title: Differential contribution of COX-1 and COX-2 derived prostanoids to cortical spreading depression-Evoked cerebral oligemia.
abstract: Cortical spreading depression (CSD) is considered a significant phenomenon for human neurological conditions and one of its key signatures is the development of persistent cortical oligemia. The factors underlying this reduction in cerebral blood flow (CBF) remain incompletely understood but may involve locally elaborated vasoconstricting eicosanoids. We employed laser Doppler flowmetry in urethane-anesthetized rats, together with a local pharmacological blockade approach, to test the relative contribution of cyclooxygenase (COX)-derived prostanoids to the oligemic response following CSD. Administration of the non-selective COX inhibitor naproxen completely inhibited the oligemic response. Selective inhibition of COX-1 with SC-560 preferentially reduced the early reduction in CBF while selective COX-2 inhibition with NS-398 affected only the later response. Blocking the action of thromboxane A2(TXA2), using the selective thromboxane synthase inhibitor ozagrel, reduced only the initial CBF decrease, while inhibition of prostaglandin F2alpha action, using the selective FP receptor antagonist AL-8810, blocked the later phase of the oligemia. Our results suggest that the long-lasting oligemia following CSD consists of at least two distinct temporal phases, mediated by preferential actions of COX-1- and COX-2-derived prostanoids: an initial phase mediated by COX-1 that involves TXA2followed by a later phase, mediated by COX-2 and PGF2alpha.
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Helaine
authors.initials: H
authors.lastname: Gariepy
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Levy
mesh_terms: D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D013181:Cortical Spreading Depression / Q000187:drug effects*; D051545:Cyclooxygenase 1 / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000502:physiology; D017078:Laser-Doppler Flowmetry; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D013928:Thromboxane A2 / Q000502:physiology; D013997:Time Factors
chemical_list: D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D013928:Thromboxane A2; D015237:Dinoprost; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2
keywords: Animal models; arachidonic acid; cerebral blood flow; prostaglandin; spreading depression