Role of leukotriene B4 in 5-lipoxygenase metabolite- and allergy-induced itch-associated responses in mice.
We investigated the role of leukotriene (LT) B(4) in 5-lipoxygenase metabolite- and allergy-induced itch-associated responses using SA6541, an LTA(4) hydrolase inhibitor. Itch-associated responses were induced by intradermal injection of 5-hydroperoxyeicosatetraenoic acid (HPETE), a precursor of 5-lipoxygenase metabolites, and passive cutaneous anaphylaxis in ICR mice. By screening molecules related to arachidonic acid metabolism or pruritus, SA6541 was found to be a specific inhibitor of LTA(4) hydrolase. Pharmacokinetic studies confirmed the specificity of SA6541 at an oral dose of 100 mg/kg in mice. 5-HPETE induced scratching behavior, which was inhibited by SA6541 (100 mg/kg). However, SA6541 (100 mg/kg) hardly attenuated the 5-HPETE-induced increase in vascular permeability. Moreover, SA6541 (100 mg/kg) partially attenuated scratching behavior, but did not affect the increase in vascular permeability caused by passive cutaneous anaphylaxis. On the other hand, ketotifen fumarate, a histamine H1 antagonist, strongly inhibited the scratching behavior and the increase in vascular permeability caused by passive cutaneous anaphylaxis. These results suggest that LTB(4) is an endogenous itch mediator in the skin and is involved in the pruritus response in allergic reactions.
Research and Development Center, Santen Pharmaceutical Co., Ltd., Ikoma, Nara 630-0101, Japan. ftsuji@minuet.plala.or.jp
Fumio
F
Tsuji
Hiroyuki
H
Aono
Takashi
T
Tsuboi
Tadahiro
T
Murakami
Hiroshi
H
Enomoto
Keiko
K
Mizutani
Naoki
N
Inagaki
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D006634:Histamine H1 Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006967:Hypersensitivity / Q000150:complications; D007665:Ketotifen / Q000494:pharmacology / Q000627:therapeutic use; D007975:Leukotriene B4 / Q000378:metabolism*; D008084:Lipoxygenase; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010323:Passive Cutaneous Anaphylaxis / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology*; D011537:Pruritus / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000378:metabolism*
D006634:Histamine H1 Antagonists; D011480:Protease Inhibitors; D007975:Leukotriene B4; D016718:Arachidonic Acid; D008084:Lipoxygenase; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase; D007665:Ketotifen