Evaluation of Drugs Targeting NMDA and Opioid Receptors in Preclinical Models of Parkinson’s Disease and L-Dopa-Induced Dyskinesia
AuthorBartlett, Mitchell Julian
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PublisherThe University of Arizona.
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EmbargoRelease after 08/29/2021
AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease. It is characterized by its cardinal motor symptoms, but patients also experience significant non-motor symptoms, including depression and pain. Dopamine replacement therapy by L-DOPA is the gold-standard therapy for PD, but it only treats the motor symptoms and can result in the development of L-DOPA-induced dyskinesia (LID), a debilitating side effect. Effective LID treatment is limited to neurosurgery, therefore an effective non-invasive pharmacological therapy is a critical unmet need to extend the therapeutic lifetime and improve the quality of life in PD patients taking L-DOPA. The opioid receptor system and N-methyl-D-aspartate receptors (NMDARs) have been identified as two potential targets for the development of novel or repurposed drugs for the treatment of LID. The endogenous opioid peptides enkephalin and dynorphin modulate the dopamine system. They are important co-transmitters of gamma-aminobutyric acid (GABA) and glutamate transmission in the direct and indirect striatofugal pathways that are disrupted in PD and have been implicated in genesis and expression of LID. NMDAR antagonism has also been studied in preclinical LID models, with mixed results. This dissertation provides evidence for the use of novel and repurposed compounds that target both opioid receptors and NMDARs for the treatment of LID. Here we investigated the potential therapeutic effects of a highly-specific μ-opioid receptor antagonist CTAP and its glycopeptide congener (gCTAP5), based on data showing that a μ-opioid receptor antagonist, ADL5510, with modest selectivity for μ- over δ-opioid receptors is anti-dyskinetic in a preclinical non-human primate model. Our data indicate that highly-selective μ-opioid receptor antagonism alone might not be sufficient to be anti-dyskinetic and suggests that additional opioid receptor properties in less specific μ-opioid receptor antagonists might contribute to the published anti-dyskinetic effects. This is further supported by our investigation of the use of sub-anesthetic ketamine, a well-known, multi-ligand binding compound with known NMDAR-antagonist activity and opioid activity. Here we show that sub-anesthetic doses of ketamine provide a long-term suppression of LID in two preclinical rodent models that are mediated by the release of brain-derived neurotrophic factor-release in the striatum, followed by activation of ERK1/2 and mTOR pathway signaling. These molecular changes ultimately lead to morphological changes, specifically a reduction in the density of mushroom spines on dendrites in the striatal medium spiny neurons, which we show to be highly correlated with dyskinesia in this model. These molecular and cellular changes are similar to those caused by ketamine in preclinical models of depression. This suggests that ketamine-treatment for these two diseases may have similar underlying molecular and cellular mechanisms. Given its therapeutic benefit in a few PD patient case studies and the clinically proven therapeutic benefits for both treatment-resistant depression and several pain states, both common co-morbidities in PD, sub-anesthetic ketamine could provide a triple benefit to PD patients in the future. The preclinical mechanistic studies complement currently ongoing clinical testing of sub-anesthetic ketamine infusions for the treatment of LID by our group, and provide further evidence to support repurposing of sub-anesthetic ketamine to treat PD patients.
Degree ProgramGraduate College