Pyrrolylquinoxaline-2-One Derivative as a Potent Therapeutic Factor for Brain Trauma Rehabilitation

Abstract

Traumatic brain injury (TBI) often causes massive brain cell death accompanied by the accumulation of toxic factors in interstitial and cerebrospinal fluids. The persistence of the damaged brain area is not transient and may occur within days and weeks. Chaperone Hsp70 is known for its cytoprotective and antiapoptotic activity, and thus, a therapeutic approach based on chemically induced Hsp70 expression may become a promising approach to lower post-traumatic complications. To simulate the processes of secondary damage, we used an animal model of TBI and a cell model based on the cultivation of target cells in the presence of cerebrospinal fluid (CSF) from injured rats. Here we present a novel low molecular weight substance, PQ-29, which induces the synthesis of Hsp70 and empowers the resistance of rat C6 glioma cells to the cytotoxic effect of rat cerebrospinal fluid taken from rats subjected to TBI. In an animal model of TBI, PQ-29 elevated the Hsp70 level in brain cells and significantly slowed the process of the apoptosis in acceptor cells in response to cerebrospinal fluid action. The compound was also shown to rescue the motor function of traumatized rats, thus proving its potential application in rehabilitation therapy after TBI.

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

“…During the first stage of the work, we tested the effectiveness of the therapeutic use of a combination of PQ-29 and RX624 (the chemical structures of the compounds are shown in Scheme 1 ) drugs on an in vitro TBI model. We used a previously designed TBI-based model, in which C6 rat glioma cells were incubated in the presence of the CSF of traumatized animals; this incubation inhibited cell growth and increased the level of cell death, events that usually accompany the post-trauma period [ 15 ]. To estimate the efficacy of combination therapy, we supplemented the CSF of traumatized animals with RX624 and PQ-29.…”

“…Male Wistar rats from the Rappolovo livestock breeding complex (Russia) weighing 200–250 g on the 75th–80th days of life were used in this study. TBI was induced with the aid of a weight drop (150 g) according to the protocol of Mychasiuk et al [ 25 ] with a slight difference: the fall height was 120 cm (instead of 100 cm) [ 15 ]. For the cell experiments, CSF was collected through the foramen magnum 3 days after injury.…”

“…To analyze the cell index, C6 cells (10 5 cells per mL) were added to the wells of a 16-well E-board, at the bottom of which a gold electrode was placed. C6 cells were incubated in a growth medium mixed with the CSF of traumatized animals at a 1:1 volume ratio, and a cell index evaluation (measurement of cell resistance) was performed every 15 min, as we described earlier [ 15 ]. Recording was conducted for 3 days.…”

“…Thus, Hsp70 can affect the pathogenic processes caused by TBI through multiple interactions with cellular proteins; the result of such reactions is an increased survival of brain cells and a restoration of neuronal function. We have previously shown that inducers of heat shock protein synthesis, including Hsp70, can prevent neurodegeneration in in vitro and in vivo [ 15 ] TBI models. One of these potential therapeutic agents may be a PQ-29 compound belonging to the class of pyrrolylazines, for which we have demonstrated a therapeutic effect in Alzheimer’s disease and TBI [ 16 ] models ( Figure 1 ).…”

Dataset of NMR-spectra pyrrolyl- and indolylazines and evidence of their ability to induce heat shock genes expression in human neurons

“…Previously, for compounds from these classes it was demonstrated antineoplastic ( THZ531 [1] , Variolin B [2] ), antianginal ( BDBM92080 [3] ), cytotoxic ( Meriolin 2 [4] , Hyrtinadine A [5] ), and antiasthmatic ( US9999619 [6] ) activities, as well as including α-adrenoceptor blocking agents ( Nicergoline [7] ) and potent inhibitors of serine-threonine protein phosphatases. This work presents the data of nuclear magnetic resonance (NMR) analysis of the pyrrolyl- and indolylazines synthesized by us, which previously demonstrated neuroprotective potential in the cellular model of Alzheimer's disease [8] and in the model of traumatic brain injury [9] .…”