediated by Aß-, Aδ-, C-fibres and post-discharge. Behavioural nociception and motor impairment were evaluated under subcutaneous AVP (0.1-10 µg) using formalin and rotarod tests. Selective antagonists to vasopressin (V1A R) or oxytocin receptors (OTR) were used. Additionally, vasopressin and oxytocin receptors were explored immunohistochemically in skin tissues. RESULTS: Subcutaneous AVP (1 and 10 µg/paw) induced antinociception and a transitory reduction of the end-tidal CO2 . The neuronal activity associated with Aδ- and C-fibre activation was diminished, but no effect was observed on Aß-fibres. AVP also reduced paw flinches in the formalin test and a transitory locomotor impairment was also found. The AVP-induced antinociception was blocked by the selective antagonist to V1A R (SR49059) or OTR (L368,899). Immunohistochemical evidence of skin VP and OT receptors is given. CONCLUSIONS: Subcutaneous AVP produces antinociception and behavioural analgesia. Both V1a and OTR participate in those effects. Our findings suggest that antinociception could be produced in a local manner using a novel vasopressin receptor located in cutaneous sensorial fibres. Additionally, subcutaneous AVP also produces important systemic effects such as respiratory and locomotor impairment. SIGNIFICANCE: Our findings support that AVP produces peripheral antinociception and behavioural analgesia in a local manner; nevertheless, systemic effects are also presented. Additionally, this is the first detailed electrophysiological analysis of AVP antinociceptive action after subcutaneous administration. The results are reasonably explained by the demonstration of V1A R and OTR in cutaneous fibres.


Assuntos
Potenciais Evocados/efeitos dos fármacos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Receptores de Ocitocina/efeitos dos fármacos , Receptores de Vasopressinas/efeitos dos fármacos , Vasopressinas/farmacologia , Analgésicos/farmacologia , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Indóis/farmacologia , Injeções Subcutâneas , Locomoção/efeitos dos fármacos , Masculino , Medição da Dor , Piperazinas/farmacologia , Pirrolidinas/farmacologia , Ratos , Receptores de Ocitocina/antagonistas & inibidores
16.
Anesth Analg ; 127(1): 263-266, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28991117

RESUMO

We investigated the effect of isoflurane on 2 main types of thermal nociceptors: A-δ and C-fibers. Surprisingly, 1% inhaled isoflurane led to a hyperalgesic response to C-fiber thermal stimulation, whereas responses to A-δ thermal stimulation were blunted. We explored the hypothesis that differences in withdrawal behavior are mediated by differential expression of isoflurane-sensitive proteins between these types of thermal nociceptors. Multiple transcriptomic databases of peripheral neurons were integrated to reveal that isoflurane-susceptible proteins Htr3a, Kcna2, and Scn8a were enriched in thermosensitive A-δ neurons. This exploratory analysis highlights the differing role that volatile anesthetics might have on nociceptors in the peripheral nervous system.


Assuntos
Anestésicos Inalatórios/administração & dosagem , Perfilação da Expressão Gênica/métodos , Isoflurano/administração & dosagem , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Dor Nociceptiva/prevenção & controle , Nociceptores/efeitos dos fármacos , Administração por Inalação , Anestésicos Inalatórios/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Temperatura Alta , Hiperalgesia/induzido quimicamente , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Isoflurano/toxicidade , Canal de Potássio Kv1.2/genética , Canal de Potássio Kv1.2/metabolismo , Masculino , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Amielínicas/metabolismo , Dor Nociceptiva/genética , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Nociceptores/metabolismo , Limiar da Dor/efeitos dos fármacos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Receptores 5-HT3 de Serotonina/genética , Receptores 5-HT3 de Serotonina/metabolismo
17.
Neuropharmacology ; 128: 231-243, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29054367

RESUMO

Monoamine oxidase-B (MAOB), a flavin adenine dinucleotide (FAD), is an enzyme which catalyzes the oxidation of amines. MAOB is proposed to play a major role in the pathogenesis of neurodegeneration through the production of reactive oxygen species (ROS) and neurotoxins. The present study was designed to outline the effects of the MAOB inhibitor (MAOB-I) on neuroprotection of spinal neurons, regeneration of sciatic nerve fibers, and recovery of sensory-motor functions in the sciatic nerve crush injury model. Male Wistar rats (4-months-old) were assigned to i) Naïve (N), ii) Sham (S), iii) Sciatic nerve crush and treated with saline (CRUSH + SALINE) and iv) Sciatic nerve crush and treated with MAOB inhibitor (CRUSH + MAOB-I) groups (n = 10/group). In groups iii and iv, the crush injury was produced by crushing the sciatic nerve followed by treatment with saline or MAOB-I (Selegiline® 2.5 mg/kg) intraperitoneally for 10 days. Behavioral tests were conducted from week 1 to week 6. At the end of the study, sciatic nerve and lumbar spinal cord were examined by immunohistochemistry, light and electron microscopy. MAOB-I treatment showed significant improvement in sensory and motor functions compared to saline treatment (p < 0.05-0.001) in injured nerves. The morphological study showed a significantly increased number of nerve fibers in sciatic nerve distal to the site of injury (p < 0.05), with better myelination pattern in CRUSH + MAOB-I treated group compared to CRUSH + SALINE group. Spinal cord ventral horns showed a significant increase in the number of NeuN-immunoreactive neurons in the MAOB-I treated group compared to Saline treated group (p < 0.01). MAOB-I has a significant potential for protecting the degenerating spinal cord neurons and enhancing the regeneration of injured sciatic nerve fibers following crush injury.


Assuntos
Inibidores da Monoaminoxidase/uso terapêutico , Degeneração Neural/prevenção & controle , Regeneração Nervosa/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Neuropatia Ciática/complicações , Medula Espinal/patologia , Animais , Células do Corno Anterior/efeitos dos fármacos , Células do Corno Anterior/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Movimento/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/patologia , Fibras Nervosas Mielinizadas/ultraestrutura , Limiar da Dor/efeitos dos fármacos , Fosfopiruvato Hidratase/metabolismo , Ratos , Ratos Wistar , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/patologia , Selegilina/farmacologia , Selegilina/uso terapêutico , Suporte de Carga/fisiologia
18.
J Neurosci ; 37(44): 10587-10596, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28972120

RESUMO

Calcitonin gene-related peptide (CGRP), the most abundant neuropeptide in primary afferent sensory neurons, is strongly implicated in the pathophysiology of migraine headache, but its role in migraine is still equivocal. As a new approach to migraine treatment, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs) were developed to reduce the availability of CGRP, and were found effective in reducing the frequency of chronic and episodic migraine. We recently tested the effect of fremanezumab (TEV-48125), a CGRP-mAb, on the activity of second-order trigeminovascular dorsal horn neurons that receive peripheral input from the cranial dura, and found a selective inhibition of high-threshold but not wide-dynamic range class of neurons. To investigate the basis for this selective inhibitory effect, and further explore the mechanism of action of CGRP-mAbs, we tested the effect of fremanezumab on the cortical spreading depression-evoked activation of mechanosensitive primary afferent meningeal nociceptors that innervate the cranial dura, using single-unit recording in the trigeminal ganglion of anesthetized male rats. Fremanezumab pretreatment selectively inhibited the responsiveness of Aδ neurons, but not C-fiber neurons, as reflected in a decrease in the percentage of neurons that showed activation by cortical spreading depression. These findings identify Aδ meningeal nociceptors as a likely site of action of fremanezumab in the prevention of headache. The selectivity in its peripheral inhibitory action may partly account for fremanezumab's selective inhibition of high-threshold, as a result of a predominant A-δ input to high-threshold neurons, but not wide dynamic-range dorsal horn neurons, and why it may not be effective in all migraine patients.SIGNIFICANCE STATEMENT Recently, we reported that humanized CGRP monoclonal antibodies (CGRP-mAbs) prevent activation and sensitization of high-threshold (HT) but not wide-dynamic range trigeminovascular neurons by cortical spreading depression (CSD). In the current paper, we report that CGRP-mAbs prevent the activation of Aδ but not C-type meningeal nociceptors by CSD. This is the first identification of an anti-migraine drug that appears to be selective for Aδ-fibers (peripherally) and HT neurons (centrally). As the main CGRP-mAb site of action appears to be situated outside the brain, we conclude that the initiation of the headache phase of migraine depends on activation of meningeal nociceptors, and that for selected patients, activation of the Aδ-HT pain pathway may be sufficient for the generation of headache perception.


Assuntos
Anticorpos Monoclonais/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Bainha de Mielina/efeitos dos fármacos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Amielínicas/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Animais , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Humanos , Masculino , Bainha de Mielina/fisiologia , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Nociceptores/fisiologia , Ratos , Ratos Sprague-Dawley
19.
Neurobiol Dis ; 106: 235-243, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28709993

RESUMO

Severed CNS axons often retract or dieback away from the injury site and fail to regenerate. The precise mechanisms underlying acute axonal dieback and secondary axonal degeneration remain poorly understood. Here we investigate the role of Ca2+ store mediated intra-axonal Ca2+ release in acute axonal dieback and secondary axonal degeneration. To differentiate between primary (directly transected) and "bystander" axonal injury (axons spared by the initial injury but then succumb to secondary degeneration) in real-time we use our previously published highly focal laser-induced spinal cord injury (LiSCI) ex vivo model. Ascending spinal cord dorsal column axons that express YFP were severed using an 800 nm laser pulse while being imaged continuously using two-photon excitation microscopy. We inhibited two major intra-axonal Ca2+ store channels, ryanodine receptors (RyR) and IP3R, with ryanodine or 2-APB, respectively, to individually determine their role in axonal dieback and secondary axonal degeneration. Each antagonist was dissolved in artificial CSF and applied 1h post-injury alone or in combination, and continuously perfused for the remainder of the imaging session. Initially following LiSCI, transected axons retracted equal distances both distal and proximal to the lesion. However, by 4h after injury, the distal axonal segments that are destined for Wallerian degeneration had significantly retracted further than their proximal counterparts. We also found that targeting either RyR or IP3R using pharmacological and genetic approaches significantly reduced proximal axonal dieback and "bystander" secondary degeneration of axons compared to vehicle controls at 6h post-injury. Combined treatment effects on secondary axonal degeneration were similar to either drug in isolation. Together, these results suggest that intra-axonal Ca2+ store mediated Ca2+ release through RyR or IP3R contributes to secondary axonal degeneration following SCI.


Assuntos
Axônios/metabolismo , Cálcio/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Espaço Intracelular/metabolismo , Degeneração Neural/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Bloqueadores dos Canais de Cálcio/farmacologia , Cátions Bivalentes/metabolismo , Técnicas de Silenciamento de Genes , Receptores de Inositol 1,4,5-Trifosfato/antagonistas & inibidores , Receptores de Inositol 1,4,5-Trifosfato/genética , Espaço Intracelular/efeitos dos fármacos , Lasers , Camundongos Transgênicos , Degeneração Neural/patologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , RNA Mensageiro/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Técnicas de Cultura de Tecidos
20.
J Neurosci ; 37(35): 8385-8398, 2017 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-28751457

RESUMO

The failure to undergo remyelination is a critical impediment to recovery in multiple sclerosis. Chondroitin sulfate proteoglycans (CSPGs) accumulate at demyelinating lesions creating a nonpermissive environment that impairs axon regeneration and remyelination. Here, we reveal a new role for 2-arachidonoylglycerol (2-AG), the major CNS endocannabinoid, in the modulation of CSPGs deposition in a progressive model of multiple sclerosis, the Theiler's murine encephalomyelitis virus-induced demyelinating disease. Treatment with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-AG degradation in the mouse CNS, modulates neuroinflammation and reduces CSPGs accumulation and astrogliosis around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. Inhibition of 2-AG hydrolysis augments the number of mature oligodendrocytes and increases MBP, leading to remyelination and functional recovery of mice. Our findings establish a mechanism for 2-AG promotion of remyelination with implications in axonal repair in CNS demyelinating pathologies.SIGNIFICANCE STATEMENT The deposition of chondroitin sulfate proteoglycans contributes to the failure in remyelination associated with multiple sclerosis. Here we unveil a new role for 2-arachidonoylglycerol, the major CNS endocannabinoid, in the modulation of chondroitin sulfate proteoglycan accumulation in Theiler's murine encephalomyelitis virus-induced demyelinating disease. The treatment during the chronic phase with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-arachidonoylglycerol degradation in the mouse CNS, modulates neuroinflammation and reduces chondroitin sulfate proteoglycan deposition around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. The increased 2-arachidonoylglycerol tone promotes remyelination in a model of progressive multiple sclerosis ameliorating motor dysfunction.


Assuntos
Ácidos Araquidônicos/farmacologia , Ácidos Araquidônicos/uso terapêutico , Endocanabinoides/farmacologia , Endocanabinoides/uso terapêutico , Glicerídeos/farmacologia , Glicerídeos/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/fisiopatologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/patologia , Proteoglicanas/metabolismo , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Feminino , Camundongos , Esclerose Múltipla/patologia , Neurogênese/efeitos dos fármacos
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