Improvement in recovery after experimental intracerebral hemorrhage using a selective cathepsin B and L inhibitor.
OBJECTIVE
This study investigates a potential novel application of a selective cathepsin B and L inhibitor in experimental intracerebral hemorrhage (ICH) in rats.


METHODS
Forty adult male Wistar rats received an ICH by stereotactic injection of 100 μl of autologous blood or sham via needle insertion into the right striatum. The rats were treated with a selective cathepsin B and L inhibitor (CP-1) or 1% dimethyl sulfoxide sterile saline intravenously at 2 and 4 hours after injury. Modified neurological severity scores were obtained and corner turn tests were performed at 1, 4, 7, and 14 days after ICH. The rats were sacrificed at 3 and 14 days after ICH for immunohistological analysis of tissue loss, neurogenesis, angiogenesis, and apoptosis.


RESULTS
The animals treated with CP-1 demonstrated significantly reduced apoptosis as well as tissue loss compared with controls (p < 0.05 for each). Neurological function as assessed by modified neurological severity score and corner turn tests showed improvement after CP-1 treatment at 7 and 14 days (p < 0.05). Angiogenesis and neurogenesis parameters demonstrated improvement after CP-1 treatment compared with controls (p < 0.05) at 14 days.


CONCLUSIONS
This study is the first report of treatment of ICH with a selective cathepsin B and L inhibitor. Cathepsin B and L inhibition has been shown to be beneficial after cerebral ischemia, likely because of its upstream regulation of the other prominent cysteine proteases, calpains, and caspases. While ICH may not induce a major component of ischemia, the cellular stress in the border zone may activate these proteolytic pathways. The observation that cathepsin B and L blockade is efficacious in this model is provocative for further investigation.
Yang
Dongmei
D
Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Han
Yuxia
Y
Zhang
Jianfeng
J
Ding
Christopher
C
Anagli
John
J
Seyfried
Donald M
DM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D056668:Cathepsin L / Q000037:antagonists & inhibitors*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D003978:Diazomethane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004151:Dipeptides / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008279:Magnetic Resonance Imaging; D008297:Male; D018919:Neovascularization, Physiologic / Q000502:physiology; D009422:Nervous System Diseases / Q000209:etiology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D016708:Synaptophysin / Q000378:metabolism; D016896:Treatment Outcome
D004151:Dipeptides; D016708:Synaptophysin; C431444:carbobenoxy-phenylalanyl-serine(O-benzyl)diazomethane; D003978:Diazomethane; D002401:Cathepsin B; D056668:Cathepsin L