(Stroke. 1997;28:1233-1244.)
© 1997 American Heart Association, Inc.
Articles |
Tumor Necrosis Factor-
A Mediator of Focal Ischemic Brain Injury
From the Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa, and Department of Neurology, Carmel Medical Center, Haifa, Israel (A.M.).
Correspondence to Frank C. Barone, PhD, Department of Cardiovascular Pharmacology UW2521, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd, PO Box 1539, King of Prussia, PA 19406. E-mail Frank_C_Barone{at}SBPHRD.DOC
Background and Purpose Tumor necrosis factor- (TNF-) is
a pleiotropic cytokine that rapidly upregulates in the brain
after injury. The present study was designed to explore the
pathophysiological significance of brain TNF- in
the ischemic brain by systematically evaluating the effects of
lateral cerebroventricular administration of exogenous
TNF- and agents that block the effects of TNF- on focal stroke
and by examining the potential direct toxic effects of TNF- on
cultured neurons to better understand how TNF- might mediate stroke
injury.
Methods TNF- (2.5 or 25 pmol) was administered
intracerebroventricularly to
spontaneously hypertensive rats 24 hours before permanent or transient
(80 minutes and 160 minutes) middle cerebral artery occlusion (MCAO).
Animals were examined 24 hours later for neurological deficits and
ischemic hemisphere necrosis and swelling. In some of these
studies, neutralizing anti–TNF- monoclonal antibody (mAb) (60 pmol)
was injected intracerebroventricularly
30 minutes before exogenous TNF- (25 pmol). In addition, the effects
of blocking endogenous TNF- on permanent focal
ischemic injury were determined with the use of either mAb (60
pmol) or soluble TNF receptor I (sTNF-RI) (0.3 or 0.7 nmol)
administered intracerebroventricularly
30 minutes before and 3 and 6 hours after MCAO. Finally, the direct
neurotoxic effects of TNF- were studied in cultured rat cerebellar
granule cells exposed to TNF- (10 to 2000 U/mL for 6 to 24 hours),
and neurotransmitter release, glutamate toxicity, and oxygen radical
toxicity were studied.
Results TNF- increased the percent hemispheric infarct
induced by permanent MCAO in a dose-related manner from 13.1±1.3%
(vehicle) to 18.9±1.7% at 2.5 pmol (P<.05) and
27.1±1.3% at 25 pmol (P<.0001). The high dose of TNF-
increased ischemia-induced forelimb deficits from 1.6±0.2 to
2.3±0.2 (P<.01). TNF- (2.5 pmol) also increased the
infarction induced by 80 or 160 minutes of transient MCAO from
1.9±0.9% to 4.3±0.4% (P<.01) and from 14.2±1.3% to
21.6±2.2% (P<.05), respectively. The exacerbation of
infarct size, swelling, and neurological deficit after exogenous
TNF- was reversed by preinjection of 60 pmol mAb. Blocking
endogenous TNF- also significantly reduced focal
ischemic brain injury. Treatment with 60 pmol mAb before and
after permanent MCAO significantly reduced infarct size compared with
control (nonimmune) antibody treatment by 20.2% (P<.05).
Reduced brain infarction also was produced by brain administration of
0.3 nmol (decreased 18.2%) or 0.7 nmol (decreased 26.1%;
P<.05) sTNF-RI before and after focal stroke. The
intracerebroventricular administration
of TNF- or sTNF-RI did not alter brain or body temperature, blood
gases or pH, blood pressure, blood glucose, or general blood chemistry.
In cultured cerebellar granule cells, the application of TNF- did
not directly affect neurotransmitter release or glutamate or oxygen
free radical toxicity.
Conclusions These studies demonstrate that exogenous
TNF- exacerbates focal ischemic injury and that blocking
endogenous TNF- is neuroprotective. The specificity of
the action(s) of TNF- was demonstrated by antagonism of its effects
with specific anti–TNF- tools (ie, mAb and sTNF-RI). TNF-
toxicity does not appear to be due to a direct effect on neurons or
modulation of neuronal sensitivity to glutamate or oxygen radicals and
apparently is mediated through nonneuronal cells. These data suggest
that inhibiting TNF- may represent a novel pharmacological
strategy to treat ischemic stroke.
Key Words: cerebral ischemia • middle cerebral artery occlusion • neuroprotection • tumor necrosis factor • rats
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