Document Type

Dissertation - Open Access

Award Date

2019

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Shafiqur Rahman

Abstract

Major depressive disorder (MDD) is the most prevalent psychiatric disorder, affecting about 10% of the global population and is the leading cause of disability in USA. Nearly one-third of depressed patients fail to respond to conventional antidepressant therapies. Therefore, novel therapies are needed, and require a new target and molecular mechanisms underlying MDD. Brain glial mechanisms, specifically, microglial α7 nicotinic acetylcholine receptors (nAChRs) have been proposed as an important target for MDD associated with neuroinflammation. We hypothesized that microglial α7 nAChRs positive allosteric modulator (PAM) has an important role in the regulation of behavioral, cellular, biochemical and molecular mechanisms underlying MDD associated with neuroinflammation in the hippocampus and prefrontal cortex. The primary goal of this dissertation research was to evaluate the role of microglial α7 nAChRs PAM in the regulation of behavioral, cellular and molecular mechanisms linked to depression-like behavior associated with neuroinflmmation in the hippocampus and prefrontal cortex using animal models. We have demonstrated that systemic administration of microglial α7 nAChR PAM PNU120596 prevents lipopolysaccharide-induced depression-like behavior in mice, an inflammatory animal model of MDD. The PNU120596 also reduced LPS-induced depression-related behaviors such as anxiety and cognitive deficit. Methyllycaconitine, an α7 nAChR antagonist reversed the antidepressant, anxiolytic, and pro-cognitive-like effects of PNU120596, indicating the involvement of α7 nAChR. The PNU120596 decreased the expression of microglial markers, ionized calcium binding adaptor molecule 1 and cluster of differentiation 11b, and astroglial marker, glial fibrillary acidic protein. In addition, PNU120596 reduced expression of interleukin 1β and tumor necrosis factor-α and increased the level of norepinephrine. The PNU120596 increased nuclear peroxisome proliferator-activated receptor type-α expression and inactivated nuclear factor-κB. The PNU120596 regulated neurotoxic glutaminergic transmission by decreasing 3-hydroxyanthranilate 3,4-dioxygenase expression and quinolinic acid formation. The PNU120596 also modulated neuronal excitability by decreasing Brainderived neurotrophic factor and sodium-potassium-chloride co-transporter 1 expression and increasing potassium-chloride co-transporter 2. Overall, our findings demonstrated that positive allosteric modulation of microglial α7 nAChR-mediated signaling regulate behavioral, cellular, biochemical and molecular mechanisms underlying MDD. Therefore, targeting microglial α7 nAChR in the hippocampus and prefrontal cortex by positive allosteric modulators represents a novel strategy for the treatment of MDD.

Library of Congress Subject Headings

Depression, Mental -- Immunological aspects.
Nicotinic receptors.
Neuroprotective agents.
Inflammation.

Publisher

South Dakota State University

Rights

In Copyright - Non-Commercial Use Permitted
http://rightsstatements.org/vocab/InC-NC/1.0/

Available for download on Thursday, April 28, 2022

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