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

Abstract

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.

Hyperexcitable Neurons Enable Precise and Persistent Information Encoding in the Superficial Retrosplenial Cortex

“…The RS and LR neuron models received 50 AMPAergic background inputs. The time course of synaptic conductance of these background inputs is given by the following equation (Sterratt et al, 2011;Sudhakar et al, 2019),…”

Inhibition of the NKCC1/NF-κB Signaling Pathway Decreases Inflammation and Improves Brain Edema and Nerve Cell Apoptosis in an SBI Rat Model

“…The primary function of NKCC1 is to regulate the entry of Na + , K + , Cl – , and water into cells to regulate the transfer and invasion of inflammatory mediators and other related factors, which can lead to brain edema, inflammation, and secondary brain damage. NKCC1 is closely related to cerebral hemorrhage ( Wu et al, 2020a ), stroke ( Wu et al, 2020b ), epilepsy ( Gharaylou et al, 2019 ; Zhang et al, 2020b ), traumatic brain injury ( Sudhakar et al, 2019 ), and other brain diseases. However, the activity of NKCC1 is mainly regulated by the STE20-related proline/alanine kinase (SPAK)/oxidative stress response 1 (OSR1) signaling pathway.…”

A Multiscale Model of Traumatic Brain Injury Suggests Possible Mechanisms of Post-Traumatic Psychosis

“…As shown above, we utilised the Larter-Breakspear model of ionic kinetics in neural firing to model how mean field neural firing dynamics depends on parameters of the synapse and membrane [49,50]. We based our parameter manipulations off of chemical pathologies recorded in [3,5,6,15,51], with estimations of parameter values taken from [52,53]. Specifically, membrane conductances were increased to model the effect of TBI on cell membrane integrity, and ionic Nernst potentials were increased to correspond to the increase in extracellular concentration of all ions.…”