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UBC Theses and Dissertations

A natural diketopiperazine stimulates axon sprouting and sensory recovery following dorsal rhizotomy Wong, Jennifer Wai Jing

Abstract

During prenatal and early postnatal development, the mammalian nervous system has the remarkable ability to build its intricate array of connections and circuitries with the help of a variety guidance cues. When the nervous system matures, it appears to lose its ability to rebuild damaged connections following traumatic insults. This can be attributed in part to the expression of inhibitory molecules that hinder axon regeneration and reconnection. The goal of this thesis is to identify novel compounds that can stimulate axon outgrowth in the unfavourable environment of the adult central nervous system (CNS) by manipulating the axon outgrowth machinery in the neuronal growth cone. To isolate compounds of therapeutic potential, we first developed a novel high-throughput screening technology to rapidly identify candidate neurite outgrowth promoting molecules from a bioactive marine sponge extract library. Using the high-throughput screening technology, we identified a natural diketopiperazine DKP101516 that demonstrated robust axon outgrowth promoting activity through the phosphotidyl-3-inositol kinase (PI3K) signalling pathway. Further in vivo studies revealed that while DKP101516 did not stimulate afferent regeneration, it markedly enhanced intraspinal axon sprouting following dorsal rhizotomy. Lastly, behavioural studies suggest that DKP10516 also promoted rapid and transient recovery in mechanosensation, concomitant to the sprouting of VGLUT1 positive mechanosensory afferents. Collectively, our data suggest that DKP101516 may be a promising therapeutic to stimulate axon repair and functional recovery following injuries in the CNS.

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Attribution-NonCommercial-NoDerivs 3.0 Unported

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