Therapeutic inducers of the HSP70/HSP110 protect mice against traumatic brain injury

Abstract

Traumatic brain injury (TBI) induces severe harm and disability in many accident victims and combat-related activities. The heat shock proteins Hsp70/Hsp110 protect cells against death and ischemic damage. In this study, we used mice deficient in Hsp110 or Hsp70 to examine their potential requirement following TBI. Data indicate that loss of Hsp110 or Hsp70 increases brain injury and death of neurons. One of the mechanisms underlying the increased cell death observed in the absence of Hsp110 and Hsp70 following TBI is the increased expression of ROS-induced p53 target genes Pig1, Pig8 and Pig12. To examine whether drugs that increase the levels of Hsp70/Hsp110 can protect cells against TBI, we subjected mice to TBI and administered Celastrol or BGP-15. In contrast to Hsp110 or Hsp70i-deficient mice that were not protected following TBI and Celastrol treatment, there was a significant improvement of wild-type mice following administration of these drugs during the first week following TBI. In addition, assessment of neurological injury shows significant improvement of Contextual and Cued Fear Conditioning tests and beam balance in wild-type mice that were treated with Celastrol or BGP-15 following TBI compared to TBI-treated mice. These studies indicate a significant role of Hsp70/Hsp110 in neuronal survival following TBI and the beneficial effects of Hsp70/Hsp110 inducers toward reducing the pathological consequences of TBI.

Impact of traumatic brain injury on sleep structure, electrocorticographic activity and transcriptome in mice

“…The latter also applies to Hif1a (Higashida et al, 2011). DnajB5 was selected because of its hypothesized role in sleep homeostasis (Mongrain et al, 2010), and because heat-shock protein pathways seem to benefit brain recovery after TBI (Eroglu et al, 2014). The list of primers, probes and TaqMan Gene expression assays used is provided in Table S1 (Supplementary material).…”

Pharmacological Overview of the BGP-15 Chemical Agent as a New Drug Candidate for the Treatment of Symptoms of Metabolic Syndrome

“…It additionally has protective effects in nephrotoxicity induced by cisplatin [21]. Administration of BGP-15 also has potential in traumatic brain injury [22], and it could be effective in the therapy of ventilation induced diaphragm dysfunction [23]. This molecule can be efficient in oxidative-stress-related diseases as well [24].…”

Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift

“…Modulation of HSPs therefore has the potential to improve outcome in TBI patients. Along these lines, several studies in animals have shown that therapeutic induction of HSP70/110 is indeed neuroprotective (Eroglu et al, 2014; Kim et al, 2015). One recent study used 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), which is a potent HSP90 antagonist known to increase HSP70 levels (Kim et al, 2015).…”

“…Following CCI-induced TBI, overexpression of HSP70 reduced brain lesion size, hemorrhage, and expression of metalloproteinases, whereas the opposite was observed in HSP70-deficient mice (Kim et al, 2013). Deficiency in HSP110 similarly resulted in enhanced brain damage following TBI (Eroglu et al, 2014). Modulation of HSPs therefore has the potential to improve outcome in TBI patients.…”