(Stroke. 2001;32:240.)
© 2001 American Heart Association, Inc.
Original Contributions |
Antisense Oligodeoxynucleotide Inhibition of Tumor Necrosis Factor-
Expression Is Neuroprotective After Intracerebral Hemorrhage
From the Departments of Pharmacology and Therapeutics (M.M., H.J.Y., J.P., C.P.) and Pathology (M.X., M.R.D.B.), University of Manitoba, Winnipeg, Manitoba, and Department of Clinical Neurosciences, Microbiology, and Infectious Diseases, University of Calgary, Calgary, Alberta (W.N., J.B.J., C.P.), Canada.
Correspondence to Dr C. Power, Department of Clinical Neurosciences, University of Calgary, HMRB 150, 3330 Hospital Dr, Calgary, AB T2N 4N1 Canada. E-mail power{at}ucalgary.ca
Background
and Purpose—Tumor necrosis factor-
(TNF-) expression is increased in brain after cerebral
ischemia, although little is known about its abundance and role
in intracerebral hemorrhage (ICH). A
TNF-–specific antisense oligodeoxynucleotide
(ORF4-PE) was used to study the extent to which TNF- expression
influenced neurobehavioral outcomes and brain damage in a
collagenase-induced ICH model in
rat.
Methods—Male
Sprague-Dawley rats were anesthetized, and ICH was induced by
intrastriatal administration of heparin and collagenase.
Immediately before or 3 hours after ICH induction, ORF4-PE was
administered directly into the site of ICH. TNF- mRNA and protein
levels were measured by reverse transcriptase–polymerase chain
reaction and immunoblot analyses. Cell death was
measured by terminal deoxynucleotidyl
transferase–mediated uridine 5'triphosphate-biotin nick end labeling
(TUNEL). Neurobehavioral deficits were measured for 4 weeks after
ICH.
Results—ICH induction
(n=6) elevated TNF- mRNA and protein levels
(P<0.01) at 24 hours after the
onset of injury compared with sham controls (n=6). Immunohistochemical
labeling indicated that ICH was accompanied by elevated expression of
TNF- in neutrophils, macrophages, and microglia.
Administration of ORF4-PE (2.0 nmol) directly into striatal parenchyma,
15 minutes before (n=4) or 3 hours after (n=6) ICH, decreased levels of
TNF- mRNA (P<0.001) and
protein (P<0.01) in the brain
tissue surrounding the hematoma compared with animals treated with
saline alone (n=6). Mean±SEM striatal cell death (cells per
high-powered field) was also reduced in animals receiving ORF4-PE
(34.1±5.0) compared with the saline-treated ICH group (80.3±7.50)
(P<0.001). ORF4-PE treatment
improved neurobehavioral deficits observed at 24 hours
(P<0.001) after induction of
ICH (n=6) compared with the untreated ICH group (n=6). This improvement
was maintained at 28 days after hemorrhage induction
(P<0.001).
Conclusions—These
results indicate a pathogenic role for TNF- during ICH and
demonstrate that reducing TNF- expression using antisense
oligodeoxynucleotides is
neuroprotective.
Editorial Comment
Cardiovascular Sciences, DuPont Pharmaceuticals Company, Wilmington, Delaware
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