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The Role of Membrane Transporters in Traumatic Brain Injury

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THE ROLE OF MEMBRANE TRANSPORTERS IN TRAUMATIC BRAIN INJURY: INTERVENTIONAL AND GENETIC INVESTIGATIONS by Fanuel T. Hagos BSc, Pharmacy, University of Asmara, 2006 MS, Oncological Sciences, University of Utah, 2011 Submitted to the Graduate Faculty of The School of Pharmacy in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2018 UNIVERSITY OF PITTSBURGH School of Pharmacy This thesis was presented by Fanuel T. Hagos It was defended on May 23rd, 2018 and approved by Patrick Kochanek, MD, Professor, Department of Critical Care Medicine Samuel M. Poloyac, PharmD, PhD, Professor, Department of Pharmaceutical Sciences Robert S. B. Clark, MD, Professor, Department of Critical Care Medicine Michael Tortorici, PharmD, PhD, Senior Director, Clinical Pharmacology and Pharmacometrics, CSL Behring Xiaochao Ma, PhD, Associate Professor, Department of Pharmaceutical Sciences Dissertation Advisor: Philip E. Empey, PharmD, PhD, Assistant Professor, Department of Pharmacy and Therapeutics ii THE ROLE OF MEMBRANE TRANSPORTERS IN TRAUMATIC BRAIN INJURY: INTERVENTIONAL AND GENETIC INVESTIGATIONS Fanuel T. Hagos University of Pittsburgh, 2018 Copyright © by Fanuel T. Hagos 2018 iii THE ROLE OF MEMBRANE TRANSPORTERS IN TRAUMATIC BRAIN INJURY: INTERVENTIONAL AND GENETIC INVESTIGATIONS Fanuel T. Hagos, PhD University of Pittsburgh, 2018 Traumatic brain injury (TBI) is a leading cause of death and disability in children and young adults in the US. The neurovascular unit conceptual frame work emphasizes the dynamic interplay between neurons, endothelial cells and glial cells in understanding the pathophysiology of TBI. Membrane transporters, as mediators of the movement of numerous endogenous and exogenous molecules within the neurovascular unit, are critical components of the functional neurovascular unit in TBI. The aim of this thesis is to understand the role of membrane transporters in the pathogenesis and pharmacotherapy of TBI through interventional and genetic approaches. In the first part of the thesis, we investigated the utility of inhibition of transporters with probenecid, as a therapeutic strategy to simultaneously increase the systemic and brain concentration of the anti-oxidant drug, n-acetylcysteine, and the endogenous anti-oxidant, glutathione, in TBI. This approach counters oxidative stress, a major injury mechanism in TBI. Preclinical pharmacokinetic study showed that probenecid increases plasma and brain levels of n-acetylcysteine by inhibiting OAT1 and OAT3 transporters. In rat model of pediatric TBI, n- acetylcysteine showed potential in attenuating TBI-induced learning and memory deficits. iv Probenecid caused transient motor function impairment. A combination of the two resulted in smaller cortical tissue volume loss. Optimization of dosage regimen for both drugs to enhance the effects of n-acetylcysteine and minimize the side effects of probenecid is warranted. Metabolomic and pathway analyses of cerebrospinal fluid of TBI patients treated with placebo or a combination of probenecid and n-acetylcysteine showed that the combination therapy enriched glutathione mediated anti-oxidative stress pathways. In the second part of this thesis, we examined the association of genetic alterations in monocarboxylate transporters – responsible for shuttling lactate within the neurovascular unit – with clinical outcomes. In discovery and replication cohorts, patients with one or two alternate alleles at SLC16A7 rs10506399 showed favorable outcomes. The alternate allele at the SNP was associated with increased expression of SLC16A7 which suggests that increased uptake of lactate by neurons may be beneficial in TBI. Collectively, this work has provided interventional and genetic evidence that transporters are important component of the injury mechanism and attractive therapeutic targets in TBI. Keywords: Traumatic Brain Injury, Membrane Transporters, Oxidative Stress, Lactate, Metabolomics, N-acetylcysteine, Probenecid, Monocarboxylates, Neurovascular Unit. v TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................................... vi LIST OF TABLES ........................................................................................................................ xii LIST OF FIGURES ..................................................................................................................... xiii PREFACE .................................................................................................................................... xvi ABBREVIATIONS ................................................................................................................... xviii 1. Introduction ............................................................................................................................. 1 1.1. Review of the Role of Membrane Transporters in TBI ................................................... 1 1.1.1. Traumatic Brain Injury – Background ...................................................................... 1 1.1.2. Membrane Transporters in CNS – Background ........................................................ 3 1.1.3. Membrane Transporters in TBI ................................................................................ 6 1.1.4. SLC Transporters in TBI .......................................................................................... 6 1.1.4.1. Glutamate Transporters ............................................................................................. 6 1.1.4.2. MCT Transporters ................................................................................................... 12 1.1.4.3. Other SLC Transporters .......................................................................................... 20 1.1.5. ABC Transporters in TBI........................................................................................ 24 vi 1.1.6. Conclusion – TBI and Membrane Transporters...................................................... 37 1.2. Targeting Transporters to Attenuate Oxidative Stress in TBI........................................ 41 1.2.1. Oxidative Stress in TBI ........................................................................................... 41 1.2.2. Targeting Transporters with Probenecid to Simultaneously Increase Brain Levels of N-acetylcysteine and Glutathione .......................................................................................... 42 1.3. Examining the Role of SLC16A1, SLC16A3 and SLC16A7 transporters in Human TBI Patients with a Genetic Approach ............................................................................................. 44 2. Pharmacokinetic interaction between probenecid and n-acetylcysteine, in-vitro and in-vivo evidence. ....................................................................................................................................... 46 2.1. Introduction .................................................................................................................... 46 2.2. Material and Methods..................................................................................................... 48 2.2.1. Animals and treatment. ........................................................................................... 48 2.2.2. Drug administration and pharmacokinetic sampling. ............................................. 48 2.2.3. Drug analysis by LC-MS/MS. ................................................................................ 49 2.2.4. Pharmacokinetic analysis. ....................................................................................... 50 2.2.5. Cell uptake studies. ................................................................................................. 50 2.2.6. Vesicular uptake assay. ........................................................................................... 52 2.2.7. Statistical analysis. .................................................................................................. 53 2.3. Results ............................................................................................................................ 53 2.3.1. Probenecid increased n-acetylcysteine plasma and brain exposure and decreased apparent plasma clearance. .................................................................................................... 53 vii 2.3.2. N-acetylcysteine uptake by OAT3 and OAT1. ....................................................... 57 2.4. Discussion ...................................................................................................................... 62 3. The effect of a combination of n-acetylcysteine and probenecid on functional outcomes in rat, traumatic brain injury model .................................................................................................. 67 3.1. Introduction .................................................................................................................... 67 3.2. Methods .......................................................................................................................... 69 3.2.1. Animals ................................................................................................................... 69 3.2.2. Surgery .................................................................................................................... 70 3.2.3. Animal pharmacokinetics study .............................................................................
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