biostudies-literatureSudhakar SKNIMH NIH HHS1632-1645https://www.ebi.ac.uk/biostudies/studies/S-EPMC6531909biostudies-literatureUnknown36(10)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-transportJournal of neurotraumaBiophysical Modeling Suggests Optimal Drug Combinations for Improving the Efficacy of GABA Agonists after Traumatic Brain Injuries.PMC6531909R03 MH111316Choi TJAhmed OJSudhakar SKfalseBiophysical Modeling Suggests Optimal Drug Combinations for Improving the Efficacy of GABA Agonists after Traumatic Brain Injuries.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-transport2019-01-01T00:00:00Z2019 May2025-04-21T16:07:40.71Z2025-04-21T16:07:40.71ZS-EPMC65319093048436210.1089/neu.2018.6065