A novel calpastatin-based inhibitor improves postischemic neurological recovery.
Calpastatin, a naturally occurring protein, is the only inhibitor that is specific for calpain. A novel blood-brain barrier (BBB)-permeant calpastatin-based calpain inhibitor, named B27-HYD, was developed and used to assess calpain's contribution to neurological dysfunction after stroke in rats. Postischemic administration of B27-HYD reduced infarct volume and neurological deficits by 35% and 44%, respectively, compared to untreated animals. We also show that the pharmacologic intervention has engaged the intended biologic target. Our data further demonstrates the potential utility of SBDP145, a signature biomarker of acute brain injury, in evaluating possible mechanisms of calpain in the pathogenesis of stroke and as an adjunct in guiding therapeutic decision making.
Anagli
John
J
Department of Pathology, Henry Ford Hospital, 1 Ford Place, 5D, Detroit, MI 48202, USA. janagli1@hfhs.org
Han
Yuxia
Y
Stewart
Laura
L
Yang
Dongmei
D
Movsisyan
Ashkhen
A
Abounit
Kadija
K
Seyfried
Donald
D
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D002154:Calpain / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000503:physiopathology; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D004195:Disease Models, Animal; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013049:Spectrin / Q000378:metabolism
C541420:B27-HYD peptide; D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; D010446:Peptide Fragments; D013049:Spectrin; C033668:calpastatin; D002154:Calpain