Gary M Fiskum

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Early processing of Bid and caspase-6, -8, -10, -14 in the canine brain during cardiac arrest and resuscitation.

Maryla Krajewska; Robert E Rosenthal; Jowita Mikolajczyk; Henning R Stennicke; Thomas Wiesenthal; Juergen Mai; Mikihiko Naito; Guy S Salvesen; John C Reed; Gary Fiskum; et al. (Profiled Authors: Gary M Fiskum; Robert E Rosenthal)

The Burnham Institute, La Jolla, CA 92037, USA.
Experimental neurology 2004;189(2):261-79.

A clinically relevant model of transient global brain ischemia involving cardiac arrest followed by resuscitation in dogs was utilized to study the expression and proteolytic processing of apoptosis-regulatory proteins. In the hippocampus, an increase in pro-apoptotic Bcl-2 family proteins Bcl-XS and Bak was detected, concomitant with proteolysis of Bcl-XL and Bcl-2, following ischemia-reperfusion injury. Also, biphasic cleavage of Bid was found in this region of the brain, with early generation of tBid-p11 within 10 min of cardiac arrest, followed by generation of tBid-p15 within 30-min reperfusion, consistent with activation of this pro-apoptotic protein. In addition, cardiac arrest and resuscitation induced early, reperfusion-dependent proteolytic processing of pro-caspase-6, -8, -10, and -14, which preceded caspase-3 activation. Immunohistochemical analysis using antibodies, which preferentially recognize processed caspase-3, -6, -8, and -10, provided evidence of time-dependent activation of these proteases in both neurons and glia in ischemia-sensitive regions of the brain. In conclusion, extremely rapid, cell-selective processing of apoptosis-regulatory proteins occurs in a clinically relevant model of ischemic brain injury caused by cardiac arrest and resuscitation. The early cleavage of Bid and rapid depletion of 32-kDa pro-caspase-14 from the canine hippocampus after induction of ischemia suggests the involvement of calpains in the processing of these proteins. Demonstration of in vitro cleavage of recombinant mouse caspase-14 by calpain I in the present study lends support to this hypothesis, further implicating cross-talk between different protease families in the pathophysiology of ischemic neural cell death.

1 Originating Grant

• 1.

  Fiskum, Gary

  Molecular Mechanisms of Ischemia Reperfusion Brain Injury

  1 May 1995 - 31 December 2008

  NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

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