Biophysical Modeling Suggests Optimal Drug Combinations for Improving the Efficacy of GABA Agonists after Traumatic...

Traumatic brain injuries (TBI) lead to dramatic changes in the surviving brain tissue. Altered ion concentrations, coupled with changes in the expression of membrane-spanning proteins, create a post-TBI brain state that can lead to further neuronal loss caused by secondary excitotoxicity. Several GABA receptor agonists have been tested in the search for neuroprotection immediately after an injury, with paradoxical results. These drugs not only fail to offer neuroprotection, but can also slow down functional recovery after TBI. Here, using computational modeling, we provide a biophysical hypothesis to explain these observations. We show that the accumulation of intracellular chloride ions caused by a transient upregulation of Na⁺-K⁺-2Cl^- (NKCC1) co-transporters as observed following TBI, causes GABA receptor agonists to lead to excitation and depolarization block, rather than the expected hyperpolarization. The likelihood of prolonged, excitotoxic depolarization block is further exacerbated by the extremely high levels of extracellular potassium seen after TBI. Our modeling results predict that the neuroprotective efficacy of GABA receptor agonists can be substantially enhanced when they are combined with NKCC1 co-transporter inhibitors. This suggests a rational, biophysically principled method for identifying drug combinations for neuroprotection after TBI.