Towards a Better Treatment of Parkinson's disease

<p>Current therapies for Parkinson's Disease, the second most common neurodegenerative disorder, do not prevent disease progression, and induce extremely detrimental side-effects. Improving the best current pharmacological therapy, L-DOPA, carries important clinical benefits, partly by reducing the dose-related side-effects which occur after five to ten years of use. Thus the central aim of this proposal is to determine whether low doses of a D2 antagonist may, by selectively blocking the dopamine autoreceptor-mediated feedback inhibition of dopamine neurons, potentiate L-DOPA's effect on individual basal ganglia neurons and its antiparkinsonian effects in Parkinsonian animals. Electrophysiology (extracellular single-cell recording in the globus pallidus) and behavioral (cylinder test) studies were performed to determine if co-administration of a small dose of the D2 antagonist raclopride with L-DOPA results in an enhanced therapeutic effect of L-DOPA in 6-OHDA lesioned (parkinsonian) rats. Preliminary data revealed different subgroups of pallidal neurons, with different responses to L-DOPA injection. However, we showed that a major method by which sub-groups of pallidal neurons have been identified in previous studies was unreliable, halting further study of L-DOPA's effect on different subgroups of pallidal neurons using that method. Thus, we focused on classification of pallidal neurons and the changes of these neurons in Parkinsonian animals. Previous studies report pallidal neurons as Type-I (negative initial peak) or Type-II (initial positive peak). Our studies suggest electrode impedance determines whether the recorded waveform is Type-I (low impedance electrode) or Type-II (high impedance electrode). Pallidal neurons can be more reliably classified based on functional connectivity with cortical neurons. More importantly, our findings showed that, in Parkinsonian rats, pallidal neurons positively coupled to cortical activity usually lag, while in control rats close to half of pallidal neurons lead cortical activity. Also, we found significantly increased cortical control of pallidal neurons in Parkinsonian rats indicated by a significant increase in the observed number of pallidal cells negatively coupled to cortical activity. The quantity of pallidal neurons uncoupled to cortical activity was observed to significantly decrease in 6-OHDA lesioned rats compared to controls. Behaviorally, raclopride (5 μg/kg, i.p.) was found to significantly potentiate the therapeutic benefit of L-DOPA (3 mg/kg, i.p.).</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Basic Sciences

Year

2014

Author dc:creator

• Karain, Bradley Darryl

Contributors dc:contributor

• Shi, Wei-Xing
• Brantley, Eileen
• Hartman, Richard
• Johnson, Mark
• Soto-Wegner, Ubaldo

• Medical Genetics
• Medical Microbiology
• Parkinson's Disease - Treatment; Movement Disorders - Treatment; Receptors; Dopamine; Dopamine - Physiology; Molecular Biology; Neurons - Physiology; Neurotransmitter Agents - Physiology;
• Parkinson's Disease - Therapy
• Pallidal neurons
• Dopamine Autoreceptor-mediated feedback inhibition
• Cortical controlmedia

Statement dc:rights

• This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Language dc:language

English

Repository record dc:identifier

https://scholarsrepository.llu.edu/etd/160

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-1159