Secretory phospholipase A2 inhibitor PX-18 preserves microvascular reactivity after cerebral ischemia in piglets.
Cerebral ischemia/reperfusion (I/R) results in cellular energy failure and dysfunction of the neurovascular unit that contribute to subsequent neuronal cell death in the neonate. PX-18 is a putative neuroprotective inhibitor of secretory phospholipase A(2) (sPLA(2)) but its in vivo testing has been limited by its poor solubility. Our purpose was to assess whether PX-18 preserved neuronal-vascular reactivity to I/R-sensitive endothelium-dependent (hypercapnia, bradykinin) and/or neuron-dependent (N-methyl-D-aspartate; NMDA) stimuli. To make the drug available for in vivo studies, PX-18 was formulated as a 3% nanosuspension applying high pressure homogenization. Newborn piglets (1-day old, n=40) were anesthetized and ventilated, and cerebrovascular reactivity to the above stimuli was determined by measuring changes in pial arteriolar diameters using the closed cranial window/intravital videomicroscopy technique. Intravenous infusion of PX-18 nanosuspension (6 mg/kg, 20 min) did not affect baseline arteriolar diameters, or hypercapnia-, bradykinin-, or NMDA-induced pial arteriolar vasodilation under normoxic conditions. Global cerebral ischemia (10 min) followed by 1 h of reperfusion significantly attenuated hypercapnia-, bradykinin-, and NMDA-induced vasodilation in untreated or vehicle-treated controls. However, PX-18 resulted in nearly full preservation of cerebrovascular reactivity to all these stimuli. In conclusion, inhibition of sPLA(2) by PX-18 improves neurovascular function both at the neuronal and the microvascular level following I/R. This effect of PX-18 likely contributes to its neuroprotective effect.
Domoki
Ferenc
F
Department of Physiology, Faculty of Medicine, University of Szeged, H-6720 Szeged, Dóm tér 10, Hungary. domoki@phys.szote.u-szeged.hu
Zimmermann
Alíz
A
Lenti
Laura
L
Tóth-Szuki
Valéria
V
Pardeike
Jana
J
Müller
Rainer H
RH
Bari
Ferenc
F
D017738:Alkanesulfonic Acids / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001920:Bradykinin / Q000494:pharmacology; D002545:Brain Ischemia / Q000503:physiopathology*; D002536:Cerebral Arteries / Q000187:drug effects / Q000294:innervation; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006935:Hypercapnia / Q000503:physiopathology; D018715:Microscopy, Video; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D009829:Oleic Acids / Q000494:pharmacology*; D010316:Particle Size; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors*; D010841:Pia Mater / Q000098:blood supply / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy; D013552:Swine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
C545517:2-(N,N-bis(oleoyloxyethyl)amino)-1-ethanesulfonic acid; D017738:Alkanesulfonic Acids; D004791:Enzyme Inhibitors; D009829:Oleic Acids; D014665:Vasodilator Agents; D016202:N-Methylaspartate; D054497:Phospholipases A2, Secretory; D001920:Bradykinin