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. 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
