Indomethacin promotes germinal matrix microvessel maturation in the newborn beagle pup.

Abstract

Background and Purpose:Although indomethacin has been demonstrated to prevent germinal matrix and intraventricular hemorrhage in clinical and animal studies, the mechanism of action of this agent to prevent hemorrhage remains unclear. Previous studies have demonstrated both that the microvessels in the germinal matrix of newborn beagle pups undergo basement membrane maturation during the first 4 postnatal days and that indomethacin may promote laminin deposition in tumor cell culture systems.Methods: We employed the newborn beagle pup model to test the hypothesis that indomethacin may stimulate laminin deposition in germinal matrix microvessels. Newborn pups were randomized to receive either 0.1 nig/ kg/dose i.p. indomethacin or an equal volume of saline diluent. Pups received doses of study medication once a day for 1, 2, or 3 days and were studied on postnatal days 1, 2, 3, or 4. Pups were anesthetized and systemically perfused with buffered formalin; the brains were removed and prepared for immunohistochemical study.Results: Sections stained with Bandeiraea lectin demonstrated that there was no difference in germinal matrix vessel density among the postnatal ages studied; similarly, there were no differences in vessel density between saline-and indomethacin-treated animals at any postnatal age. Quantification of germinal matrix stained intensity by confocal microscopy demonstrated significant increases in indomethacin-treated pups for both laminin staining at postnatal days 2 (p=0.05) and 3 (/?=0.0009) and type V collagen staining at postnatal day 2 (p=0.011). Although staining for /3 t integrins increased across postnatal ages, there were no differences between saline-and indomethacin-treated animals.Conclusions: These data suggest that indomethacin may stimulate basement membrane deposition in the germinal matrix microvessels of newborn beagle pups to prevent germinal matrix and/or intraventricular hemorrhage. (Stroke 1992;23:1132-1137

Immunolocalization of tight junction proteins in blood vessels in human germinal matrix and cortex

“…Germinal matrix hemorrhage (GMH)-intraventricular hemorrhage (IVH) begins with rupture of a vessel, usually a vein, in the GM (Ghazi-Birry et al 1997;Volpe 2001). The incidence of GMH-IVH declines as gestational age increases from 24 weeks PC to term (Ment et al 1992(Ment et al , 1993(Ment et al , 1995. Ongoing GM vessel maturation during this period is one explanation for this age-associated decline of hemorrhage.…”

Prophylactic Ibuprofen for the Prevention of Intraventricular Hemorrhage Among Preterm Infants: A Multicenter, Randomized Study

“…[6][7][8][9][10] Indomethacin was shown to decrease baseline cerebral blood flow (CBF), to modulate CBF changes in response to hypercarbic insults, to decrease serum prostaglandin levels, and to promote germinal matrix maturation in animal models. [11][12][13][14] However, indomethacin prophylaxis for IVH has never been used widely, because of the adverse effects of indomethacin on renal function and the gastrointestinal tract. 10,[15][16][17][18][19] In contrast, experimental 20 and preliminary clinical [21][22][23][24] studies demonstrated that ibuprofen (another cyclooxygenase inhibitor of prostaglandin synthesis) was effective in closing PDA without reducing CBF 25 or affecting cerebral vasoreactivity to arterial carbon dioxide tension 26 or intestinal 27,28 or renal 29 hemodynamics.…”

CT measurement of indomethacin-induced cerebral hemodynamic changes in the newborn piglet

“…While IVH is believed to be triggered by changes in blood flow in the microvasculature of the immature germinal matrix, the mechanism by which indomethacin prevents IVH remains uncertain. Clinical studies do not support prolonged alterations in CBF as the primary mechanism by which indomethacin prevents germinal matrix hemorrhage (GMH) and/or IVH 19,22 . Ment et al showed that in newborn beagle pups indomethacin may stimulate basement membrane deposition around the microvessels of the germinal matrix and that this would increase the structural integrity of the germinal matrix, thus helping to prevent hemorrhage 22 .…”

“…Clinical studies do not support prolonged alterations in CBF as the primary mechanism by which indomethacin prevents germinal matrix hemorrhage (GMH) and/or IVH 19,22 . Ment et al showed that in newborn beagle pups indomethacin may stimulate basement membrane deposition around the microvessels of the germinal matrix and that this would increase the structural integrity of the germinal matrix, thus helping to prevent hemorrhage 22 . It is possible then, that the protective effects of indomethacin persist even in the presence of relatively large transient changes in cerebral hemodynamics as observed in this study.…”