Dopamine D1-like receptor antagonist, SCH23390, exhibits a preventive effect on diabetes mellitus that occurs naturally in NOD mice.
Dopamine receptors have five isoforms, termed D1-D5. The D1 and D5 receptors form the D1-like group that couples with the Galphas class of G proteins, while D2, D3 and D4 form the D2-like group that couples with the Galphai class of G proteins. In our previous studies, a D1-like-R antagonist, SCH23390, inhibited DC-mediated Th17 differentiation and exhibited preventive and therapeutic effects on experimental autoimmune encephalomyelitis (EAE) in mice. We herein demonstrate in the current study that in the pancreas obtained from NOD mice, islet infiltrates appear to be composed of mononuclear cells positive for IL-23R, one of the specific markers for Th17. Thereafter, NOD mice were orally administered SCH23390 from week 6 to week 26. At week 26, 67% and 25% of mice developed diabetes in the control and the SCH23390 groups, respectively (p<0.05). A histological examination of SCH23390-treated mice exhibited a typical normal islet structure with no signs of periductal and perivascular infiltrates, whereas the islets from vehicle controls showed insulitis. In week 26, spleen cells were re-stimulated with anti-CD3 and anti-CD28 antibodies in vitro and exhibited an augmentation of IFNgamma induction and the suppression of IL-17 induction in the SCH23390-treated mice. These findings indicate that antagonizing D1-like-R suppresses IL-17 expression, thereby leading to a decreased occurrence of NOD.
Hashimoto
Kumiko
K
Department of Allergy and Immunology, Saitama Medical University, Saitama, 38 Morohongo, Moroyama, Saitama 350-0495, Japan.
Inoue
Tsutomu
T
Higashi
Takehiro
T
Takei
Shin-Ichiro
S
Awata
Takuya
T
Katayama
Shigehiro
S
Takagi
Rie
R
Okada
Hirokazu
H
Matsushita
Sho
S
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology* / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000473:pathology / Q000517:prevention & control*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D018123:Receptors, Interleukin / Q000378:metabolism
D001552:Benzazepines; D020381:Interleukin-17; D017447:Receptors, Dopamine D1; D018123:Receptors, Interleukin; C534628:SCH 23390; C528688:interleukin-23 receptor, mouse