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.
Department of Pathology, Henry Ford Hospital, 1 Ford Place, 5D, Detroit, MI 48202, USA. janagli1@hfhs.org
John
J
Anagli
Yuxia
Y
Han
Laura
L
Stewart
Dongmei
D
Yang
Ashkhen
A
Movsisyan
Kadija
K
Abounit
Donald
D
Seyfried
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