Research reportNeuroprotective effects of TNF binding protein in focal cerebral ischemia
Introduction
There are several lines of evidence that anti-cytokine therapies are beneficial to acute ischemic stroke 5, 9, 18. Inhibiting the action of the proinflammatory cytokine, TNF-α, ameliorates brain infarction 24 h after middle cerebral artery occlusion (MCAO) in mice [17]and Barone et al. [1]demonstrated a similar neuroprotective effect with soluble TNF-α receptor I and anti-TNF-α antibodies in a rat MCAO model. TNF-α, however, may also play a vital role in tissue recovery and promote survival of neurons after ischemic brain injury by means of upregulation of manganese superoxide dismutase (Mn-SOD) 16, 20and induction of neurotrophic factors 6, 8. Effects of delayed inhibition of TNF-α following focal cerebral ischemia have not been clearly documented. We have tested the effect of the dimeric form of the type I soluble TNF receptor linked to polyethylene glycol, `TNF binding protein' (TNFbp) (kindly provided by Amgen Inc., Boulder, CO, USA), on the volume of ischemic brain damage induced by (MCAO) in mice 24 h and 2 weeks after insults. To test the therapeutic value of TNF inhibition, we administered TNFbp up to 60 min post-occlusion. Furthermore, to permit comparisons with other neuroprotective drugs in this model, the spin-trapping agent α-phenyl-N-tert-butyl nitrone (PBN) which is known to be potent in neuroprotection against focal cerebral ischemia in rats or IL-1 receptor antagonist (IL-1ra) (kindly provided by Amgen Inc., Boulder, CO), were administered to groups of animals beginning immediately after MCAO.
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Materials and methods
Mature male BALB/C mice, weighing 22–26 g, were used in the study. Animals were obtained from Charles River Labs. (Wilmington, MA, USA) and were given free access to food and water prior to surgery. Animals were housed and cared for in accordance with Guide for the Care and Use of Laboratory Animals [DHEW (DHHS) publication no. (NIH) 85–23, rev. 1985, Office of Science and Health Reports, DRR/NIH, Bethesda, MD 20205, USA]. Procedures using animals were approved by the NIH Animal Care and Use
Results
The volume of ischemic brain damage 24 h after MCAO averaged 22.6±3.5 mm3 in Group 1 (n=9) (TNFbp), 30.3±3.5 mm3 in Group 2 (n=11) (control), 25.2±2.4 mm3 in Group 3 (n=10) (TNFbp/1h-post MCAO), 31.0±3.7 mm3 in Group 4 (n=8) (control/1h-post MCAO), 26.7±2.1 mm3 in Group 5 (n=8) (IL-1ra), and 23.9±2.4 mm3 in Group 6 (n=7) (PBN), respectively (mean±S.D.) (Fig. 1). All types of treatment produced a significant reduction in infarct volumes, however, the treatment by TNFbp appeared on the average to
Discussion
TNF-α is a potent pro-inflammatory cytokine, and is expressed and secreted at an early stage of the inflammatory process. It has been reported that TNF-α is expressed in ischemic neurons after focal ischemia produced by permanent MCAO in rats [13]. TNF-α mRNA is upregulated within only an hour of MCAO and reaches a peak at 6 to 12 h post-ischemia 3, 13. TNF-α stimulates acute phase protein production, enhances the permeability of blood-brain barrier, and induces expression of endothelial
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