Access Type

Open Access Dissertation

Date of Award

January 2017

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmaceutical Sciences

First Advisor

Anna A. Moszczynska

Second Advisor

Bryan Yamamoto

Abstract

Methamphetamine (METH) is a commonly abuse psychostimulant. Exposure to chronic high doses of METH can result in neurotoxicity primarily characterized by damage to striatal dopaminergic (DAergic) axons. There are currently no therapeutic interventions for METH neurotoxicity. To some extent damage to striatal DAergic axons is reversible and DAergic axon function may return following abstinence from METH. The reversible nature of METH neurotoxicity suggests that normal striatal function could be restored following exposure to METH. However, potential targets to treat METH neurotoxicity are needed. Axonal transport is required for restoration of DAergic axon components damaged or lost following METH. Here we investigated several potential novel drug targets to treat METH neurotoxicity including with emphasis on targeting axonal transport. We also investigated the E3 ligase parkin and the aggregation prone nerve terminal protein α-synuclein. To investigate the role of axonal transport in METH neurotoxicity we treated a rat model of METH neurotoxicity with axonal transport enhancing drug, epothilone D. Results show that epothilone D could to some extent prevent METH-induced damage to DAergic axons in the striatum. To investigate parkin’s role in METH neurotoxicity we treated parkin knockout rats with a neurotoxic dose of METH. We found that parkin knockout rats were hypersensitive to the METH induced DAergic neurotoxicity, confirming the neuroprotective role of parkin for DAergic neurons. To investigate the role of α-synuclein in METH neurotoxicity we developed a novel method of measuring α-synuclein oligomerization in complex biological samples. In conclusion, here we lay the experimental foundation for three potential targets of METH neurotoxicity.

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