The 70-kDa heat shock protein (Hsp70) as a therapeutic target for stroke

Abstract

Introduction: The 70-kDa heat shock protein (Hsp70) is a cytosolic chaperone which facilitates protein folding, degradation, complex assembly, and translocation. Following stroke, these functions have the potential to lead to cytoprotection, and this has been demonstrated using genetic mutant models, direct gene transfer or the induction of Hsp70 via heat stress, approaches which limit its translational utility. Recently, the investigation of Hsp70-inducing pharmacological compounds, which, through their ability to inhibit Hsp90, has obvious clinical implications in terms of potential therapies to mitigate cell death and inflammation, and lead to neuroprotection from brain injury. Areas covered: In this review, we will focus on the role of Hsp70 in cell death and inflammation, and the current literature surrounding the pharmacological induction in acute ischemic stroke models with comments on potential applications at the clinical level. Expert opinion: Such neuroprotectants could be used to synergistically improve neurological outcome or to extend the time window of existing interventions, thus increasing the numbers of stroke victims eligible for treatment.

Intra-arterial transplantation of neural stem cells improve functional recovery after transient ischemic stroke in adult rats

“…Therefore, re-perfusion reduces cell damage in the cortex. In addition, hypoxia-induced genes that play a neuroprotective role, such as heat shock protein 70, Bcl-2, Bcl-XL, and Bax, are expressed exclusively in the cortex, and transplantation of NSCs within 24 hours after the onset of ischemia can reduce cortex cell death (22,23). Due to these reasons, 60-minute MCAO seems to be more suitable for creating a local ischemia stroke model.…”

Heat shock protein signaling in brain ischemia and injury

“…Inducible HSPs are upregulated in response to cell stress, including thermal, ischemic and traumatic stresses to the tissue. While previously debated whether their upregulation reflected cell stress, or actively represented a cytoprotective mechanism, work over the past few decades now indicate that HSPs represent the latter [6] In the brain and in cultures of brain cells, heat and ischemic stress have been shown by several labs to trigger robust induction of HSP70 [7]. As such, HSP70 has been the most widely studied stress protein in terms of its neuroprotective properties.…”

The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization

“…Long-term administration of LA1011 was shown to improve learning ability, counteract neuronal loss, increase dendritic spine density, and restrain tau pathology and amyloid plaque formation in a transgenic mouse model of Alzheimer's disease (Kasza et al, 2016), possibly by maintaining protein homeostasis (Penke et al, 2018). Taken that Hsp27 and Hsp70 activation has been suggested to be protective against ischaemic neurodegeneration (Kim, Han, Lee, & Yenari, 2018;van der Weerd et al, 2010;Yenari et al, 2005), it is of interest whether LA1011, a co-inducer of Hsp, has the potential to preserve neuronal function under cerebral ischaemia. Hence, here, we set out to assess the impact of LA1011 treatment on neuronal activation in the acutely ischaemic rat cerebral cortex.…”