Effect of MX-68 on airway inflammation and hyperresponsiveness in mice and guinea-pigs.
MX-68 is a newly synthesized antifolate, which is a derivative of methotrexate (MTX). In this paper, the effect of MX-68 on allergic airway responses in mice and guinea-pigs was studied. In the first experiment, antigen-induced airway inflammation and airway hyperresponsiveness (AHR) to acetylcholine in mice were examined and compared with the effects of classical antifolate methotrexate and prednisolone. Mice were sensitized with ovalbumin as an antigen and challenged with ovalbumin inhalation three times. After the last inhalation, AHR and airway inflammation were observed. An increase in Th2 cytokines (IL-4 and IL-5) and a decrease in a Th1 cytokine (IFN-gamma) in the bronchoalveolar lavage fluid (BALF), as well as an elevation of the immunoglobulin level in serum, were observed in sensitized mice. Oral administration of MX-68 had no effect on changes of body weight, but prednisolone reduced body weight during the experiment. The antigen-induced AHR and increases in the number of eosinophils and lymphocytes in BALF were significantly inhibited by MX-68. MX-68 interfered with the elevation of IL-4 and IL-5 levels in BALF, but had no effect on the decrease in IFN-gamma. Moreover, MX-68 significantly inhibited the elevation of serum IgE and IgG levels. In the guinea-pig model for bronchial asthma, biphasic increases in airway resistance (immediate asthmatic response, IAR, and late asthmatic response, LAR), as well as accumulated inflammatory cells in BALF, were observed after repeated antigen challenge. These asthmatic responses and inflammatory signs were significantly decreased by administration of MX-68. These results suggest that MX-68 obviously has an anti-inflammatory effect in an animal model of asthma and would be useful clinically for the treatment of bronchial asthma.
Department of Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
Koichi
K
Nagao
Hirotomo
H
Akabane
Taisei
T
Masuda
Masato
M
Komai
Hiroyuki
H
Tanaka
Hiroichi
H
Nagai
D015074:2-Aminoadipic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D000109:Acetylcholine / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors; D000280:Administration, Inhalation; D000485:Allergens / Q000276:immunology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D001991:Bronchitis / Q000188:drug therapy* / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007136:Immunoglobulins / Q000096:biosynthesis / Q000737:chemistry / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000737:chemistry; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors; D011239:Prednisolone / Q000008:administration & dosage / Q000627:therapeutic use
D000485:Allergens; D007136:Immunoglobulins; D015848:Interleukin-5; C104193:N-(1-((2,4-diamino-6-pteridinyl)methyl)-3,4-dihydro -2H-1,4-benzothiazine-7-carbonyl)-L-2-aminoadipic acid; D015074:2-Aminoadipic Acid; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin; D011239:Prednisolone; D000109:Acetylcholine; D008727:Methotrexate