From Hoechst Marion Roussel, Inc (C.G.M., N.L.V., M.P.J., D.R.M., S.M.,
J.R.K., P.A.C., M.D.L.), Cincinnati, Ohio; the Vivian L. Smith Center for
Neurological Research (C.G.M.), Department of Neurosurgery; University of
Texas–Houston Health Science Center (Tex); Procter and Gamble, Inc
(P.A.C.), Health Care Research Center, Mason, Ohio; and the Department of
Neurosurgery (M.D.L.), University of Cincinnati College of Medicine (Ohio).
Correspondence to Matthew D. Linnik, PhD, Hoechst Marion Roussel, CNS Molecular Biology, 2110 E Galbraith Rd, Cincinnati, OH 45215-6300. E-mail matt.linnik{at}hmrag.com
Background and Purpose—Stroke
patients often experience a significant temporal delay between the
onset of ischemia and the time to initiation of therapy. Thus,
there is a need for neuroprotectants with a long therapeutic window of
opportunity. The efficacy of a potent, central nervous
system–penetrating calpain inhibitor (MDL 28,170) was
evaluated in a temporary model of focal cerebral ischemia to
determine the window of opportunity for intracellular protease
inhibition.
Methods—An ex vivo brain protease inhibition assay established
pharmacodynamic dosing parameters for MDL 28,170. Middle
cerebral artery (MCA) occlusion was accomplished by advancing a
monofilament through the internal carotid artery to the origin of the
MCA. Postmortem infarct volumes were determined by quantitative image
analysis of
triphenyltetrazolium-stained brain
sections.
Results—Maximal inhibition of brain protease activity was
observed 30 minutes after injection of MDL 28,170 with an estimated
pharmacodynamic half-life of 2 hours. MDL 28,170 caused a
dose-dependent reduction in infarct volume when administered 30 minutes
after MCA occlusion. A window of opportunity study was conducted to
determine the maximal delay between the onset of ischemia and
the initiation of efficacious therapy. MDL 28,170 reduced infarct
volume when therapy was delayed for 0.5, 3, 4, and 6 hours after the
initiation of ischemia. The protective effect of MDL 28,170 was
lost after an 8-hour delay.
Conclusions—These data indicate that the therapeutic window of
opportunity for calpain inhibition is at least 6 hours in a reversible
focal cerebral ischemia model. This protection is observed
despite the lethal hypoxic and excitotoxic challenge, suggesting that
calpain activation may be an obligatory, downstream event in the
ischemic cell death cascade.
Neuroscience
Research Eli Lilly and Co Lilly Corporate
Center Indianapolis, Indiana
© 1998 American Heart Association, Inc.
Original Contributions
Six-Hour Window of Opportunity for Calpain Inhibition in Focal Cerebral Ischemia in Rats
Editorial Comment
This article has been cited by other articles:
 |
|
 |
|
  D. P. Schafer, S. Jha, F. Liu, T. Akella, L. D. McCullough, and M. N. Rasband Disruption of the Axon Initial Segment Cytoskeleton Is a New Mechanism for Neuronal Injury J. Neurosci., October 21, 2009; 29(42): 13242 - 13254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-N. Jang, Y.-S. Jung, S. H. Lee, C.-H. Moon, C.-H. Kim, and E. J. Baik Calpain-Mediated N-Cadherin Proteolytic Processing in Brain Injury J. Neurosci., May 6, 2009; 29(18): 5974 - 5984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Tsubokawa, I. Solaroglu, H. Yatsushige, J. Cahill, K. Yata, and J. H. Zhang Cathepsin and Calpain Inhibitor E64d Attenuates Matrix Metalloproteinase-9 Activity After Focal Cerebral Ischemia in Rats Stroke, July 1, 2006; 37(7): 1888 - 1894. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Han, Y. Shirasaki, and K. Fukunaga 3-[2-[4-(3-Chloro-2-methylphenylmethyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole Dihydro-chloride 3.5 Hydrate (DY-9760e) Is Neuroprotective in Rat Microsphere Embolism: Role of the Cross-Talk between Calpain and Caspase-3 through Calpastatin J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 529 - 536. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Rashidian, G. Iyirhiaro, H. Aleyasin, M. Rios, I. Vincent, S. Callaghan, R. J. Bland, R. S. Slack, M. J. During, and D. S. Park Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo PNAS, September 27, 2005; 102(39): 14080 - 14085. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Polster, G. Basanez, A. Etxebarria, J. M. Hardwick, and D. G. Nicholls Calpain I Induces Cleavage and Release of Apoptosis-inducing Factor from Isolated Mitochondria J. Biol. Chem., February 25, 2005; 280(8): 6447 - 6454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Nakajima, N. Kakui, K. Ohkuma, M. Ishikawa, and T. Hasegawa A Newly Synthesized Poly(ADP-Ribose) Polymerase Inhibitor, DR2313 [2-Methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]-pyrimidine-4-one]: Pharmacological Profiles, Neuroprotective Effects, and Therapeutic Time Window in Cerebral Ischemia in Rats J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 472 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wang, T. R. Van De Water, C. Bonny, F. de Ribaupierre, J. L. Puel, and A. Zine A Peptide Inhibitor of c-Jun N-Terminal Kinase Protects against Both Aminoglycoside and Acoustic Trauma-Induced Auditory Hair Cell Death and Hearing Loss J. Neurosci., September 17, 2003; 23(24): 8596 - 8607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sedarous, E. Keramaris, M. O'Hare, E. Melloni, R. S. Slack, J. S. Elce, P. A. Greer, and D. S. Park Calpains Mediate p53 Activation and Neuronal Death Evoked by DNA Damage J. Biol. Chem., July 3, 2003; 278(28): 26031 - 26038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Crocker, P. D. Smith, V. Jackson-Lewis, W. R. Lamba, S. P. Hayley, E. Grimm, S. M. Callaghan, R. S. Slack, E. Melloni, S. Przedborski, et al. Inhibition of Calpains Prevents Neuronal and Behavioral Deficits in an MPTP Mouse Model of Parkinson's Disease J. Neurosci., May 15, 2003; 23(10): 4081 - 4091. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-J. Kim, D.-G. Jo, G.-S. Hong, B. J. Kim, M. Lai, D.-H. Cho, K.-W. Kim, A. Bandyopadhyay, Y.-M. Hong, D. H. Kim, et al. Calpain-dependent cleavage of cain/cabin1 activates calcineurin to mediate calcium-triggered cell death PNAS, July 23, 2002; 99(15): 9870 - 9875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Liu, J. F. Harriman, and R. G. Schnellmann Cytoprotective Properties of Novel Nonpeptide Calpain Inhibitors in Renal Cells J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 88 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Zeitz, A. E. Maass, P. Van Nguyen, G. Hensmann, H. Kogler, K. Moller, G. Hasenfuss, and P. M.L. Janssen Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na+-Ca2+ Exchange Circ. Res., May 17, 2002; 90(9): 988 - 995. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ikeda, L. H. Young, and A. M. Lefer Attenuation of neutrophil-mediated myocardial ischemia-reperfusion injury by a calpain inhibitor Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1421 - H1426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Cuzzocrea, M C McDonald, E Mazzon, H Mota-Filipe, T Centorrino, M L Terranova, A Ciccolo, D Britti, A P Caputi, and C Thiemermann Calpain inhibitor I reduces colon injury caused by dinitrobenzene sulphonic acid in the rat Gut, April 1, 2001; 48(4): 478 - 488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. McDONALD, H. MOTA-FILIPE, A. PAUL, S. CUZZOCREA, M. ABDELRAHMAN, S. HARWOOD, R. PLEVIN, P. K. CHATTERJEE, M. M. YAQOOB, and C. THIEMERMANN Calpain inhibitor I reduces the activation of nuclear factor-{kappa}B and organ injury/dysfunction in hemorrhagic shock FASEB J, January 1, 2001; 15(1): 171 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Cuzzocrea, M. C. McDonald, E. Mazzon, D. Siriwardena, I. Serraino, L. Dugo, D. Britti, G. Mazzullo, A. P. Caputi, and C. Thiemermann Calpain Inhibitor I Reduces the Development of Acute and Chronic Inflammation Am. J. Pathol., December 1, 2000; 157(6): 2065 - 2079. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nakagawa and J. Yuan Cross-Talk between Two Cysteine Protease Families: Activation of Caspase-12 by Calpain in Apoptosis J. Cell Biol., August 21, 2000; 150(4): 887 - 894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Reglodi, A. Somogyvari-Vigh, S. Vigh, T. Kozicz, A. Arimura, and S. P. Finklestein Delayed Systemic Administration of PACAP38 Is Neuroprotective in Transient Middle Cerebral Artery Occlusion in the Rat Editorial Comment Stroke, June 1, 2000; 31(6): 1411 - 1417. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Callaway, M. J. Knight, D. J. Watkins, P. M. Beart, B. Jarrott, and J. A. Clemens Delayed Treatment With AM-36, a Novel Neuroprotective Agent, Reduces Neuronal Damage After Endothelin-1-Induced Middle Cerebral Artery Occlusion in Conscious Rats • Editorial Comment Stroke, December 1, 1999; 30(12): 2704 - 2712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Lipton Ischemic Cell Death in Brain Neurons Physiol Rev, October 1, 1999; 79(4): 1431 - 1568. [Abstract] [Full Text] [PDF]
|
|