title: Increased 20-HETE synthesis explains reduced cerebral blood flow but not impaired neurovascular coupling after cortical spreading depression in rat cerebral cortex.
abstract: Cortical spreading depression (CSD) is associated with release of arachidonic acid, impaired neurovascular coupling, and reduced cerebral blood flow (CBF), caused by cortical vasoconstriction. We tested the hypothesis that the released arachidonic acid is metabolized by the cytochrome P450 enzyme to produce the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE), and that this mechanism explains cortical vasoconstriction and vascular dysfunction after CSD. CSD was induced in the frontal cortex of rats and the cortical electrical activity and local field potentials recorded by glass microelectrodes, CBF by laser Doppler flowmetry, and tissue oxygen tension (tpO(2)) using polarographic microelectrodes. 20-HETE synthesis was measured in parallel experiments in cortical brain slices exposed to CSD. We used the specific inhibitor HET0016 (N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine) to block 20-HETE synthesis. CSD increased 20-HETE synthesis in brain slices for 120 min, and the time course of the increase in 20-HETE paralleled the reduction in CBF after CSD in vivo. HET0016 blocked the CSD-induced increase in 20-HETE synthesis and ameliorated the persistent reduction in CBF, but not the impaired neurovascular coupling after CSD. These findings suggest that CSD-induced increments in 20-HETE cause the reduction in CBF after CSD and that the attenuation of stimulation-induced CBF responses after CSD has a different mechanism. We suggest that blockade of 20-HETE synthesis may be clinically relevant to ameliorate reduced CBF in patients with migraine and acute brain cortex injuries.
authors: Department of Neuroscience and Pharmacology and Center for Healthy Aging, Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors: Jonas C
authors: JC
authors: Fordsmann
authors: Rebecca W Y
authors: RW
authors: Ko
authors: Hyun B
authors: HB
authors: Choi
authors: Kirsten
authors: K
authors: Thomsen
authors: Brent M
authors: BM
authors: Witgen
authors: Claus
authors: C
authors: Mathiesen
authors: Micael
authors: M
authors: Lønstrup
authors: Henning
authors: H
authors: Piilgaard
authors: Brian A
authors: BA
authors: MacVicar
authors: Martin
authors: M
authors: Lauritzen
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology*; D002540:Cerebral Cortex / Q000098:blood supply* / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D013181:Cortical Spreading Depression / Q000502:physiology*; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis*; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid
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