All ETDs from UAB

Advisory Committee Chair

Candace L Floyd

Advisory Committee Members

Lori L McMahon

Suzanne Oparil

Harald Sontheimer

Scott Wilson

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Traumatic brain injury (TBI) affects millions of persons per year, potentially leading to permanent disability or death, and exacts a staggering financial toll. Despite the severity of this public health problem, there are no clinically proven pharmacotherapeutics available that effectively attenuate the secondary neurochemically-mediated damage that follows the initial biomechanical insult. In addition, the heterogeneous nature of TBI and complexity of secondary injury cascades suggest that a polytherapeutic approach could be a powerful strategy with which to simultaneously target more than one deleterious pathway. Recently, sex steroid hormones have sparked interest as possible neuroprotective agents after traumatic injury. One of these is 17ß-estradiol (E2), the most potent endogenous vertebrate estrogen. We investigated the acute potential protective effects of E2 or the specific G protein-coupled estrogen receptor 1 (GPER) agonist G-1 administered 1 hour post-injury in the lateral fluid percussion (LFP) rodent model of TBI. A bolus dose of E2 or G-1 significantly increased neuronal survival and decreased neuronal degeneration, apoptosis, and reactive astrogliosis in the ipsilateral hippocampus and cortex. In primary hippocampal mixed cell cultures subjected to the in vitro mechanical strain injury model of TBI, we found a significant reduction in the percentage of viable cells in the injured group compared to uninjured control, but treatment with either E2 or G-1 reversed this effect. In addition, we provide compelling evidence that activation of GPER leads to transactivation of the epidermal growth factor receptor (EGFR) and subsequent downstream modulation of Bcl-2 family members through the PI3K/Akt signaling pathway. We contend that a key mechanism underlying GPER-mediated protection is transactivation of the EGFR. Finally, we evaluated a polytherapeutic treatment, assessing the neuroprotective potential of an acute intravenous bolus dose of a combination of memantine and E2 following induction of experimental TBI in the LFP model. We determined that the combination therapy conferred neuroprotection by decreasing neuronal degeneration in the ipsilateral hippocampus and cortex, and improved vestibulomotor performance. Our findings further elucidate estrogenic compounds as a clinically relevant pharmacotherapeutic strategy for treatment of secondary injury following TBI, and intriguingly, reveal a novel potential therapeutic target in GPER.

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