Medicine and Health Sciences Commons^™

Novel Targets For Mitochondrial Dysfunction Following Traumatic Brain Injury, Heather M. Yonutas

Theses and Dissertations--Neuroscience

Mitochondrial dysfunction is a phenomenon observed in models of Traumatic Brain Injury (TBI). Loss of mitochondrial bioenergetics can result in diminished cellular homeostasis leading to cellular dysfunction and possible cellular death. Consequently, the resultant tissue damage can manifest as functional deficits and/or disease states. Therapeutic strategies to target this mitochondrial dysfunction have been investigated for models TBI and have shown promising effects.

For this project, we tested the hypothesis that mitoNEET, a novel mitochondrial membrane protein, is a target for pioglitazone mediated neuroprotection. To test this, we used a severe Controlled Cortical Impact (CCI) injury model in mitoNEET null and …

Histological And Behavioral Consequences Of Repeated Mild Traumatic Brain Injury In Mice, Amanda Nicholle Bolton Hall

Theses and Dissertations--Physiology

The majority of the estimated three million traumatic brain injuries that occur each year are classified as “mild” and do not require surgical intervention. However, debilitating symptoms such as difficulties focusing on tasks, anxiety, depression, and visual deficits can persist chronically after a mild traumatic brain injury (TBI) even if an individual appears “fine”. These symptoms have been observed to worsen or be prolonged when an individual has suffered multiple mild TBIs. To test the hypothesis that increasing the amount of time between head injuries can reduce the histopathological and behavioral consequences of repeated mild TBI, a mouse model of …

Inhibition Of Calpains By Calpastatin: Implications For Cellular And Functional Damage Following Traumatic Brain Injury, Kathleen M. Schoch

Theses and Dissertations--Physiology

Traumatic brain injury (TBI) is a devastating health problem based on its high incidence, economic burden, and lack of effective pharmacological treatment. Individuals who suffer an injury often experience lifelong disability. TBI results in abrupt, initial cell damage leading to delayed neuronal death. The calcium-activated proteases, calpains, are known to contribute to this secondary neurodegenerative cascade. Prolonged activation of calpains results in proteolysis of numerous cellular substrates including cytoskeletal components, membrane receptors, and cytosolic proteins, contributing to cell demise despite coincident expression of calpastatin, the specific inhibitor of calpains.

A comprehensive analysis using two separate calpastatin transgenic mouse lines was …

Evaluation Of Insulin-Like Growth Factor-1 As A Therapeutic Approach For The Treatment Of Traumatic Brain Injury, Shaun W. Carlson

Theses and Dissertations--Physiology

Traumatic brain injury (TBI) is a prevalent CNS neurodegenerative condition that results in lasting neurological dysfunction, including potentially debilitating cognitive impairments. Despite the advancements in understanding the complex damage that can culminate in cellular dysfunction and loss, no therapeutic treatment has been effective in clinical trials, highlighting that new approaches are desperately needed. A therapy that limits cell death while simultaneously promoting reparative mechanisms, including post-traumatic neurogenesis, in the injured brain may have maximum effectiveness in improving recovery of function after TBI. Insulin-like growth factor-1 (IGF-1) is a potent growth factor that has previously been shown to promote recovery of …

Traumatic Brain Injury: Cyclophilin D As A Therapeutic Target And The Neuropathology Caused By Blast, Ryan Douglas Readnower

University of Kentucky Doctoral Dissertations

With an estimated incidence of 1.5 million each year, traumatic brain injury (TBI) is a major cause of mortality and morbidity in the United States. Opening of the mitochondrial permeability transition pore (mPTP) is a key event contributing to TBI pathology. Cyclophilin D (CypD), a matrix peptidyl-prolyl cis-trans isomerase, is believed to be the regulating component of the mPTP. Cyclosporin A, an immunosuppressant drug, inhibits CypD and blocks mPTP formation and has been shown to be neuroprotective following TBI. However, it is unclear if CsA’s neuroprotective mechanism is due to inhibition of CypD and/or immuno-suppression. Therefore to directly assess the …

Age May Be Hazardous To Outcome Following Traumatic Brain Injury: The Mitochondrial Connection, Lesley Knight Gilmer

University of Kentucky Doctoral Dissertations

Older individuals sustaining traumatic brain injury (TBI) experience a much higher incidence of morbidity and mortality. This age-related exacerbated response to neurological insult has been demonstrated experimentally in aged animals, which can serve as a model to combat this devastating clinical problem. The reasons for this worse initial response are unknown but may be related to age-related changes in mitochondrial respiration.

Evidence is shown that mitochondrial dysfunction occurs early following traumatic brain injury (TBI), persists long after the initial insult, and is severitydependent. Synaptic and extrasynaptic mitochondrial fractions display distinct respiration capacities, stressing the importance to analyze these fractions separately. …

The Underlying Mechanism(S) Of Fasting Induced Neuroprotection After Moderate Traumatic Brain Injury, Laurie Michelle Helene Davis

University of Kentucky Doctoral Dissertations

Traumatic brain injury (TBI) is becoming a national epidemic, as it accounts for 1.5 million cases each year. This disorder affects primarily the young population and elderly. Currently, there is no treatment for TBI, which means that ~2% of the U.S. population is currently living with prolonged neurological damage and dysfunction. Recently, there have been many studies showing that TBI negatively impacts mitochondrial function. It has been proposed that in order to save the cell from destruction mitochondrial function must be preserved. The ketogenic diet, originally designed to mimic fasting physiology, is effective in treating epilepsy. Therefore, we have used …