Human-Derived Physiological Heat Shock Protein 27 Complex Protects Brain after Focal Cerebral Ischemia in Mice

Abstract

Although challenging, neuroprotective therapies for ischemic stroke remain an interesting strategy for countering ischemic injury and suppressing brain tissue damage. Among potential neuroprotective molecules, heat shock protein 27 (HSP27) is a strong cell death suppressor. To assess the neuroprotective effects of HSP27 in a mouse model of transient middle cerebral artery occlusion, we purified a “physiological” HSP27 (hHSP27) from normal human lymphocytes. hHSP27 differed from recombinant HSP27 in that it formed dimeric, tetrameric, and multimeric complexes, was phosphorylated, and contained small amounts of αβ-crystallin and HSP20. Mice received intravenous injections of hHSP27 following focal cerebral ischemia. Infarct volume, neurological deficit scores, physiological parameters, and immunohistochemical analyses were evaluated 24 h after reperfusion. Intravenous injections of hHSP27 1 h after reperfusion significantly reduced infarct size and improved neurological deficits. Injected hHSP27 was localized in neurons on the ischemic side of the brain. hHSP27 suppressed neuronal cell death resulting from cytochrome c-mediated caspase activation, oxidative stress, and inflammatory responses. Recombinant HSP27 (rHSP27), which was artificially expressed and purified from Escherichia coli, and dephosphorylated hHSP27 did not have brain protective effects, suggesting that the phosphorylation of hHSP27 may be important for neuroprotection after ischemic insults. The present study suggests that hHSP27 with posttranslational modifications provided neuroprotection against ischemia/reperfusion injury and that the protection was mediated through the inhibition of apoptosis, oxidative stress, and inflammation. Intravenously injected human HSP27 should be explored for the treatment of acute ischemic strokes.

Stem Cell-Like Dog Placenta Cells Afford Neuroprotection against Ischemic Stroke Model via Heat Shock Protein Upregulation

“…Previous studies have implicated the role of Hsp27 as a neuroprotective element in ischemic brain injuries [43], [44], [45]. Our in vitro immunocytochemical analysis shows an increase in Hsp27 concentration in rat neural cells co-cultured with DPCs compared to that of the vehicle in response to OGD conditions.…”

Upregulation and phosphorylation of HspB1/Hsp25 and HspB5/αB-crystallin after transient middle cerebral artery occlusion in rats

“…HspB1 transgenic mice showed significantly reduced cortical damage after permanent MCAO (van der Weerd et al 2010). In addition, it was shown that intravenous injection of HspB1 in mice reduced infarct volume after tMCAO (Teramoto et al 2013). Our data show that HspB1 is upregulated after tMCAO in astrocytes and in neurons indicating that it protects glial cells as well as neurons.…”

Decreased ceramide underlies mitochondrial dysfunction in Charcot‐Marie‐Tooth 2F

“…There is an extensive literature on the protective effects of Hsp27 in the nervous system. Overexpression of Hsp27 reduces neuronal cell death and the severity of drug-induced seizures (8), and Hsp27 injection ABBREVIATIONS: ALS, amylotrophic lateral sclerosis; CerS, ceramide synthase; CMT, Charcot-Marie-Tooth; CMT1/2/2F, Charcot-Marie-Tooth type 1/2/2F; co-IP, coimmunoprecipitation; DRG, dorsal root ganglia; ER, endoplasmic reticulum; FB1, fumonisin B1; HA, hemagglutinin; Hsp27, heat shock protein 27; IP, immunoprecipitation; KO, knockout; LC/MS, liquid chromatography/mass spectrometry; MOC, Manders' overlap coefficient; PCC, Pearson's correlation coefficient; S1P, sphingosine-1-phosphate; SIM, structured illumination microscopy; TrpV1, transient receptor potential cation channel subfamily V member 1; Tuj1, neuron-specific class III b-tubulin; WT, wild type reduces severity of sequelae of cerebral ischemia in mice (9). Hsp27 expression is upregulated in neuronal injury and thought to have a role protecting injury-induced motor neuron death (10).…”