Short communication4-(2-Aminoethyl)benzenesulfonyl fluoride attenuates tumor-necrosis-factor-α-induced blood–brain barrier opening
Introduction
Tumor necrosis factor-α (TNF-α) plays a crucial role in the development of acquired immunodeficiency syndrome, malaria, meningococcal disease, parasitic infections and sepsis (Beutler and Grau, 1993; Feuerstein et al., 1994) and it proved to be an important mediator of brain injury during cerebral ischemia–reperfusion (Del Zoppo, 1994) and neurodegenerative diseases (Sharief and Thompson, 1992). The blood–brain barrier, formed by cerebral endothelial cells in cooperation with astrocytes, neurons, pericytes and microglia, plays an active role in TNF-α-induced cerebral damage. Stimulated cells located at either side of this barrier can produce TNF-α which induces capillary endothelial cell proinflammatory responses (e.g., leukocyte–endothelial adhesion, neutrophil transmigration), and increased procoagulant activity by the activation of some serine proteases (Beutler and Grau, 1993; Del Zoppo, 1994; Feuerstein et al., 1994). On the other hand, TNF-α has a specific bidirectional transport system through which it passes the blood–brain barrier (Gutierrez et al., 1993).
Previous studies indicated that both intravascular and intracisternal TNF-α administration resulted in vasogenic brain edema formation in newborn pigs (Megyeri et al., 1992; Ábrahám et al., 1996). It is assumed that activated leukocytes contribute to the acute blood–brain barrier opening, because no similar changes in permeability were found in an in vitro reconstituted model of the blood–brain barrier (cerebral endothelial cells cocultured with astrocytes) (Deli et al., 1995). The vasoconstrictor effect of intracisternal TNF-α (Megyeri et al., 1992; Tureen, 1995) suggests the involvement of cerebrovascular smooth muscle cells, too. It is known that oxygen free radicals produced by endothelial cells, brain cells or white blood cells play a role in the mediation of the TNF-α-induced brain injuries (Del Zoppo, 1994; Feuerstein et al., 1994; Tureen, 1995). Our recent data suggested that TNF-α maintains high superoxide production of human monocytes in vitro which was blocked by the addition of 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), a nontoxic, water-soluble, irreversible inhibitor of serine proteases (Megyeri et al., 1995). Similarly, the in vitro activation of respiratory burst in stimulated neutrophil granulocytes could also be prevented by AEBSF pretreatment (Remold-O'Donnell and Parent, 1995).
The aim of the present study was to reveal the possible in vivo effect of AEBSF on the prevention of TNF-α-induced vasogenic brain edema formation.
Section snippets
Animal study
Newborn pigs of either sex (n=36, 4–8 h, 1170–1580 g) were included. After pentobarbital (30 mg/kg) anesthesia, one of the umbilical arteries was catheterized, and cardiovascular, blood gas and acid–base parameters were monitored (Ábrahám et al., 1996). The left internal carotid artery of the animals was catheterized through the external branch, and 10,000 IU rhTNF-α diluted in 0.5 ml isotonic saline was given in slow intraarterial injection to 30 animals, while six newborn pigs receiving
Results
During the experimental period vital cardiovascular parameters did not change significantly after administration of TNF-α and AEBSF compared to those measured in control animals (data not shown).
On the other hand, 10,000 IU rhTNF-α resulted in blood–brain barrier opening both for sodium fluorescein and albumin in porcine brain (Fig. 1). AEBSF pretreatment, in the doses of 4.8–19.2 mg/kg, significantly (P<0.05) inhibited the TNF-α induced increase in sodium fluorescein permeability in all
Discussion
In accordance with previous observations (Ábrahám et al., 1996), our present data confirm that intracarotid TNF-α administration results in blood–brain barrier opening for sodium fluorescein and Evan's blue-albumin in the brain of newborn pigs. Though AEBSF pretreatment dose-dependently inhibited the TNF-α-induced barrier opening for sodium fluorescein, its effect on the increase in albumin permeability was moderate. However, it is suggested that permeability tracers used can pass through the
Acknowledgements
The research was partly supported by grants from OTKA (T-2680, F-16682, F-25984), ETT (T07 154/96), and INSERM (réseau Est-Ouest 94EO06). The authors are grateful to Mrs. Ildikó Wellinger for her skillful technical assistance.
References (19)
- et al.
Intracarotid tumor necrosis factor-α administration increases the blood–brain barrier permeability in the cerebral cortex of newborn pig: quantitative aspects of double-labelling studies and confocal laser scanning analysis
Neurosci. Lett.
(1996) - et al.
Inhibition of amyloid κ-protein production in neural cells by the serine protease inhibitor AEBSF
Neuron
(1996) - et al.
Murine tumor necrosis factor alpha is transported from blood to brain in the mouse
J. Neuroimmunol.
(1993) - et al.
Antioxidants differentially affect nuclear factor kappa β-mediated nitric oxide synthase expression in vascular smooth muscle cells
FEBS Lett.
(1996) - et al.
Recombinant human tumor necrosis factor α constricts pial arterioles and increases blood–brain barrier permeability in newborn piglets
Neurosci. Lett.
(1992) - et al.
Downregulation of neutrophil CD43 by opsonized zymosan
Blood
(1995) - et al.
Tumor necrosis factor-α-induced gelatinase B causes delayed opening of the blood–brain barrier: an expanded therapeutic window
Brain Res.
(1995) - et al.
Blood to brain and brain to blood passage of native horseradish peroxidase, wheat germ agglutinin, and albumin: pharmacokinetic and morphological assessments
J. Neurochem.
(1994) - et al.
Tumor necrosis factor in the pathogenesis of infectious diseases
Crit. Care Med.
(1993)