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.
Highlights
The processes accompanying the recovery from traumatic brain injury (TBI) can cause additional damage to the brain, so called secondary damage [1]
The collection from the Ural Federal University (UrFU) was employed to search for the activators of Hsp70 synthesis; the chemicals were selected based on the similarity of their domain to the indole-like pharmacophore found earlier that increased the Hsp70 level [35]
Measuring heat shock element (HSE)-controlled luciferase activity, we found the compound that caused the significant accumulation of luciferase in the cells (Figure 1B)
Summary
The processes accompanying the recovery from traumatic brain injury (TBI) can cause additional damage to the brain, so called secondary damage [1]. Secondary damage factors include changes in blood supply to the brain, ischemia, cerebral hypoxia, inflammation, cerebral edema, and increased intracranial pressure [2]. The most common TBI effects that may occur over time due to secondary damage are memory deficit [3], motor dysfunction [4], and anxiety-like behavior [5]. Factors that induce secondary damage are the burst of reactive oxygen species, excessive release of the glutamate neurotransmitter, the influx of calcium and sodium ions into neurons, and mitochondrial dysfunction, which leads to the death of glial and neuronal cells, most often through apoptosis [6,7] or necrosis mechanisms [8]. Protein aggregates can be detected in the CSF of rats after TBI, and the CSF itself may have a cytotoxic effect imitating post-trauma conditions in the animal brain [11]
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