RESUMEN
Stroke is the leading cause of disability in much of the world, with few treatment options available. Following unilateral stroke in rats, inosine, a naturally occurring purine nucleoside, stimulates the growth of projections from the undamaged hemisphere into denervated areas of the spinal cord and improves skilled use of the impaired forelimb. Inosine augments neurons' intrinsic growth potential by activating Mst3b, a component of the signal transduction pathway through which trophic factors regulate axon outgrowth. The present study investigated whether inosine would complement the effects of treatments that promote plasticity through other mechanisms. Following unilateral stroke in the rat forelimb motor area, inosine combined with NEP1-40, a Nogo receptor antagonist, doubled the number of axon branches extending from neurons in the intact hemisphere into the denervated side of the spinal cord compared with either treatment alone, and restored rats' level of skilled reaching using the impaired forepaw to preoperative levels. Similar functional improvements were seen when inosine was combined with environmental enrichment (EE). The latter effect was associated with changes in gene expression in layer 5 pyramidal neurons of the undamaged cortex well beyond those seen with inosine or EE alone. Inosine is now in clinical trials for other indications, making it an attractive candidate for the treatment of stroke patients.
Asunto(s)
Miembro Anterior/efectos de los fármacos , Inosina/uso terapéutico , Proteínas de la Mielina/uso terapéutico , Neuronas/efectos de los fármacos , Fragmentos de Péptidos/uso terapéutico , Recuperación de la Función/efectos de los fármacos , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Axones/efectos de los fármacos , Axones/fisiología , Ambiente , Miembro Anterior/fisiopatología , Inosina/farmacología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Movimiento/efectos de los fármacos , Movimiento/fisiología , Proteínas de la Mielina/farmacología , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Fragmentos de Péptidos/farmacología , Ratas , Recuperación de la Función/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiopatología , Accidente Cerebrovascular/fisiopatologíaRESUMEN
Recovery after stroke and other types of brain injury is restricted in part by the limited ability of undamaged neurons to form compensatory connections. Inosine, a naturally occurring purine nucleoside, stimulates neurons to extend axons in culture and, in vivo, enhances the ability of undamaged neurons to form axon collaterals after brain damage. The molecular changes induced by inosine are unknown, as is the ability of inosine to restore complex functions associated with a specific cortical area. Using a unilateral injury model limited to the sensorimotor cortex, we show that inosine triples the number of corticospinal tract axons that project from the unaffected hemisphere and form synaptic bouton-like structures in the denervated half of the spinal cord. These changes correlate with improved recovery in animals' ability to grasp and consume food pellets with the affected forepaw. Studies using laser-capture microdissection and microarray analysis show that inosine profoundly affects gene expression in corticospinal neurons contralateral to the injury. Inosine attenuates transcriptional changes caused by the stroke, while upregulating the expression of genes associated with axon growth and the complement cascade. Thus, inosine alters gene expression in neurons contralateral to a stroke, enhances the ability of these neurons to form connections on the denervated side of the spinal cord, and improves performance with the impaired limb.