Semester

Fall

Date of Graduation

2009

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Jason D Huber

Abstract

Stroke is the leading cause of long-term adult disability and the third leading cause of death in the United States. More that 72% of stroke victims are over the age of 65, yet most studies utilize young animals. Aged rats suffer exacerbated stroke volume and inflammation, as well as worsened functional outcome when compared to young adult rats. While the blood brain barrier (BBB) remains intact with age, it becomes more susceptible to external factors. BBB permeability in the penumbra appears acutely, 20 min after middle cerebral artery occlusion (MCAO) in aged rats. Importantly, BBB permeability is earlier and more severe in aged animals and occurs before neuronal damage. Interestingly, our permeability studies using a small vascular space marker indicated small, subtle, permeability changes in the contralateral hemisphere. Permeability changes in the contralateral hemisphere were not found in young rats and were not found in aged rats when using a large vascular space marker (Evan's blue).;The free radical theory of aging contends that age-related diseases result from accumulation of oxidative stress damage as a result of increased generation of reactive oxygen species (ROS) and decreased antioxidant enzyme activity. Of particular interest are the NADPH oxidases (NOX1, NOX2, and NOX4), which have been implicated as a damaging source of ROS during the aging process. However, the role of NADPH oxidase isoforms during the progression of cerebral ischemia in aged rats is poorly understood. Apocynin, a NOX2 inhibitor, reduces infarct volume, neuron death, activated microglia, and edema formation in young rodents following brain injury. However, when administered to aged rats, apocynin significantly increased mortality and edema formation. These results indicate an age-dependent difference in the mechanism of action of apocynin.;Our studies demonstrate that aged rats have significantly worse strokes both in gross size as well as structure as compared to young rats. Aged rats consistently have worsened and prolonged functional impairment, exacerbated BBB permeability, increased neuronal damage, and intensified inflammatory cell infiltration post MCAO and reperfusion when compared to young adult rats. Importantly, BBB permeability and increased oxidative stress markers were found in the contralateral hemisphere of aged rats after MCAO and reperfusion. These findings provide evidence for a compensatory role of the contralateral hemisphere after stroke that can only be studied in aged animals. Utilizing aged animals to study the mechanisms of brain injury after MCAO and reperfusion is vital to finding clinically applicable therapies.

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