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The Journal of Neuroscience, June 15, 2000, 20(12):4398-4404
Inhibition of Caspase-1-Like Activity by
Ac-Tyr-Val-Ala-Asp-Chloromethyl Ketone Induces Long-Lasting
Neuroprotection in Cerebral Ischemia through Apoptosis Reduction and
Decrease of Proinflammatory Cytokines
M.
Rabuffetti1,
C.
Sciorati1,
G.
Tarozzo1,
E.
Clementi2, 3,
A. A.
Manfredi4, and
M.
Beltramo1
1 Schering-Plough Research Institute, and
2 Department of Biotechnology, San Raffaele Science Park,
Milan, Italy, 3 Department of Pharmacobiology, University
of Calabria, Rende, 87036 Italy, and 4 Department of
Medicine, San Raffaele Biomedical Science Park, Milan, 20132 Italy
Broad spectrum caspase inhibitors have been found to reduce
neurodegeneration caused by cerebral ischemia. We studied whether blockade of group I caspases, mainly caspase-1, using the inhibitor Ac-YVAD.cmk reduced infarct volume and produced prolonged
neuroprotection. Ac-YVAD.cmk (300 ng/rat) was injected
intracerebroventricularly 10 min after permanent middle cerebral artery
occlusion in the rat. Drug treatment induced a significant
reduction of infarct volume not only 24 hr after ischemia (total
damage, percentage of hemisphere volume: control, 41.1 ± 2.3%;
treated, 26.5 ± 2.1%; p < 0.05) but also
6 d later (total damage: control, 30.6 ± 2.2%; treated,
23.0 ± 2.2%; p < 0.05). Ac-YVAD.cmk
treatment resulted in a reduction not only of caspase-1 (control,
100 ± 20.3%; treated, 3.4 ± 10.4%; p < 0.01) but also of caspase-3 (control, 100 ± 30.3%; treated,
13.2 ± 9.5%; p < 0.05) activity at 24 hr
and led to a parallel decrease of apoptosis as measured by nucleosome
quantitation (control, 100 ± 11.8%; treated, 47 ± 5.9%;
p < 0.05). Six days after treatment no differences
in these parameters could be detected between control and treated
animals. Likewise, brain levels of the proinflammatory cytokines
IL-1 and TNF- were reduced at 24 hr (39.5 ± 23.7 and
51.9 ± 10.3% of control, respectively) but not at 6 d.
Other cytokines, IL-10, MCP-1, MIP-2, and the gaseous mediator nitric
oxide, were not modified by the treatment. These findings indicate that
blockade of caspase-1-like activity induces a long-lasting
neuroprotective effect that, in our experimental conditions, takes
place in the early stages of damage progression. Finally, this effect
is achieved by interfering with both apoptotic and inflammatory mechanisms.
Key words:
permanent focal cerebral ischemia; caspase inhibition; Ac-YVAD.cmk; neuroprotection; apoptosis; TNF-; IL-1
Copyright © 2000 Society for Neuroscience 0270-6474/00/20124398-07$05.00/0
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