Neuroprotection with delayed calpain inhibition after transient forebrain ischemia.
OBJECTIVE
Delayed neurodegeneration after transient global brain ischemia offers a therapeutic window for inhibiting molecular injury mechanisms. One such mechanism is calpain-mediated proteolysis, which peaks 24 to 48 hrs after transient forebrain ischemia in rats. This study tests the hypothesis that delayed calpain inhibitor therapy can reduce brain calpain activity and neurodegeneration after transient forebrain ischemia.


METHODS
Prospective randomized placebo-controlled animal trial.


METHODS
University research laboratory.


METHODS
Adult male Long-Evans rats.


METHODS
Rats subjected to 10-min transient forebrain ischemia were randomized to intravenous infusion of calpain inhibitor CEP-3453 or vehicle beginning 22 hrs after injury.


RESULTS
In a dose-response study, a 60 mg/kg bolus followed by 30 mg/kg infusion was required to reduce postischemic brain calpain activity measured by Western blot of hippocampal homogenates at 48 hrs after injury. The same dosing protocol decreased degeneration of CA1 pyramidal neurons measured at 72 hrs after injury.


CONCLUSIONS
These results suggest a causal role for calpains in delayed postischemic neurodegeneration, and demonstrate a broad therapeutic window for calpain inhibition in this model.
Frederick
James R
JR
Department of Emergency Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Chen
Zhaoming
Z
Bevers
Matthew B
MB
Ingleton
Lori P
LP
Ma
Marek
M
Neumar
Robert W
RW
D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002154:Calpain / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017966:Pyramidal Cells / Q000187:drug effects* / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D020318:Rats, Long-Evans; D013997:Time Factors
C549946:CEP-3453; D004151:Dipeptides; D018696:Neuroprotective Agents; D002154:Calpain
Exp Neurol. 2001 Jul;170(1):27-35
11421581
Physiol Rev. 2003 Jul;83(3):731-801
12843408
Can J Physiol Pharmacol. 1992;70 Suppl:S190-3
1295670
Hippocampus. 2003;13(7):791-800
14620874
EMBO J. 1999 Sep 15;18(18):4988-98
10487751
J Gen Physiol. 1990 May;95(5):837-66
2163431
J Neurosci. 2007 Aug 29;27(35):9278-93
17728442
J Neurosci. 1994 Jun;14(6):3934-44
8207497
J Biol Chem. 2001 Mar 30;276(13):10191-8
11124942
J Neurochem. 1996 Jan;66(1):421-4
8522983
Cell Growth Differ. 2000 May;11(5):247-53
10845425
J Cereb Blood Flow Metab. 1995 Nov;15(6):969-79
7593358
Neurosci Lett. 1987 Aug 5;78(3):295-300
3627566
Stroke. 1981 Mar-Apr;12(2):236-40
7233472
Brain Res. 1999 Feb 20;819(1-2):8-14
10082855
Eur J Neurosci. 1996 Sep;8(9):1932-44
8921284
J Biol Chem. 2005 Apr 22;280(16):16175-84
15691848
J Biol Chem. 1993 Nov 25;268(33):25239-43
8227089
J Neurochem. 2007 Jul;102(1):133-40
17506859
Brain Res. 1993 Apr 23;609(1-2):67-70
8508322
Stroke. 1994 Mar;25(3):663-9
8128523
Cell Calcium. 2004 Sep-Oct;36(3-4):285-93
15261484
J Cereb Blood Flow Metab. 1992 Sep;12(5):759-72
1324251
Brain Res. 2000 Jun 2;866(1-2):299-312
10825507
Brain Res. 1998 Apr 20;790(1-2):1-13
9593800
Stroke. 1998 Jan;29(1):152-8
9445345
Neurosci Lett. 1998 May 8;247(1):17-20
9637399
J Neurosci Res. 1999 Oct 1;58(1):167-90
10491581
Brain Res. 1994 Oct 24;661(1-2):43-50
7834383
J Med Chem. 1998 Jul 16;41(15):2663-6
9667954
J Cereb Blood Flow Metab. 2008 Apr;28(4):655-73
18073773
J Neurochem. 2001 Jun;77(6):1531-41
11413236
J Cell Biol. 2000 Aug 21;150(4):887-94
10953012
Science. 1984 Jun 8;224(4653):1057-63
6144182
Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7233-7
1871130
J Cereb Blood Flow Metab. 1995 May;15(3):398-408
7713997
Stroke. 1998 Mar;29(3):705-18
9506616
J Neurosci Res. 1994 Nov 1;39(4):474-81
7884824
J Neurochem. 1994 Nov;63(5):1812-9
7931337
J Neurosci. 2006 Feb 22;26(8):2241-9
16495451
Mol Cell Biol. 1997 May;17(5):2806-15
9111352
J Neurosci. 2005 Sep 28;25(39):8954-66
16192386
Stroke. 1995 Oct;26(10):1901-7
7570746
Biochem Biophys Res Commun. 1988 Dec 30;157(3):1117-23
2849930
Neurobiol Dis. 2002 Aug;10(3):289-05
12270691
Life Sci. 2002 Dec 20;72(4-5):355-61
12467876