Molecular and Cellular Neuroscience Commons^™

The Effect Of Novel Microtubule Modulators On Experimental Lewy Body Disease, Anuj S. Jamenis

Electronic Theses and Dissertations

In Lewy body disorders, α-synuclein aggregates are believed to destabilize the microtubular framework. However, microtubules are a challenging therapeutic target, as excessive rigidity or flexibility afforded by microtubule modulators may be neurotoxic. Thus, the objective of the present study was to evaluate dual-acting microtubule- stabilizing/destabilizing agents in cellular and animal models of early-stage Lewy body disease.

In Aim 1 we tested the dual-acting tricylic pyrimido[4,5-b]indole analogs AG161-47 and AG161-41 in an in vitro preformed fibril induced model of Lewy body disease. We found that both compounds reduced preformed fibril-seeded α-synucleinopathy without toxicity in primary hippocampal cultures. AG161-47 subtly impacted microtubule …

Role Of The Anti-Viral Immune Response In Neural Cell Modulation And Neurological Sequelae Of Childhood Viral Infections, Yashika Kamte

Electronic Theses and Dissertations

Viral infections of the central nervous system (CNS) often result in neurological sequelae and are considered a risk factor for the development of neurological disease. Moreover, the outcomes of a viral infection are largely dependent on the age of the host, with younger hosts developing more profound neuropathology. Perhaps the developing brain coupled with an immature immune system contributes to worse outcomes in the very young. Children suffering from brain infections are more prone to develop enduring neurological impairments even after recovery from the infection. Although majority of the brain growth occurs in utero, neurodevelopment continues throughout the juvenile …

Evaluating Sex Differences In The Neuroimmune Response Following Neuroinflammation And Relief Due To Nanotheranostic Treatment, Brooke Deal

Electronic Theses and Dissertations

Until recently, the majority of preclinical neuroinflammatory studies were performed on males. Because of this, less is known about the female neuroinflammatory response to injury, formation of pain, or response to pain-relieving therapies. The neuroinflammatory response is multifaceted with neuronal, glial, and immune cells all contributing to the induction and resolution of neuroinflammation. During this response, macrophages typically undergo an upregulation of cyclooxygenase-2 (COX-2) leading to the production of prostaglandin E2 (PGE2), which is linked to neuronal sensitization and pain. Non-steroidal anti-inflammatory drugs (NSAIDs) attenuate PGE2 by the inhibition of COX-2. A limitation with NSAIDs is that due to the …

Neural Stem Cells: Age-Dependent Outcomes During Viral Infections In The Central Nervous System, Manisha N. Chandwani

Electronic Theses and Dissertations

Viral infections in the central nervous system (CNS) are associated with neurodevelopmental and neurobehavioral deficits. The outcomes of viral infections can be driven by damage and death of neurons. Neural stem cells (NSCs) play key roles in neurodevelopment, repair, and physiological brain function. During a viral infection, NSC activity can disturbed by direct infection of NSCs by the virus or by anti-viral immune response. Here, we aimed to assess whether the anti-viral immune response can impact NSC activity during an immunocompetent response in the adult brain. We utilized a transgenic mouse model of Measles virus infection where only the CNS …

Sex-Specific Effects Of Chaperone And Glial Defenses On Experimental Lewy Body Disease, Tarun Bhatia

Electronic Theses and Dissertations

Lewy body disorders are a group of neurodegenerative conditions characterized by the pathological misfolding and aggregation of the abundant protein, α-synuclein. The most common Lewy body disorders are Parkinson’s disease and dementia with Lewy bodies. Apart from ageing, male sex is a major risk factor for Lewy body disorders, as men are at ~1.5-fold higher risk for these diseases than women. Yet, preclinical studies on Lewy body disorders rarely examine sex as a biological variable, and the mechanisms underlying sex-skewedness in disease risk remain undetermined.

Here, we developed a sex-stratified model of Lewy body disorders by exposing primary neurons harvested …

Differential Expression Of Rna In The Rat Peripheral Nervous System Following Nerve Injury And Treatment With Pain-Relieving Celecoxib-Loaded Nanomedicine, Andrea Stevens

Electronic Theses and Dissertations

The neuroinflammatory response to peripheral nerve injury is associated with chronic pain and significant changes in the expression profiles of RNAs in neurons, glia and infiltrating immune cells: a neuro-immune triad. Chronic constriction injury (CCI) of the rat sciatic nerve provides an opportunity to mimic neuropathic injury and quantitatively assess behavior and differential gene expression in individual animals. Macrophages that phagocytose intravenously injected nanoemulsion carrying the non-steroidal anti-inflammatory, NSAID, Celecoxib, naturally accumulate at the site of injury resulting in relief of CCI behavioral hyper-sensitivity. It is not known beyond the inhibition of cyclooxygenase-2 (COX-2) activity and the reduction in prostaglandin …

Nanomedicine-Driven Neuropathic Pain Relief In Rat Model Is Associated With Macrophage Polarity And Mast Cell Activation, Muzamil Saleem

Electronic Theses and Dissertations

We explored the immune neuropathology underlying multi-day relief from neuropathic pain in a rat model initiated at the sciatic nerve by using a nanoemulsion-based nanomedicine as a biological probe. The nanomedicine is theranostic: both therapeutic (containing celecoxib drug) and diagnostic (containing near-infrared fluorescent (NIRF) dye) and is small enough to be phagocytosed by circulating monocytes. A model of neuropathic pain is initiated by tying four 1mm spaced knots around the sciatic nerve with chromic gut suture, which results in neuroinflammation, and a resultant pain-like behavior manifests. We show that pain-like behavior reaches a plateau of maximum hypersensitivity 8 days post-surgery, …