RESUMO
Accumulating evidence indicates that in addition to its immunosuppressant properties, FK506 (tacrolimus), an FDA-approved molecule, promotes nerve regeneration. However, the neuroprotective and neurotrophic effects of this molecule on sensitive fiber regeneration have never been studied. In order to fill this gap in our knowledge, we assessed the therapeutic potential of FK506 in a rat model of peripheral nerve repair. A 1-cm segment of left peroneal nerve was cut out and immediately autografted in an inverted position. After surgery, the animals were treated with FK506 (1.2 mg/kg/d) via an osmotic pump and compared to untreated animals. Recovery of use of the injured leg was assessed weekly for 12 weeks using a walking track apparatus and a camcorder. At the end of this period, motor and metabosensitive responses of the regenerated axons were recorded and histological analysis was performed. We observed that FK506 significantly: (1) increased the diameter of regenerated axons in the distal portion of the graft; (2) improved the responses of sensory neurons to metabolites such as potassium chloride and lactic acid; and (3) induced a fast-to-slow-fiber-type transition of the tibialis anterior muscle. Taken together, these data indicate that FK506 potentiates metabosensitive nerve fiber regeneration. Pharmacological studies of various dosages and concentrations of FK506 are required before recommending this drug for therapeutic treatment of nerve injuries.
Assuntos
Regeneração Nervosa/efeitos dos fármacos , Traumatismos dos Nervos Periféricos , Nervos Periféricos/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Tacrolimo/farmacologia , Animais , Modelos Animais de Doenças , Cones de Crescimento/efeitos dos fármacos , Cones de Crescimento/metabolismo , Cones de Crescimento/patologia , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Ácido Láctico/agonistas , Ácido Láctico/metabolismo , Masculino , Fibras Musculares de Contração Rápida/efeitos dos fármacos , Fibras Musculares de Contração Rápida/metabolismo , Regeneração Nervosa/fisiologia , Nervos Periféricos/fisiopatologia , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Nervo Fibular/efeitos dos fármacos , Nervo Fibular/lesões , Nervo Fibular/fisiopatologia , Cloreto de Potássio/agonistas , Cloreto de Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Tacrolimo/uso terapêutico , Resultado do TratamentoRESUMO
The coumarin scopoletin was isolated in a pure form from the roots of Brunfelsia hopeana Benth. (Solanaceae). In isolated rat aortic rings, scopoletin (26-520 microM) inhibited to approximately the same extent the contractions induced by a variety of substances, including phenylephrine, potassium chloride, serotonin and PGF(2) (alpha). The effect of the coumarin on phenylephrine-induced contractions was not affected by endothelium removal or NO-synthase blockade by L-NAME (100 microM). Scopoletin (78 - 590 microM) antagonized in a concentration-dependent manner (IC(50) = 300 +/- 20 microM, n = 5), transient contractions in Ca(2+)-free media induced by noradrenaline, but not those induced by caffeine. Also, scopoletin did not interfere with the refilling of noradrenaline-sensitive intracellular calcium stores. It is suggested that the non-specific spasmolytic action of scopoletin can be attributed, at least in part, to its ability to inhibit the intracellular calcium mobilization from the noradrenaline-sensitive stores.
