Graduation Date

Fall 12-15-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmacology and Experimental Neuroscience

First Advisor

Howard Gendelman

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative

disorder, second only to Alzheimer’s disease (AD). It is characterized by a

progressive loss of dopaminergic neurons along the nigrostriatal axis and the

formation of proteinaceous inclusions of alpha-synuclein (α-syn). Secondary to

the loss of dopaminergic neurons is a progression in motor and non-motor

symptoms. Motor symptoms are characterized by slowness in movement,

stiffness and tremor. Non-motor symptoms include depression, constipation,

sleep abnormalities and loss of sense of smell. The cause of disease remains

incompletely understood. However, age, genetics, environment, viral infection,

and interplay between the innate and adaptive immune system can contribute to

disease onset and progression. Currently, treatments are palliative, and no

known intervention to halt disease progression exists. Drug therapies employ

dopamine or a dopamine precursor that affect neurotransmitter signaling while

showing no effect on the neurodegenerative process. Nonetheless, the available

therapies improve walking, movement and tremor debilities. Therefore, it remains

essential that therapies are developed to combat PD itself rather than simply

alleviating symptoms.

Neuroinflammation and immunity can speed nigrostriatal degeneration in

PD. The neuroinflammatory cascade begins with aggregation of misfolded or

post-translationally modified alpha synuclein (α-syn) resulting in the occurrence

of neuronal cell death and the presence of chronically activated glia. Such

changes in the glial phenotypes can affect the central nervous system (CNS)

microenvironment by producing pro-inflammatory factors that speed nigrostriatal

degeneration.

To halt or slow disease progression, a change in the microenvironment of

the brain may be necessary. One potential mechanism to achieve this goal is

through the induction and/or enhancement of immune-modulating cells such as

regulatory T cells (Tregs). Tregs maintain immune homeostasis by suppressing

pro-inflammatory immune responses, such as those associated with

neuroinflammation and PD. Furthermore, Tregs taken from PD patients

compared to control subjects lack the capacity to suppress proliferation of other

immune cells, suggesting a dysfunctional Treg response associated with

disease. Previously, our laboratory utilized granulocyte-macrophage colonystimulating

factor (GM-CSF) to restore Treg numbers and function in animal

models and a clinical trial. This cytokine induced a neuroprotective phenotype

when assessed in animal models; however, in the clinical setting, some mild to

moderately severe adverse events were identified. Thus, it remains important to

identify different means for drug delivery or other compounds with Treg-inducing

activity and without potential untoward side effects for easy translation to human

use.

With this goal in mind, our lab evaluated the efficacy of vasoactive

intestinal peptide (VIP) analogs in the 1-methyl-4-phenyl-1,2,3,6-

tetrahydropyridine (MPTP) mouse model of PD. Our data indicate that treatment

with a stable VIP analog results in a decrease in pro-inflammatory cytokine

production, decrease in microglial reactivity, increase in neuron survival, and

increase in suppressive immune phenotypes. Taken together, these findings

support the use of VIP as a potential immunotherapy for the treatment of PD.

Available for download on Sunday, June 03, 2018

Share

COinS