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(Stroke. 2003;34:776.)
© 2003 American Heart Association, Inc.

Original Contributions

Selective Neuromicrovascular Endothelial Cell Death by 8-Iso-Prostaglandin F₂

Possible Role in Ischemic Brain Injury

Sonia Brault, MSc; Ana Katherine Martinez-Bermudez, MSc; Anne Marilise Marrache, BSc; Fernand Gobeil, Jr, PhD; Xin Hou, MD, PhD; Martin Beauchamp, BSc; Christiane Quiniou, MSc; Guillermina Almazan, PhD; Christian Lachance, MD; Jackson Roberts, II, MD, PhD; Daya R. Varma, MD, PhD Sylvain Chemtob, MD, PhD

From the Centre de Recherche de l’Hôpital Sainte-Justine, Department of Pediatrics and Pharmacology, Université de Montréal, Montréal, Québec, Canada (S.B., A.K.M-B., A.M.M., F.G., X.H., M.B., C.Q., C.L., S.C.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (S.B., A.K.M-B., A.M.M., G.A., D.R.V., S.C.); and Department of Pharmacology and Medicine, Vanderbilt University, Nashville, Tenn (J.R.).

Correspondence to Sylvain Chemtob, MD, PhD, FRCPC, Departments of Pediatrics, Ophthalmology, and Pharmacology, Research Center, Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal, Quebec H3T 1C5, Canada. E-mail sylvain.chemtob{at}umontreal.ca

Background and Purpose— Free radical-induced peroxidation is an important factor in the genesis of hypoxic-ischemic encephalopathy, including that of the preterm infant. Isoprostanes are major peroxidation products. Since microvascular dysfunction seems to contribute to ischemic encephalopathies, we studied the cytotoxicity of 8-iso-prostaglandin F₂ (PGF₂) on cerebral microvascular cells.

Methods— Microvascular endothelial, astroglial, and smooth muscle cells from newborn brain were cultured. The cytotoxicity of 8-iso-PGF₂ on these cells was determined by MTT assays and lactate dehydrogenase (LDH) release, propidium iodide incorporation, and DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling [TUNEL]). In addition, effects of intraventricular injections of 8-iso-PGF₂ and possible involvement of thromboxane in 8-iso-PGF₂-induced cytotoxicity were determined.

Results— 8-Iso-PGF₂ induced time- and concentration-dependent endothelial cell death (EC₅₀=0.1 nmol/L) but exerted little effect on smooth muscle and astroglial cells; endothelial cell death seemed mostly of oncotic nature (propidium iodide incorporation and LDH release). Cell death was associated with increased endothelial thromboxane A₂ (TXA₂) formation and was prevented by TXA₂ synthase inhibitors (CGS12970 and U63557A); TXA₂ mimetics U46619 and I-BOP also caused endothelial cell death. Intraventricular injection of 8-iso-PGF₂ induced periventricular damage, which was attenuated by CGS12970 pretreatment.

Conclusions— These data disclose a novel action of 8-iso-PGF₂ involving TXA₂ in oxidant stress-induced cerebral microvascular injury and brain damage.

Key Words: apoptosis • brain damage • necrosis • oxidants • thromboxanes • white matter

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