The novel 5-lipoxygenase inhibitor ABT-761 attenuates cerebral vasospasm in a rabbit model of subarachnoid hemorrhage.
OBJECTIVE
Eicosanoids have been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). Leukotrienes, 5-hydroxyperoxyeicosatetraenoic acid, and 5-hydroxyeicosatetraenoic acid are part of this group of substances, resulting from the 5-lipoxygenase activity on arachidonic acid metabolism. This study examined the effects of ABT-761, a new 5-lipoxygenase inhibitor, on cerebral vasospasm in an in vivo rabbit model of SAH.


METHODS
A total of 48 rabbits were assigned to one of six groups: SAH + placebo (n = 8), SAH + ABT-761 20 mg/kg (n = 8), SAH + ABT-761 30 mg/kg (n = 8), control + placebo (n = 8), control + ABT-761 20 mg/kg (n = 8), and control + ABT-761 30 mg/kg (n = 8). Drug administration was initiated 30 minutes after induction of SAH and repeated 24 hours later. The animals were killed 48 hours after SAH, using the perfusion-fixation method. The cross sectional areas of basilar artery histological sections were measured by an investigator blinded to the treatment groups of the individual samples.


RESULTS
In placebo-treated animals, the average luminal cross sectional area of the basilar artery was reduced by 68% after SAH as compared with controls (P < 0.0001). After SAH, the vasospastic response was attenuated in animals treated with 20 or 30 mg/kg representing a 28 or 35% reduction, respectively (P = 0.0011 and P = 0.0038).


CONCLUSIONS
The results demonstrated that ABT-761 is effective in attenuating experimental cerebral vasospasm, indicating that this new drug represents a potential therapeutic agent for the treatment of vasospasm after SAH.
Barbosa
M D
MD
Department of Neurological Surgery, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
Arthur
A S
AS
Louis
R H
RH
MacDonald
T
T
Polin
R S
RS
Gazak
C
C
Kassell
N F
NF
D000818:Animals; D001488:Basilar Artery / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors; D008297:Male; D011817:Rabbits; D013345:Subarachnoid Hemorrhage / Q000473:pathology*; D020301:Vasospasm, Intracranial / Q000473:pathology*
D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; C096921:atreleuton; D006918:Hydroxyurea