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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.
Item Metadata
Title |
A natural diketopiperazine stimulates axon sprouting and sensory recovery following dorsal rhizotomy
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2010
|
Description |
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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Genre | |
Type | |
Language |
eng
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Date Available |
2010-01-21
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivs 3.0 Unported
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DOI |
10.14288/1.0068993
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2010-05
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
Aggregated Source Repository |
DSpace
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Item Citations and Data
Rights
Attribution-NonCommercial-NoDerivs 3.0 Unported