Year

2017

Degree Name

Doctor of Philosophy

Abstract

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B(PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotropic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogensis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogensis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.

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