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A Potential Combination Therapy for Traumatic Brain Injury

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A Potential Combination Therapy for Traumatic Brain Injury A potential combination therapy for traumatic brain injury: 17beta-estradiol and memantine Michael Robert Lamprecht Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2015 © 2015 Michael Robert Lamprecht All rights reserved ABSTRACT A potential combination therapy for traumatic brain injury: 17β-estradiol and memantine Michael Robert Lamprecht Every year, in the United States alone, there are 1.7 million incidences of traumatic brain injury (TBI). Unfortunately, despite the tremendous societal and economic cost and decades of research, current pharmacological treatments for TBI are lacking. The specific aims of this thesis are: (1) to determine the efficacy of 17β-estradiol (E2) monotherapy treatment post-TBI, (2) determine if a combination treatment of E2 and memantine provides statistically significant benefits over monotherapy treatments post-TBI, and (3) to investigate the utility of an in vitro model to recapitulate the pathobiology of an in vivo model of TBI and to assess its potential to discover novel and clinically relevant therapeutic targets for future studies. The neuroprotective properties of E2 have been investigated for several decades in several different models including excitotoxicity, ischemia, and TBI. Organotypic hippocampal slice cultures (OHSCs) were mechanically injured at specified strain and strain rates which are relevant to TBI, and the efficacy of E2 post-TBI was investigated. Physiological concentrations of E2 were more effective at preventing cell death than supraphysiological concentrations. Further, GPR30, a novel G protein-coupled receptor, was not activated at physiological concentrations. These results suggest that the classical estrogen receptors (ERs) were primarily responsible for E2-mediated neuroprotection following TBI, and that GPR30 is neither necessary nor sufficient. While monotherapy treatments have shown preclinical success post-TBI, none have been successful in clinical trials. Combination therapies are a promising area of research that focuses on synergistic effects between compounds for significant increases in neuroprotection, potentially resulting in a clinically relevant treatment. A combination treatment of E2 and memantine was statistically more neuroprotective than either monotherapy post-TBI. Using micro-electrode arrays (MEAs), we recorded and quantified increased evoked responses in OHSCs after physiological concentrations of E2 and showed that memantine significantly reduces these effects. Our results suggest a potential combination treatment for TBI and a possible mechanism for its synergistic effects. TBI is a complex injury which initiates a multitude of secondary injuries causing delayed cell death for days or beyond. The utility of in vitro models depends on their ability to recapitulate the in vivo injury cascade after TBI. We used a genome wide approach to study changes in gene expression after injury in both an in vitro model and an in vivo model of TBI to compare the post-TBI pathobiology. There was a strong correlation in gene expression changes between the two models providing confidence that the in vitro model represented the in vivo injury cascade. From these data, we searched for genes with significant changes in expression over time and identified Sorla. Sorla directs amyloid precursor protein (APP) to the recycling pathway by direct binding and away from amyloid beta (Aβ) producing enzymes. Mutations of Sorla have been linked to Alzheimer’s disease (AD). We confirmed the down regulation of SORLA expression in OHSCs by immunohistochemistry (IHC) and western blotting. Together, these data suggests that the in vitro model of TBI that was tested strongly recapitulates the in vivo TBI pathobiology and is well-suited for future mechanistic or therapeutic studies. The data also suggest a novel target, Sorla, which may play a role in AD caused by TBI. In conclusion, we discovered a potentially clinically relevant combination treatment of E2 and memantine for post-TBI therapy. We also confirmed that our in vitro model of TBI is well representative of in vivo models, and that relevant, novel targets for future TBI studies can be elucidated with this model. A potential link between AD and TBI was suggested and warrants future study. Together, these studies address the growing public health concern of TBI. Table of Contents List of Figures ................................................................................................................................ vi List of Tables ................................................................................................................................ vii List of Abbreviations ................................................................................................................... viii 1 Introduction ............................................................................................................................. 1 1.1 17β-estradiol and neuroprotection .................................................................................... 2 1.2 Increased excitatory post synaptic potentials induced by E2 ........................................... 5 1.3 Neuroprotection and memantine ...................................................................................... 5 1.4 Combination therapies ...................................................................................................... 7 1.5 Global changes in gene expression after injury ............................................................... 8 1.6 Significance ...................................................................................................................... 9 2 E2 is neuroprotective after in vitro models of TBI and stroke .............................................. 12 2.1 Introduction .................................................................................................................... 12 2.2 Materials and Methods ................................................................................................... 16 2.2.1 Organotypic hippocampal slice cultures ................................................................. 16 2.2.2 In vitro model of ischemia ...................................................................................... 17 2.2.3 In vitro model of TBI .............................................................................................. 17 2.2.4 Cell death assessment ............................................................................................. 18 2.2.5 Western blots .......................................................................................................... 18 2.2.6 Statistics .................................................................................................................. 19 i 2.3 Results ............................................................................................................................ 20 2.3.1 E2 provides neuroprotection of OHSCs after OGD ............................................... 20 2.3.2 Therapeutic time window of E2 after OGD ............................................................ 21 2.3.3 ERα and ERβ are necessary for neuroprotection after OGD .................................. 21 2.3.4 E2 is neuroprotective after mechanical injury of OHSCs ....................................... 23 2.3.5 Neuroprotective concentrations of E2 do not activate GPR30 ............................... 24 2.4 Discussion ...................................................................................................................... 25 3 Combination therapy of 17β-estradiol and memantine ......................................................... 29 3.1 Introduction .................................................................................................................... 29 3.2 Materials and Methods ................................................................................................... 31 3.2.1 Organotypic hippocampal slice cultures ................................................................. 31 3.2.2 In vitro model of TBI .............................................................................................. 32 3.2.3 Cell death assessment ............................................................................................. 32 3.2.4 Electrophysiology ................................................................................................... 33 3.2.5 Statistical analysis ................................................................................................... 34 3.3 Results ............................................................................................................................ 34 3.3.1 Memantine after mechanical injury of OHSCs ....................................................... 35 3.3.2 Combination treatments significantly decreased cell death .................................... 36 3.3.3 Delayed treatment with combination therapy ......................................................... 39 3.3.4 Memantine significantly reduced evoked responses............................................... 40 ii 3.4 Discussion ...................................................................................................................... 43 3.4.1 Estrogen as a monotherapy ..................................................................................... 44 3.4.2 Memantine as a monotherapy ................................................................................
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