Semester

Fall

Date of Graduation

2022

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Jason D. Huber

Committee Co-Chair

Werner J. Geldenhuys

Committee Member

Werner J. Geldenhuys

Committee Member

Mohammed A Nayeem

Committee Member

Gordon P. Meares

Committee Member

Tavarekere N Nagaraja

Abstract

One of the main reasons for CNS drugs to fail in clinical development is not considering age as a risk factor while studying chronic age-related neurological/neurodegenerative diseases in preclinical studies. We first set out to gain a comprehensive understanding of the impact of age on various aspects (anatomical, immunological, and biochemical) in rodents that play a key role in determining the onset, progression, and evolution of disease severity. With advancing age, the vascular structure and function are compromised which is hypothesized to accelerate cognitive decline. The initial step toward developing novel therapeutics is to characterize the age-related vascular modifications. Utilizing a vessel painting technique, we labelled the surface cortical vessels of young and aged Sprague-Dawley rats and analyzed for classical angiographic features (junctions, lengths, end points, density, etc). We found significant decrease in vascular components while vascular complexity and lacunarity were significantly increased in the aged brain compared to young brain. These age-dependent changes were prominent at the level of right and left middle cerebral artery (MCA) as well as on a global scale. Next, we investigated the changes on the peripheral immune response following lipopolysaccharide (LPS) induced acute systemic inflammation in young and aged Sprague Dawley rats. We observed age-related immunosuppression in the splenic leukocytes indicative of reduced ability of the spleen to retain the immune cells. We also found dysregulated cytokine/chemokine expression in the plasma following LPS stimulation in aged and young animals. Interestingly, we noticed significant increase in circulatory neutrophil population in the aged animals compared to young animals in response to LPS at 24h. Taken together, these studies confirm the presence of age-related modifications in the vasculature as well as immune system suggesting altered response to injury/infection and thus emphasizing the need to utilize age-appropriate models when studying diseases of the elderly. Lastly, we wanted to test the therapeutic effect of a novel agent in case of brain injury model in aged rodents. Previous studies by our lab and others have showed that targeting mitoNEET using NL-1 was neuroprotective following brain injury models. We wanted to investigate if administration of NL-1 could improve functional outcomes following stroke in an aged rodent model of cerebral ischemia reperfusion injury. We found significant decrease in infarct volume and edema index at 24h post stroke. We also saw enhanced survival and reduced behavior deficits. Moreover, we showed improved BBB integrity, reduced oxidative stress and apoptosis at 72h post stroke. Interestingly, PLGA encapsulated NL-1 at 0.25mg/kg (which is 40-fold lesser dose than NL-1 at 10mg/kg) produced better therapeutic effects. Future studies should focus on understanding the mechanism underlying the biology of aging thus enabling the development of novel therapeutic targets for neurological disorders/diseases.

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