Elsevier

Brain Research

Volume 778, Issue 2, 19 December 1997, Pages 265-271
Brain Research

Research report
Neuroprotective effects of TNF binding protein in focal cerebral ischemia

https://doi.org/10.1016/S0006-8993(97)00981-5Get rights and content

Abstract

The effect of tumor necrosis factor binding protein (TNFbp) was studied in mice subjected to a permanent middle cerebral artery occlusion (MCAO). TNFbp is a dimeric form of the type I soluble TNF receptor linked to polyethylene glycol (TNFbp), and binds and inhibits TNF-α. TNFbp produced a significant reduction in the cortical infarct volume (22.6±3.5 mm3 immediately after MCAO; 25.2±2.4 mm3 1 h after MCAO) compared with vehicle-treated animals (30.3±3.7 mm3 immediately post MCAO; 31±3.7 mm3 1 h after MCAO (mean±S.D.) when administered intracranially up to 60 min post-occlusion. The neuroprotective effect of TNFbp was sustained in mice for 2 weeks after MCAO. DNA fragmentation at the margin of the cortical infarcts was dramatically reduced in mice treated with TNFbp whereas all control animals showed consistent and obvious DNA fragmentation 2 weeks after MCAO. TNFbp could have therapeutic value for the treatment of ischemic stroke if the problem of delivery to brain can be overcome.

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.

Section snippets

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

References (23)

  • G.Z. Feuerstein et al.

    Cytokines, inflammation, and brain injury: role of tumor necrosis factor α

    Cerebrovasc. Brain Metab. Rev.

    (1994)
  • Cited by (124)

    • TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects

      2015, Neuroscience
      Citation Excerpt :

      The observation that intravenous administration of a TNF binding protein (a recombinant type I soluble TNF receptor dimer conjugated to polyethylene glycol), completely nullified the preconditioning effect of systemically-administered LPS (Tasaki et al., 1997), showed that TNF, either or both solTNF and tmTNF, was essential for the induction of ischemia preconditioning. The further finding that pretreatment of mice by intracisternal administration of TNF preconditioned them to tolerate an otherwise damaging ischemic insult (Nawashiro et al., 1997), showed that solTNF is sufficient for initiating preconditioning tolerance through local mechanisms in the CNS. Second, in a model of cuprizone-induced demyelination and remyelination, TNF-deficient mice showed delayed remyelination and a reduction in proliferating NG2+ cells, which mainly represent oligodendrocyte precursor cells, suggesting that TNF plays an important role in the spontaneous remyelination of demyelinated axons in this model (Arnett et al., 2001).

    • Why haematomas cause flap failure: An evidence-based paradigm

      2012, Journal of Plastic, Reconstructive and Aesthetic Surgery
    View all citing articles on Scopus
    View full text