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1.
PLoS One ; 15(8): e0237156, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32780756

RESUMO

Ischemic neuropathy is common in subjects with critical limb ischemia, frequently causing chronic neuropathic pain. However, neuropathic pain caused by ischemia is hard to control despite the restoration of an adequate blood flow. Here, we used a rat model of ischemic-reperfusion nerve injury (IRI) to investigate possible effects of hepatocyte growth factor (HGF) against ischemic neuropathy. Hemagglutinating virus of Japan (HVJ) liposomes containing plasmids encoded with HGF was delivered into the peripheral nervous system by retrograde axonal transport following its repeated injections into the tibialis anterior muscle in the right hindlimb. First HGF gene transfer was done immediately after IRI, and repeated at 1, 2 and 3 weeks later. Rats with IRI exhibited pronounced mechanical allodynia and thermal hyperalgesia, decreased blood flow and skin temperature, and lowered thresholds of plantar stimuli in the hind paw. These were all significantly improved by HGF gene transfer, as also were sciatic nerve conduction velocity and muscle action potential amplitudes. Histologically, HGF gene transfer resulted in a significant increase of endoneurial microvessels in sciatic and tibial nerves and promoted nerve regeneration which were confirmed by morphometric analysis. Neovascularization was observed in the contralateral side of peripheral nerves as well. In addition, IRI elevated mRNA levels of P2X3 and P2Y1 receptors, and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in sciatic nerves, dorsal root ganglia and spinal cord, and these elevated levels were inhibited by HGF gene transfer. In conclusion, HGF gene transfer is a potent candidate for treatment of acute ischemic neuropathy caused by reperfusion injury, because of robust angiogenesis and enhanced nerve regeneration.


Assuntos
Terapia Genética/métodos , Fator de Crescimento de Hepatócito/genética , Neuralgia/terapia , Traumatismo por Reperfusão/terapia , Animais , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Técnicas de Transferência de Genes , Vetores Genéticos , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Hiperalgesia/metabolismo , Lipossomos/metabolismo , Masculino , Ratos , Ratos Wistar , Nervo Isquiático/metabolismo , Vírus Sendai/genética , Resultado do Tratamento
2.
Nat Commun ; 11(1): 4178, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826895

RESUMO

Friedreich's ataxia (FRDA) is an autosomal-recessive neurodegenerative and cardiac disorder which occurs when transcription of the FXN gene is silenced due to an excessive expansion of GAA repeats into its first intron. Herein, we generate dorsal root ganglia organoids (DRG organoids) by in vitro differentiation of human iPSCs. Bulk and single-cell RNA sequencing show that DRG organoids present a transcriptional signature similar to native DRGs and display the main peripheral sensory neuronal and glial cell subtypes. Furthermore, when co-cultured with human intrafusal muscle fibers, DRG organoid sensory neurons contact their peripheral targets and reconstitute the muscle spindle proprioceptive receptors. FRDA DRG organoids model some molecular and cellular deficits of the disease that are rescued when the entire FXN intron 1 is removed, and not with the excision of the expanded GAA tract. These results strongly suggest that removal of the repressed chromatin flanking the GAA tract might contribute to rescue FXN total expression and fully revert the pathological hallmarks of FRDA DRG neurons.


Assuntos
Ataxia de Friedreich/genética , Ataxia de Friedreich/patologia , Gânglios Espinais/metabolismo , Edição de Genes/métodos , Proteínas de Ligação ao Ferro/genética , Organoides/metabolismo , Células Receptoras Sensoriais/metabolismo , Antioxidantes/farmacologia , Sistemas CRISPR-Cas , Diferenciação Celular , Cromatina/metabolismo , Ataxia de Friedreich/tratamento farmacológico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Predisposição Genética para Doença/genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Íntrons , Mitocôndrias/metabolismo , Organoides/efeitos dos fármacos , Organoides/patologia , Células Receptoras Sensoriais/patologia , Análise de Sequência de RNA , Transcriptoma
3.
PLoS One ; 15(6): e0234176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497151

RESUMO

Chronic neuropathic pain (NP) is a growing clinical problem for which effective treatments, aside from non-steroidal anti-inflammatory drugs and opioids, are lacking. Cannabinoids are emerging as potentially promising agents to manage neuroimmune effects associated with nociception. In particular, Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination are being considered as therapeutic alternatives for treatment of NP. This study aimed to examine whether sex affects long-term outcomes on persistent mechanical hypersensitivity 7 weeks after ceasing cannabinoid administration. Clinically relevant low doses of THC, CBD, and a 1:1 combination of THC:CBD extracts, in medium chain triglyceride (MCT) oil, were orally gavaged for 14 consecutive days to age-matched groups of male and female sexually mature Sprague Dawley rats. Treatments commenced one day after surgically inducing a pro-nociceptive state using a peripheral sciatic nerve cuff. The analgesic efficacy of each phytocannabinoid was assessed relative to MCT oil using hind paw mechanical behavioural testing once a week for 9 weeks. In vivo intracellular electrophysiology was recorded at endpoint to characterize soma threshold changes in primary afferent sensory neurons within dorsal root ganglia (DRG) innervated by the affected sciatic nerve. The thymus, spleen, and DRG were collected post-sacrifice and analyzed for long-term effects on markers associated with T lymphocytes at the RNA level using qPCR. Administration of cannabinoids, particularly the 1:1 combination of THC, elicited a sustained mechanical anti-hypersensitive effect in males with persistent peripheral NP, which corresponded to beneficial changes in myelinated Aß mechanoreceptive fibers. Specific immune cell markers associated with T cell differentiation and pro-inflammatory cytokines, previously implicated in repair processes, were differentially up-regulated by cannabinoids in males treated with cannabinoids, but not in females, warranting further investigation into sexual dimorphisms that may underlie treatment outcomes.


Assuntos
Analgésicos/administração & dosagem , Analgésicos/farmacologia , Canabidiol/efeitos adversos , Canabidiol/farmacologia , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Óleos/química , Administração Oral , Analgésicos/química , Animais , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Canabidiol/química , Dronabinol/química , Composição de Medicamentos , Interações Medicamentosas , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
4.
Proc Natl Acad Sci U S A ; 117(27): 15955-15966, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32554499

RESUMO

Axon regeneration is regulated by a neuron-intrinsic transcriptional program that is suppressed during development but that can be reactivated following peripheral nerve injury. Here we identify Prom1, which encodes the stem cell marker prominin-1, as a regulator of the axon regeneration program. Prom1 expression is developmentally down-regulated, and the genetic deletion of Prom1 in mice inhibits axon regeneration in dorsal root ganglion (DRG) cultures and in the sciatic nerve, revealing the neuronal role of Prom1 in injury-induced regeneration. Elevating prominin-1 levels in cultured DRG neurons or in mice via adeno-associated virus-mediated gene delivery enhances axon regeneration in vitro and in vivo, allowing outgrowth on an inhibitory substrate. Prom1 overexpression induces the consistent down-regulation of cholesterol metabolism-associated genes and a reduction in cellular cholesterol levels in a Smad pathway-dependent manner, which promotes axonal regrowth. We find that prominin-1 interacts with the type I TGF-ß receptor ALK4, and that they synergistically induce phosphorylation of Smad2. These results suggest that Prom1 and cholesterol metabolism pathways are possible therapeutic targets for the promotion of neural recovery after injury.


Assuntos
Antígeno AC133/metabolismo , Axônios/metabolismo , Colesterol/metabolismo , Regeneração Nervosa/fisiologia , Transdução de Sinais , Células-Tronco/metabolismo , Antígeno AC133/genética , Receptores de Ativinas Tipo I , Animais , Axônios/patologia , Colesterol/genética , Regulação para Baixo , Gânglios Espinais/metabolismo , Deleção de Genes , Regulação da Expressão Gênica , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Nervo Isquiático
5.
Prostate ; 80(10): 782-794, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32407603

RESUMO

BACKGROUND: Over 70% to 85% of men with advanced prostate cancer (PCa) develop bone metastases characterized by severe bone pain and increased likelihood of bone fracture. These clinical features result in decreased quality of life and act as a predictor of higher mortality. Mechanistically, the skeletal pathologies such as osteolytic lesions and abnormal osteoblastic activity drive these symptoms. The role of immune cells in bone cancer pain remains understudied, here we sought to recapitulate this symptomology in a murine model. METHODS: The prostate cancer bone metastasis-induced pain model (CIBP) was established by transplanting a mouse prostate cancer cell line into the femur of immunocompetent mice. Pain development, gait dynamics, and the changes in emotional activities like depression and anxiety were evaluated. Animal tissues including femurs, dorsal root ganglion (DRG), and spinal cord were collected at killing and microcomputed tomography (µCT), histology/immunohistochemistry, and quantitative immunofluorescent analysis were performed. RESULTS: Mice receiving prostate cancer cells showed a significantly lower threshold for paw withdrawal responses induced by mechanical stimulation compared with their control counterparts. Zero maze and DigiGait analyses indicated reduced and aberrant movement associated emotional activity compared with sham control at 8-weeks postinjection. The µCT analysis showed osteolytic and osteoblastic changes and a 50% reduction of the trabecular volumes within the prostate cancer group. Neurologically we demonstrated, increased calcitonin gene-related peptide (CGRP) and neuronal p75NTR immune-reactivities in both the projected terminals of the superficial dorsal horn and partial afferent neurons in DRG at L2 to L4 level in tumor-bearing mice. Furthermore, our data show elevated nerve growth factor (NGF) and TrkA immunoreactivities in the same segment of the superficial dorsal horn that were, however, not colocalized with CGRP and p75NTR . CONCLUSIONS: This study describes a novel immunocompetent model of CIBP and demonstrates the contribution of NGF and p75NTR to chronic pain in bone metastasis.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Dor do Câncer/patologia , Neoplasias da Próstata/patologia , Animais , Comportamento Animal , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/imunologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Dor do Câncer/imunologia , Dor do Câncer/metabolismo , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Imunocompetência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neurônios/metabolismo , Neurônios/patologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Receptores de Fator de Crescimento Neural/imunologia , Receptores de Fator de Crescimento Neural/metabolismo
6.
J Virol ; 94(14)2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32404525

RESUMO

Mouse hepatitis virus (MHV) is a murine betacoronavirus (m-CoV) that causes a wide range of diseases in mice and rats, including hepatitis, enteritis, respiratory diseases, and encephalomyelitis in the central nervous system (CNS). MHV infection in mice provides an efficient cause-effect experimental model to understand the mechanisms of direct virus-induced neural-cell damage leading to demyelination and axonal loss, which are pathological features of multiple sclerosis (MS), the most common disabling neurological disease in young adults. Infiltration of T lymphocytes, activation of microglia, and their interplay are the primary pathophysiological events leading to disruption of the myelin sheath in MS. However, there is emerging evidence supporting gray matter involvement and degeneration in MS. The investigation of T cell function in the pathogenesis of deep gray matter damage is necessary. Here, we employed RSA59 (an isogenic recombinant strain of MHV-A59)-induced experimental neuroinflammation model to compare the disease in CD4-/- mice with that in CD4+/+ mice at days 5, 10, 15, and 30 postinfection (p.i.). Viral titer estimation, nucleocapsid gene amplification, and viral antinucleocapsid staining confirmed enhanced replication of the virions in the absence of functional CD4+ T cells in the brain. Histopathological analyses showed elevated susceptibility of CD4-/- mice to axonal degeneration in the CNS, with augmented progression of acute poliomyelitis and dorsal root ganglionic inflammation rarely observed in CD4+/+ mice. Depletion of CD4+ T cells showed unique pathological bulbar vacuolation in the brain parenchyma of infected mice with persistent CD11b+ microglia/macrophages in the inflamed regions on day 30 p.i. In summary, the current study suggests that CD4+ T cells are critical for controlling acute-stage poliomyelitis (gray matter inflammation), chronic axonal degeneration, and inflammatory demyelination due to loss of protective antiviral host immunity.IMPORTANCE The current trend in CNS disease biology is to attempt to understand the neural-cell-immune interaction to investigate the underlying mechanism of neuroinflammation, rather than focusing on peripheral immune activation. Most studies in MS are targeted toward understanding the involvement of CNS white matter. However, the importance of gray matter damage has become critical in understanding the long-term progressive neurological disorder. Our study highlights the importance of CD4+ T cells in safeguarding neurons against axonal blebbing and poliomyelitis from murine betacoronavirus-induced neuroinflammation. Current knowledge of the mechanisms that lead to gray matter damage in MS is limited, because the most widely used animal model, experimental autoimmune encephalomyelitis (EAE), does not present this aspect of the disease. Our results, therefore, add to the existing limited knowledge in the field. We also show that the microglia, though important for the initiation of neuroinflammation, cannot establish a protective host immune response without the help of CD4+ T cells.


Assuntos
Axônios/imunologia , Axônios/metabolismo , Antígenos CD4/deficiência , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Vírus da Hepatite Murina/fisiologia , Poliomielite/etiologia , Animais , Axônios/patologia , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Infecções por Coronavirus/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças/imunologia , Gânglios Espinais/imunologia , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Camundongos
7.
Zhongguo Zhen Jiu ; 40(4): 405-10, 2020 Apr 12.
Artigo em Chinês | MEDLINE | ID: mdl-32275370

RESUMO

OBJECTIVE: To observe the effect of early intervention of bone-nearby acupuncture (BNA) combined with electroacupuncture (EA) on the expression of histone deacetylase1(HDAC1), histone deacetylase 2 (HDAC2) andµ-opioid recepter (MOR) in dorsal root ganglia (DRG) of bone cancer pain-morphine tolerance (BCP-MT) rats, and to explore its possible mechanism. METHODS: A total of 35 SD rats were randomized into a sham BCP group (n=6), a BCP group (n=7), a MT group (n=7), a BNA+EA group (n=8) and a shame BNA group (n=7). Except of the sham BCP group, cancer cell inoculation operation at left tibia was given in the other 4 groups to establish the bone cancer pain model. In the MT group, the BNA+EA group and the shame BNA group, intraperitoneal injection of morphine hydrochloride was given to establish the morphine tolerance model. After the operation, bone-nearby acupuncture combined with electroacupuncture was applied at "Zusanli" (ST 36) and "Kunlun" (BL 60) in the BNA+EA group, with dilatational wave, 2 Hz/100 Hz in frequency, 0.5 to 1.5 mA in intensity. Intervention in the shame BNA group was applied at the same time and acupoints as those in the BNA+EA group, the needles were pierced the skin without any electrical stimulation. The needles were retained for 30 min, once a day for continuous 7 days in both BNA+EA and shame BNA groups. Before and 10, 11, 15, 22 days after the operation, the left paw withdrawal threshold (PWT) was measured in the 5 groups. The levels of HDAC1, HDAC2 and MOR in DRG were detected by Western blot. RESULTS: Ten days after the cancer cell inoculation operation, the PWT of the BCP, MT, BNA+EA and sham BNA groups was decreased compared with the sham BCP group (P<0.01). Eleven days after the operation, the PWT of the MT, BNA+EA and sham BNA groups was increased compared with the BCP group (P<0.01). Twenty-two days after the operation, the difference was no significant between the BCP group and MT group (P>0.05); the PWT of the BNA+EA group was increased compared with the MT and sham BNA group (P<0.01). In the BCP group, the DRG levels of HDAC1 and HDCA2 were increased, while the level of MOR was decreased compared with the sham BCP group (P<0.05, P<0.01). In the MT group, the DRG level of HDAC1 was increased compared with the BCP group (P<0.05). In the BNA+EA group, the DRG level of HDAC1 was decreased compared with the MT group and the sham BNA group (P<0.01, P<0.05), while the level of MOR was increased (P<0.01). CONCLUSION: Early intervention of bone-nearby acupuncture combined with electroacupuncture can relieve the morphine tolerance in bone cancer pain rats, it may relate to down-regulating the expression of HDAC1 and up-regulating the expression of MOR in the dorsal root ganglia.


Assuntos
Neoplasias Ósseas/complicações , Dor do Câncer/terapia , Eletroacupuntura , Gânglios Espinais/metabolismo , Histona Desacetilases/metabolismo , Receptores Opioides mu/metabolismo , Pontos de Acupuntura , Animais , Tolerância a Medicamentos , Morfina , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
8.
Neuron ; 106(6): 940-951.e4, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32298640

RESUMO

Itch and pain are distinct unpleasant sensations that can be triggered from the same receptive fields in the skin, raising the question of how pruriception and nociception are coded and discriminated. Here, we tested the multimodal capacity of peripheral first-order neurons, focusing on the genetically defined subpopulation of mouse C-fibers that express the chloroquine receptor MrgprA3. Using optogenetics, chemogenetics, and pharmacology, we assessed the behavioral effects of their selective stimulation in a wide variety of conditions. We show that metabotropic Gq-linked stimulation of these C-afferents, through activation of native MrgprA3 receptors or DREADDs, evokes stereotypical pruriceptive rather than nocifensive behaviors. In contrast, fast ionotropic stimulation of these same neurons through light-gated cation channels or native ATP-gated P2X3 channels predominantly evokes nocifensive rather than pruriceptive responses. We conclude that C-afferents display intrinsic multimodality, and we provide evidence that optogenetic and chemogenetic interventions on the same neuronal populations can drive distinct behavioral outputs.


Assuntos
Channelrhodopsins/metabolismo , Fibras Nervosas Amielínicas/metabolismo , Neurônios Aferentes/metabolismo , Nociceptividade/fisiologia , Dor/metabolismo , Prurido/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Trifosfato de Adenosina , Animais , Cloroquina , Gânglios Espinais/metabolismo , Peptídeo Liberador de Gastrina/metabolismo , Luz , Camundongos , Neurônios Aferentes/fisiologia , Optogenética , Receptores Opioides/metabolismo , Canais de Receptores Transientes de Potencial/metabolismo
9.
J Neurosci ; 40(18): 3517-3532, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32245829

RESUMO

One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-ß) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity.


Assuntos
Viroses do Sistema Nervoso Central/metabolismo , Interferon Tipo I/toxicidade , Nociceptores/metabolismo , Limiar da Dor/fisiologia , Dor/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Animais , Células Cultivadas , Viroses do Sistema Nervoso Central/induzido quimicamente , Viroses do Sistema Nervoso Central/patologia , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Nociceptores/efeitos dos fármacos , Nociceptores/patologia , Dor/induzido quimicamente , Dor/patologia , Limiar da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia
10.
Pain Res Manag ; 2020: 3740162, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104520

RESUMO

Background: Treatment of diabetic neuropathic pain (DNP) continues to be a major challenge, and underlying mechanisms of DNP remain elusive. We investigated treatment effects of B vitamins on DPN- and DNP-associated alterations of neurochemical signaling in the nociceptive dorsal root ganglion (DRG) neurons and the spinal cord in rats. Methods: DNP was produced in male, adult, Sprague Dawley rats by single i.p. streptozotocin (STZ). Western blot analysis and immunohistochemistry were used to analyze protein expressions in DRG and ELISA to measure the proinflammatory cytokines in the spinal cord. Behaviorally expressed DNP was determined by measuring the sensitivity of hindpaw skin to mechanical and thermal stimulation. Results: There were 87.5% (77/88) rats which developed high blood glucose within 1-2 weeks following STZ injection. Of which, 70.13% (n = 54/77) animals exhibited DNP manifested as mechanical allodynia and/or thermal hyperalgesia. Intraperitoneal administration of vitamins B1/B6/B12 (100/100/2 mg/kg, one or multiple doses) significantly attenuated DNP without affecting the blood glucose. Expressions of P2X3 and TRPV1 in CGRP-positive and IB4-positive DRG neurons as well as the interleukin-1ß, tumor necrosis factor-α, and nerve growth factor in the lumbar spinal cord were greatly increased in DNP rats. Such DNP-associated neurochemical alterations were also greatly suppressed by the B-vitamin treatment. Conclusions: B-vitamin treatment can greatly suppress chronic DNP and DNP-associated increased activities of P2X3 and TRPV1 in DRG and the spinal proinflammatory cytokines, which may contribute to the pathogenesis of DNP. Systematic administration of B vitamins can be a strategy for DNP management in clinic.


Assuntos
Neuropatias Diabéticas , Gânglios Espinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Complexo Vitamínico B/farmacologia , Animais , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Diabetes Mellitus Experimental/complicações , Gânglios Espinais/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X3/metabolismo , Medula Espinal/metabolismo , Canais de Cátion TRPV/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo
11.
Anesthesiology ; 132(4): 867-880, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32011337

RESUMO

BACKGROUND: Recent emerging evidence suggests that extra-adrenal synthesis of aldosterone occurs (e.g., within the failing heart and in certain brain areas). In this study, the authors investigated evidence for a local endogenous aldosterone production through its key processing enzyme aldosterone synthase within peripheral nociceptive neurons. METHODS: In male Wistar rats (n = 5 to 8 per group) with Freund's complete adjuvant hind paw inflammation, the authors examined aldosterone, aldosterone synthase, and mineralocorticoid receptor expression in peripheral sensory neurons using quantitative reverse transcriptase-polymerase chain reaction, Western blot, immunohistochemistry, and immunoprecipitation. Moreover, the authors explored the nociceptive behavioral changes after selective mineralocorticoid receptor antagonist, canrenoate-K, or specific aldosterone synthase inhibitor application. RESULTS: In rats with Freund's complete adjuvant-induced hind paw inflammation subcutaneous and intrathecal application of mineralocorticoid receptor antagonist, canrenoate-K, rapidly and dose-dependently attenuated nociceptive behavior (94 and 48% reduction in mean paw pressure thresholds, respectively), suggesting a tonic activation of neuronal mineralocorticoid receptors by an endogenous ligand. Indeed, aldosterone immunoreactivity was abundant in peptidergic nociceptive neurons of dorsal root ganglia and colocalized predominantly with its processing enzyme aldosterone synthase and mineralocorticoid receptors. Moreover, aldosterone and its synthesizing enzyme were significantly upregulated in peripheral sensory neurons under inflammatory conditions. The membrane mineralocorticoid receptor consistently coimmunoprecipitated with endogenous aldosterone, confirming a functional link between mineralocorticoid receptors and its endogenous ligand. Importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by a specific aldosterone synthase inhibitor attenuated nociceptive behavior after hind paw inflammation (a 32% reduction in paw pressure thresholds; inflammation, 47 ± 2 [mean ± SD] vs. inflammation + aldosterone synthase inhibitor, 62 ± 2). CONCLUSIONS: Local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity during local inflammation via intrinsic activation of neuronal mineralocorticoid receptors.


Assuntos
Citocromo P-450 CYP11B2/biossíntese , Hiperalgesia/metabolismo , Medição da Dor/métodos , Células Receptoras Sensoriais/metabolismo , Adjuvantes Imunológicos/toxicidade , Aldosterona/biossíntese , Animais , Adjuvante de Freund/toxicidade , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Medição da Dor/efeitos dos fármacos , Estimulação Física/efeitos adversos , Ratos , Ratos Wistar , Células Receptoras Sensoriais/efeitos dos fármacos
12.
Sci Rep ; 10(1): 1300, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992767

RESUMO

The dorsal root ganglia (DRG) house the primary afferent neurons responsible for somatosensation, including pain. We previously identified Jedi-1 (PEAR1/MEGF12) as a phagocytic receptor expressed by satellite glia in the DRG involved in clearing apoptotic neurons during development. Here, we further investigated the function of this receptor in vivo using Jedi-1 null mice. In addition to satellite glia, we found Jedi-1 expression in perineurial glia and endothelial cells, but not in sensory neurons. We did not detect any morphological or functional changes in the glial cells or vasculature of Jedi-1 knockout mice. Surprisingly, we did observe changes in DRG neuron activity. In neurons from Jedi-1 knockout (KO) mice, there was an increase in the fraction of capsaicin-sensitive cells relative to wild type (WT) controls. Patch-clamp electrophysiology revealed an increase in excitability, with a shift from phasic to tonic action potential firing patterns in KO neurons. We also found alterations in the properties of voltage-gated sodium channel currents in Jedi-1 null neurons. These results provide new insight into the expression pattern of Jedi-1 in the peripheral nervous system and indicate that loss of Jedi-1 alters DRG neuron activity indirectly through an intercellular interaction between non-neuronal cells and sensory neurons.


Assuntos
Potenciais de Ação , Receptores de Superfície Celular/deficiência , Células Receptoras Sensoriais/metabolismo , Animais , Biomarcadores , Linhagem Celular , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neuroglia/metabolismo , Neuroglia/ultraestrutura , Técnicas de Patch-Clamp , Células Receptoras Sensoriais/ultraestrutura
13.
Biochem Pharmacol ; 174: 113826, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31987857

RESUMO

BACKGROUND: Volatile anaesthetics (VAs) are the most widely used compounds to induce reversible loss of consciousness and maintain general anaesthesia during surgical interventions. Although the mechanism of their action is not yet fully understood, it is generally believed, that VAs depress central nervous system functions mainly through modulation of ion channels in the neuronal membrane, including 2-pore-domain K+ channels, GABA and NMDA receptors. Recent research also reported their action on nociceptive and thermosensitive TRP channels expressed in the peripheral nervous system, including TRPV1, TRPA1, and TRPM8. Here, we investigated the effect of VAs on TRPM3, a less characterized member of the thermosensitive TRP channels playing a central role in noxious heat sensation. METHODS: We investigated the effect of VAs on the activity of recombinant and native TRPM3, by monitoring changes in the intracellular Ca2+ concentration and measuring TRPM3-mediated transmembrane currents. RESULTS: All the investigated VAs (chloroform, halothane, isoflurane, sevoflurane) inhibited both the agonist-induced (pregnenolone sulfate, CIM0216) and heat-activated Ca2+ signals and transmembrane currents in a concentration dependent way in HEK293T cells overexpressing recombinant TRPM3. Among the tested VAs, halothane was the most potent blocker (IC50 = 0.52 ± 0.05 mM). We also investigated the effect of VAs on native TRPM3 channels expressed in sensory neurons of the dorsal root ganglia. While VAs activated certain sensory neurons independently of TRPM3, they strongly and reversibly inhibited the agonist-induced TRPM3 activity. CONCLUSIONS: These data provide a better insight into the molecular mechanism beyond the analgesic effect of VAs and propose novel strategies to attenuate TRPM3 dependent nociception.


Assuntos
Anestésicos Inalatórios/farmacologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPM/metabolismo , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL
14.
Cell Rep ; 30(4): 1164-1177.e7, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31995756

RESUMO

Neuronal migration, axon fasciculation, and axon guidance need to be closely coordinated for neural circuit assembly. Spinal motor neurons (MNs) face unique challenges during development because their cell bodies reside within the central nervous system (CNS) and their axons project to various targets in the body periphery. The molecular mechanisms that contain MN somata within the spinal cord while allowing their axons to exit the CNS and navigate to their final destinations remain incompletely understood. We find that the MN cell surface protein TAG-1 anchors MN cell bodies in the spinal cord to prevent their emigration, mediates motor axon fasciculation during CNS exit, and guides motor axons past dorsal root ganglia. TAG-1 executes these varied functions in MN development independently of one another. Our results identify TAG-1 as a key multifunctional regulator of MN wiring that coordinates neuronal migration, axon fasciculation, and axon guidance.


Assuntos
Orientação de Axônios/genética , Movimento Celular/genética , Contactina 2/metabolismo , Fasciculação/metabolismo , Neurônios Motores/metabolismo , Neurogênese/genética , Animais , Orientação de Axônios/fisiologia , Axônios/metabolismo , Células COS , Linhagem Celular , Chlorocebus aethiops , Contactina 2/genética , Fasciculação/genética , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/genética , Medula Espinal/metabolismo
15.
J Orthop Res ; 38(2): 422-430, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31538672

RESUMO

We investigated the efficacy of duloxetine on hyperalgesia, histopathological and radiographic findings, pain-related sensory innervation of dorsal-root ganglia (DRG), and spinal changes in a rat model of induced hip osteoarthritis (OA). The right hip joints of male Sprague-Dawley rats (n = 6 rats/group) in the Sham group were injected with 25 µl of sterile saline and 25 µl of sterile saline with 2 mg of monosodium iodoacetate (MIA) were injected to the MIA + Vehicle and MIA + Duloxetine groups. We injected duloxetine 20 mg/kg intraperitoneally in the MIA + Duloxetine group 28 days after injection, whereas rats in the MIA + Vehicle group were injected with 0.5 ml of 20% dimethyl sulfoxide. We assessed hyperalgesia, histopathological changes, immunoreactive (-ir) neurons for calcitonin gene-related peptide and activating transcription factor 3 in DRG, and immunoreactive neurons for ionized-calcium-binding adaptor molecule 1 (Iba1) in the dorsal horn of the spinal cord. MIA administration into the hip joint let to mechanical hyperalgesia of the ipsilateral hind paw (p < 0.05). A single injection of duloxetine significantly attenuated it in induced hip OA (p < 0.05) and suppressed the number of Iba1-ir microglia of the ipsilateral dorsal horn (p < 0.05). These results suggest that a single injection of duloxetine suppressed mechanical hyperalgesia and may influence the expression of Iba1 in the microglia of the ipsilateral dorsal horn in the MIA-induced hip OA. This finding implies the inhibitory effects of duloxetine against neuropathic pain, which may lead to a change of microglial activities. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:422-430, 2020.


Assuntos
Analgésicos/uso terapêutico , Cloridrato de Duloxetina/uso terapêutico , Articulação do Quadril/efeitos dos fármacos , Osteoartrite do Quadril/tratamento farmacológico , Analgésicos/farmacologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Cloridrato de Duloxetina/farmacologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Articulação do Quadril/diagnóstico por imagem , Articulação do Quadril/patologia , Ácido Iodoacético , Masculino , Osteoartrite do Quadril/induzido quimicamente , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/patologia , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/metabolismo
16.
Chem Biol Interact ; 315: 108890, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31678597

RESUMO

The monoterpenoid terpinen-4-ol (4TERP) is known to inhibit cell excitability, has low toxicity and important pharmacological activities, which are likely related to neural excitability, such as anti-inflammatory, antiepileptic and antinociceptive effects. However, the pharmacological characteristics and mechanisms underlying the effects of 4TERP on blockade of neural action potential are not completely elucidated. Since Na+ current (INa) through voltage-dependent Na+ channels (NaV) is a major mechanism for excitability, the present study investigated the pharmacological characteristics and mechanisms of the action of 4TERP on INa through NaV. For this aim, dissociated small neurons of dorsal root ganglia of adult rats were used for whole cell patch-clamp recordings. 4TERP concentration-dependently inhibits INa (IC50 0.8 ±â€¯0.3 mM; pharmacological efficacy 42.89 ±â€¯5.54%). 4TERP interfered with INa through a mechanism with various components, which includes predominantly channel pore block and sensitivity to frequency of use. In presence of 4TERP (3 mM), decreasing stimulation from 5 Hz to very low frequency (75 s of quiescence previously to stimulation) induced INa decrease to 65.17 ±â€¯5.86% of control. 4TERP also altered (left shift) voltage sensitivity of the steady state activation of NaV. Data are discussed aiming to interpret the importance of blockade of INa through NaV as participant of 4TERP-induced inhibition of membrane excitability.


Assuntos
Gânglios Espinais/efeitos dos fármacos , Monoterpenos/farmacologia , Neurônios/efeitos dos fármacos , Terpenos/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Canais de Sódio Disparados por Voltagem/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Feminino , Gânglios Espinais/metabolismo , Masculino , Neurônios/metabolismo , Técnicas de Patch-Clamp/métodos , Ratos , Ratos Wistar
17.
Am J Physiol Renal Physiol ; 318(2): F298-F314, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31790304

RESUMO

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common chronic pelvic disorder with sensory symptoms of urinary urgency, frequency, and pain, indicating a key role for hypersensitivity of bladder-innervating sensory neurons. The inflammatory mast cell mediator histamine has long been implicated in IC/BPS, yet the direct interactions between histamine and bladder afferents remain unclear. In the present study, we show, using a mouse ex vivo bladder afferent preparation, that intravesical histamine enhanced the mechanosensitivity of subpopulations of afferents to bladder distension. Histamine also recruited "silent afferents" that were previously unresponsive to bladder distension. Furthermore, in vivo intravesical histamine enhanced activation of dorsal horn neurons within the lumbosacral spinal cord, indicating increased afferent signaling in the central nervous system. Quantitative RT-PCR revealed significant expression of histamine receptor subtypes (Hrh1-Hrh3) in mouse lumbosacral dorsal root ganglia (DRG), bladder detrusor smooth muscle, mucosa, and isolated urothelial cells. In DRG, Hrh1 was the most abundantly expressed. Acute histamine exposure evoked Ca2+ influx in select populations of DRG neurons but did not elicit calcium transients in isolated primary urothelial cells. Histamine-induced mechanical hypersensitivity ex vivo was abolished in the presence of the histamine H1 receptor antagonist pyrilamine and was not present in preparations from mice lacking transient receptor potential vanilloid 1 (TRPV1). Together, these results indicate that histamine enhances the sensitivity of bladder afferents to distension via interactions with histamine H1 receptor and TRPV1. This hypersensitivity translates to increased sensory input and activation in the spinal cord, which may underlie the symptoms of bladder hypersensitivity and pain experienced in IC/BPS.


Assuntos
Cistite Intersticial/metabolismo , Histamina/administração & dosagem , Hiperalgesia/metabolismo , Mecanorreceptores/efeitos dos fármacos , Mecanotransdução Celular/efeitos dos fármacos , Receptores Histamínicos H1/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Bexiga Urinária/inervação , Administração Intravesical , Animais , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Cistite Intersticial/fisiopatologia , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Hiperalgesia/fisiopatologia , Masculino , Mecanorreceptores/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Limiar da Dor/efeitos dos fármacos , Pressão , Receptores Histamínicos H1/metabolismo , Canais de Cátion TRPV/deficiência , Canais de Cátion TRPV/genética , Urotélio/efeitos dos fármacos , Urotélio/metabolismo
18.
Proc Natl Acad Sci U S A ; 117(1): 698-707, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31848242

RESUMO

Group III/IV muscle afferents transduce nociceptive signals and modulate exercise pressor reflexes (EPRs). However, the mechanisms governing afferent responsiveness to dually modulate these processes are not well characterized. We and others have shown that ischemic injury can induce both nociception-related behaviors and exacerbated EPRs in the same mice. This correlated with primary muscle afferent sensitization and increased expression of glial cell line-derived neurotrophic factor (GDNF) in injured muscle and increased expression of GDNF family receptor α1 (GFRα1) in dorsal root ganglia (DRG). Here, we report that increased GDNF/GFRα1 signaling to sensory neurons from ischemia/reperfusion-affected muscle directly modulated nociceptive-like behaviors and increased exercise-mediated reflexes and group III/IV muscle afferent sensitization. This appeared to have taken effect through increased cyclic adenosine monophosphate (cAMP) response element binding (CREB)/CREB binding protein-mediated expression of the purinergic receptor P2X5 in the DRGs. Muscle GDNF signaling to neurons may, therefore, play an important dual role in nociception and sympathetic reflexes and could provide a therapeutic target for treating complications from ischemic injuries.


Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Mialgia/etiologia , Nociceptividade/fisiologia , Reflexo/fisiologia , Traumatismo por Reperfusão/patologia , Animais , Proteína de Ligação a CREB/metabolismo , Sistema Cardiovascular/inervação , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Exercício Físico/fisiologia , Gânglios Espinais/metabolismo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Frequência Cardíaca/fisiologia , Humanos , Masculino , Camundongos , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/inervação , Músculo Esquelético/metabolismo , Mialgia/patologia , Neurônios Aferentes/fisiologia , Receptores Purinérgicos P2X5/metabolismo , Traumatismo por Reperfusão/complicações , Transdução de Sinais/fisiologia
19.
Prostate ; 80(1): 28-37, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31573117

RESUMO

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a disorder that is characterized by persistent pelvic pain in men of any age. Although several studies suggest that the transient receptor potential vanilloid 1 (TRPV1) channel is involved in various pathways of chronic pain, the TRPV1 channel has not been implicated in chronic pelvic pain associated with CP/CPPS. METHODS: Male C57BL/6J (B6) and TRPV1 knockout (TRPV1 KO) mice (5-7 weeks old) were used to study the development of pelvic allodynia in a murine model of CP/CPPS called experimental autoimmune prostatitis (EAP). The prostate lobes, dorsal root ganglia (DRG), and spinal cord were excised at day 20. The prostate lobes were assessed for inflammation, TRPV1 expression, and mast cell activity. DRG and spinal cord, between the L6-S4 regions, were analyzed to determine the levels of phosphorylated ERK1/2 (p-ERK 1/2). To examine the therapeutic potential of TRPV1, B6 mice with EAP received intraurethral infusion of a TRPV1 antagonist at day 20 (repeated every 2 days) and pelvic pain was evaluated at days 20, 25, 30, and 35. RESULTS: Our data showed that B6 mice with EAP developed pelvic tactile allodynia at days 7, 14, and 20. In contrast, TRPV1 KO mice with EAP do not develop pelvic tactile allodynia at any time point. Although we observed no change in the levels of TRPV1 protein expression in the prostate from B6 mice with EAP, there was evidence of significant inflammation and elevated mast cell activation. Interestingly, the prostate from TRPV1 KO mice with EAP showed a lack of mast cell activation despite evidence of prostate inflammation. Next, we observed a significant increase of p-ERK1/2 in the DRG and spinal cord from B6 mice with EAP; however, p-ERK1/2 expression was unaltered in TRPV1 KO mice with EAP. Finally, we confirmed that intraurethral administration of a TRPV1 antagonist peptide reduced pelvic tactile allodynia in B6 mice with EAP after day 20. CONCLUSIONS: We demonstrated that in a murine model of CP/CPPS, the TRPV1 channel is key to persistent pelvic tactile allodynia and blocking TRPV1 in the prostate may be a promising strategy to quell chronic pelvic pain.


Assuntos
Doenças Autoimunes/metabolismo , Prostatite/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Gânglios Espinais/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/imunologia , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Masculino , Mastócitos/imunologia , Mastócitos/metabolismo , Mastócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oligopeptídeos/farmacologia , Dor Pélvica/tratamento farmacológico , Dor Pélvica/imunologia , Dor Pélvica/metabolismo , Dor Pélvica/patologia , Fosforilação , Prostatite/tratamento farmacológico , Prostatite/imunologia , Prostatite/patologia , Medula Espinal/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/deficiência
20.
Histochem Cell Biol ; 153(3): 177-184, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31879799

RESUMO

Zonisamide, an anti-epileptic and anti-Parkinson's disease drug, displays neurotrophic activity on cultured motor neurons and facilitates axonal regeneration after peripheral nerve injury in mice, but its underlying mechanisms remain unclear. In this study, zonisamide enhanced neurite outgrowth from cultured adult rat dorsal root ganglion (DRG) neurons in a concentration-dependent manner (1 µM < 10 µM < 100 µM), and its activity was significantly attenuated by co-treatment with a phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor LY294002 or a mitogen-activated protein kinase (MAPK) inhibitor U0126. In agreement with these findings, 100 µM zonisamide for 1 h induced phosphorylation of AKT and ERK1/2, key molecules of PI3K and MAPK signaling pathways, respectively in mouse neuroblastoma × rat DRG neuron hybrid cells ND7/23. In contrast, zonisamide failed to promote proliferation or migration of immortalized Fischer rat Schwann cells 1 (IFRS1). These findings suggest that the beneficial effects of zonisamide on peripheral nerve regeneration may be attributable to its direct actions on neurons through PI3K and MAPK pathways, rather than the stimulation of Schwann cells.


Assuntos
Anticonvulsivantes/farmacologia , Gânglios Espinais/efeitos dos fármacos , Neuritos/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Zonisamida/farmacologia , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Gânglios Espinais/metabolismo , Neuritos/metabolismo , Neurônios/metabolismo , Ratos , Ratos Wistar , Células de Schwann/citologia , Células de Schwann/metabolismo , Relação Estrutura-Atividade
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