From the Department of Cardiovascular Pharmacology, SmithKline Beecham
Pharmaceuticals, King of Prussia, Pa, and Department of Anatomy and
Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada (R.W.C.).
Correspondence to Frank S. Barone, PhD, Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406. E-mail Frank_C_Barone{at}SBPHRD.Com
Background and Purpose—A short
duration of ischemia (ie, ischemic preconditioning
[PC]) can provide significant brain protection to subsequent
ischemic events (ie, ischemic tolerance [IT]). The
present series of studies was conducted to characterize the
temporal pattern of a PC paradigm, to systematically evaluate the
importance of protein synthesis in PC-induced IT, and to explore
candidate gene expression changes associated with IT.
Methods—Temporary middle cerebral artery occlusion (MCAO) (10
minutes) was used for PC. Various periods of reperfusion (ie, 2, 6, and
12 hours and 1, 2, 7, 14, and 21 days) were allowed after PC and before
permanent MCAO (PMCAO) (n=7 to 9 per group) to establish IT compared
with non-PC (sham-operated) rats (n=22). Infarct size, forelimb and
hindlimb motor function, and cortical perfusion (laser-Doppler
flowmetry; n=9 per group) were measured after PMCAO. The
effects of the protein synthesis inhibitor cycloheximide
administered just before PC (n=13 to 17) or administered long after PC
but just before PMCAO (n=7 to 8) on IT were also determined.
Interleukin-1 receptor antagonist mRNA (reverse
transcriptase and polymerase chain reactions [n=20] and Northern
analysis [n=50]) and protein expression (immunohistochemistry
[n=16]) after PC and early response gene expression (Northern
analysis [n=16]) after PMCAO in PC animals were
determined.
Results—Hemispheric infarct was significantly
(P<0.01) reduced only if PC was performed 1 day
(decreased 58.4%), 2 days (decreased 58.1%), or 7 days (decreased
59.4%) before PMCAO. PC significantly (P<0.01) reduced
neurological deficits (similar to reductions in infarct size).
Cycloheximide eliminated ischemic PC–induced IT effects on
both brain injury and neurological deficits if administered before PC
(P<0.05) but not if administered long after PC but
before PMCAO. PC did not produce any significant brain injury, alter
cortical blood flow after PMCAO, or produce contralateral cortical
neuroprotection. Interleukin-1 receptor antagonist mRNA and
protein expression were increased significantly
(P<0.01) only during the IT period. PC rats also
exhibited a significant (P<0.01) reduction in
c-fos and zif268 mRNA expression after PMCAO.
Conclusions—PC is a powerful inducer of ischemic brain
tolerance as reflected by preservation of brain tissue and motor
function. PC induces IT that is dependent on de novo protein synthesis.
New protein(s) that occurs at the PC brain site 1 to 7 days after PC
contributes to the neuroprotection. Those proteins that are produced
after the more severe PMCAO in PC animals apparently do not contribute
to IT. The PC-induced IT is also associated with increased expression
of the neuroprotective protein interleukin-1 receptor
antagonist and a reduced postischemic
expression of the early response genes c-fos and zif268.
School
of Biological Sciences,
University of Manchester,
Manchester, England,
Gregory J. del Zoppo, MD, Guest Editor,
Department of Molecular and Experimental Medicine,
The Scripps Research Institute,
La Jolla, California
© 1998 American Heart Association, Inc.
Original Contributions
Ischemic Preconditioning and Brain Tolerance: Temporal Histological and Functional Outcomes, Protein Synthesis Requirement, and Interleukin-1 Receptor Antagonist and Early Gene Expression
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