Selective Neuromicrovascular Endothelial Cell Death by 8-Iso-Prostaglandin F 2α

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Abstract
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 F 2α (PGF 2α ) on cerebral microvascular cells. Methods— Microvascular endothelial, astroglial, and smooth muscle cells from newborn brain were cultured. The cytotoxicity of 8-iso-PGF 2α 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-PGF 2α and possible involvement of thromboxane in 8-iso-PGF 2α -induced cytotoxicity were determined. Results— 8-Iso-PGF 2α induced time- and concentration-dependent endothelial cell death (EC 50 =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 A 2 (TXA 2 ) formation and was prevented by TXA 2 synthase inhibitors (CGS12970 and U63557A); TXA 2 mimetics U46619 and I-BOP also caused endothelial cell death. Intraventricular injection of 8-iso-PGF 2α induced periventricular damage, which was attenuated by CGS12970 pretreatment. Conclusions— These data disclose a novel action of 8-iso-PGF 2α involving TXA 2 in oxidant stress-induced cerebral microvascular injury and brain damage.