INTRACISTERNALLY (ic) GIVEN HUMAN RECOMBINANT TUMOR NECROSIS FACTOR (TNfα) RESULTS IN A DOSE DEPENDENT INCREASE IN THE BLOOD-BRAIN BARRIER (BBB) PERMEABILITY IN NEWBORN PIGLETS

Abstract

There is a growing evidence indicating that TNFα has an important role in the mediation of CNS infections. We have studied the effect of intracisternally given TNFα on the pial-araohnoid microvasculature in vivo in newborn piglets through an open cranial window using a fluorescenee photomacroscope by giving 50 U Group 1 (n=6), 500 U Group 2 (n=6), 5000 U Group 3 (n=6), 50000 U Group 4 (n=6) TNF α (108 U/mg protein) ic in 0.5 ml artificial cerebrospinal fluid (CSF). Control animals (n=6) were given mock CSF. Intravenous Na±fluorescein (NaF) (MW= 376) was used as a BBB permeability marker and brain NaF uptake (BNU) from parietal-, frontal-, occipital cortex, brainstem, cerebellum and periventricular white matter was measured by spectrofluorometer. Start of NaF leakage from the pial microvessels was detected 81±10.5 (Gr 1), 70.5± 7 (Gr 2) 25±4 (Gr 3), 23±3 (Gr 4) minutes following TNF α administration. An elevation in BNU: 0.82±0.15 (controls), 2.97-0.56 (Gr 1), 3.52±0.58 (Gr 2) 4.99±0.49 (Gr 3), 5.81-1.1 (Gr 4) ug NaF x mg−1 protein/ug NaF x ul21 serum was found at the end of observation (4 hours). White blood eel) count in the CSF increased from zero (controls) to 25±6 (Gr 1), 75±12 (Gr 2), 95±10 (Gr 3), 780±143 (Gr 4)/mm3 by the time of sacrifice (4 hours). In groups 1-4 vasoconstriction of the small pial arteries was also observed. /Values are: x ± S.E./

Conclusion: ic TNFα results in a dose dependent BBB opening, deterioration in cerebral circulation and pleocytosis.

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