RESUMEN
Following spinal cord injury, spared axonal projections undergo spontaneous compensatory sprouting in an attempt to reinnervate synaptic targets that were deinnervated as a result of injury. However, compensatory sprouting is hindered by the expression of a myriad of inhibitory molecules throughout the adult central nervous system, including chondroitin sulfate proteoglycans (CSPGs) and myelin associated inhibitory proteins (MAIPs). In this study, we have identified a diketopiperazine designated DKP101516 that can overcome the inhibitory effects of MAIPs and CSPGs on neurite outgrowth and branching. In vivo analysis demonstrates that DKP101516 enhances the plasticity of various axonal populations following septuple dorsal rhizotomy by overcoming the inhibitory effects of CSPGs and MAIPs. Our results suggest that DKP101516 may encourage spinal cord repair by stimulating compensatory sprouting of intact axonal projections.
Asunto(s)
Axones/efectos de los fármacos , Dicetopiperazinas/farmacología , Regeneración Nerviosa/efectos de los fármacos , Péptidos Cíclicos/farmacología , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/fisiopatología , Animales , Axones/fisiología , Péptido Relacionado con Gen de Calcitonina/metabolismo , Células Cultivadas , Corteza Cerebral/citología , Embrión de Pollo , Proteoglicanos Tipo Condroitín Sulfato , Vaina de Mielina , Plasticidad Neuronal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Rizotomía , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Transducción de Señal/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismoAsunto(s)
Técnicas Genéticas , Glicosaminoglicanos/biosíntesis , Glicosaminoglicanos/genética , Animales , Astrocitos/metabolismo , Metabolismo de los Hidratos de Carbono/fisiología , Cicatriz/genética , Cicatriz/metabolismo , Cicatriz/prevención & control , Glicosaminoglicanos/deficiencia , Humanos , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/terapiaRESUMEN
Following spinal cord injury, a variety of inhibitory molecules hinder the success of axon regeneration. The motile tip of the axon, the growth cone, shares a similar cytoskeletal array as a migrating cell, and in general the cytoskeleton is regulated by a conserved set of signaling pathways that act downstream of guidance cue and growth factor receptors. We exploit these similarities by using migrating cells as a model system to screen for extracts that promote axon outgrowth. The screen is a high-throughput wound-healing assay performed by a 96-pin tool Biogrid robot where positive candidates are identified as extracts that stimulate complete wound healing. Testing of positive candidates on chick DRG explants has lead to the identification of extracts that promote neurite outgrowth on permissive and inhibitory substrates. Extracts can be fractionated to purity, identifying novel compounds that promote neurite outgrowth on inhibitory substrates.