Combination of a Chaperone Synthesis Inducer and an Inhibitor of GAPDH Aggregation for Rehabilitation after Traumatic Brain Injury: A Pilot Study

Abstract

The recovery period after traumatic brain injury (TBI) is often complicated by secondary damage that may last for days or even months after trauma. Two proteins, Hsp70 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), were recently described as modulating post-traumatic processes, and in this study, we test them as targets for combination therapy using an inhibitor of GAPDH aggregation (derivative of hydrocortisone RX624) and an inducer of Hsp70 synthesis (the pyrrolylazine derivative PQ-29). The protective effect of the combination on C6 rat glioblastoma cells treated with the cerebrospinal fluid of traumatized animals resulted in an increase in the cell index and in a reduced level of apoptosis. Using a rat weight drop model of TBI, we found that the combined use of both drugs prevented memory impairment and motor deficits, as well as a reduction of neurons and accumulation of GAPDH aggregates in brain tissue. In conclusion, we developed and tested a new approach to the treatment of TBI based on influencing distinct molecular mechanisms in brain cells.

Approbation of a New Model of Secondary Damage after Traumatic Brain Injury Based on Reprogrammed Rat Embryo Fibroblasts

“…In our previous studies, we developed and tested a new model for analyzing secondary damage after traumatic brain injury based on cells cultured in the presence of CSF of injured animals [ 8 ]. The advantages of our model were that it simultaneously took into account many factors that determined secondary damage and made it possible to test potential therapeutics by adding them to the growth medium of cells containing the cerebrospinal fluid of injured animals.…”

“…At the next stage, we studied the effect of the CSF of injured animals on the survival of neuronal cells. For this purpose, we made TBI in rats according to the previously described protocol [ 8 ]; 9 days after TBI, CSF was taken from the anesthetized animals through the foramen magnum. Then, we cultivated DFK3-Neu cells in the presence of CSF of injured (CSF-TBI) or healthy (CSF-norm) animals.…”

“…As part of the development of this model, it was necessary to test it to make sure that DFK-Neu cells are able to respond to drug treatment. For this purpose, we used pyrrolylazine and indolylazine derivatives synthesized by us [ 13 , 14 ], which can induce accumulation of chaperones in cells and were shown to have a neuroprotective effect in models of secondary damage after TBI [ 8 ] and in Alzheimer’s disease [ 14 ]. DFK3-Neu cells were cultured for 24 h in the presence of PQ-29 (a pyrrolylazine derivative) and IA-50 (an indolylazine derivative) at concentrations of 0.5, 2, and 8 μM.…”