title: 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.
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Teramoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Shimura
authors.forename: Ryota
authors.initials: R
authors.lastname: Tanaka
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Shimada
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Hajime
authors.initials: H
authors.lastname: Arai
authors.forename: Takao
authors.initials: T
authors.lastname: Urabe
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020520:Brain Infarction / Q000378:metabolism / Q000517:prevention & control; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D055551:HSP27 Heat-Shock Proteins / Q000008:administration & dosage / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D020521:Stroke / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: D055551:HSP27 Heat-Shock Proteins; D018696:Neuroprotective Agents