RESUMO
Toxic neuropathy represents an important clinical problem in the use of the chemotherapeutic substances Taxol and thalidomide. Sensory neuropathy has a high incidence, lacks an effective treatment and is the dose-limiting factor for these drugs. The pathogenic basis of these neuropathies is unknown. We investigated the hypothesis that the experimental toxic neuropathies from Taxol and thalidomide results from destruction of vasa nervorum and can be reversed by the administration of an angiogenic cytokine. In animal models of Taxol- and thalidomide-induced neuropathy, nerve blood flow has been attenuated and the number of vasa nervorum has been reduced. Intramuscular gene transfer of naked plasmid DNA encoding VEGF-1 administered in parallel with Taxol injections completely inhibited deterioration of nerve function and diminution of the peripheral nerve vasculature. Gene therapy in animals with established Taxol- or thalidomide-induced neuropathies resulted in recovery of vascularity and improved nerve electrophysiology. These findings implicate microvascular damage as the basis for toxic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment for this disorder.
Assuntos
Neovascularização Patológica/tratamento farmacológico , Paclitaxel/farmacologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Talidomida/farmacologia , Vasa Nervorum/efeitos dos fármacos , Vasa Nervorum/lesões , Fator A de Crescimento do Endotélio Vascular/farmacologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Quimioterapia Combinada , Eletrofisiologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/enzimologia , Humanos , Injeções Intramusculares , Lectinas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Plasmídeos/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Circulação RenalRESUMO
As people come frequently into contact with electrical power sources, electrical injuries to peripheral nerves are commonly seen. The authors first review the parameters determining the severity and distribution of electrical injury to nerve tissue. These include tissue resistance, tissue susceptibility, current pathway, type of current, current density, duration and size of electrical contact. Subsequently, the pathophysiology of electrical injuries to nerve tissue is reviewed. Such injuries can be the result of thermal damage, vascular impairment, histological or electrophysiological changes in peripheral nerves, or direct mechanical trauma. Each of these types of injuries causes, specific lesions. As these lesions, especially delayed peripheral neurologic injury, can cause medico-legal problems, it is important to emphasize that electroneuromyography must be performed as early as possible.