title: ISO-1, a macrophage migration inhibitory factor antagonist, prevents N-methyl-D-aspartate-induced retinal damage.
abstract: Macrophage migration inhibitory factor (MIF) has been shown to play an important role in a variety of inflammatory and immune-mediated diseases. The inflammatory responses contribute to retinal neuronal degeneration. However, the role of MIF in the progression of retinal degeneration has not yet been elucidated. In this study, we determined whether pharmacological inhibition of MIF protects against the retinal damage induced by N-methyl-D-aspartate (NMDA) in rats. Intravitreal injection of NMDA (200 nmol) resulted in (1) cell loss in the ganglion cell layer and reduction in the thickness of the inner plexiform layer, (2) an increase in apoptotic cells, (3) a decrease in parvalbumin-positive amacrine cells, (4) accumulation of leukocytes, and (5) microglia activation. Injection of (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1, 100 nmol), a MIF antagonist, significantly attenuated these NMDA-induced responses. These findings suggest that ISO-1 exerts protective effects against retinal injuries and that MIF may be a target for neuroprotective intervention in retinal diseases associated with glutamate-induced excitotoxicity.
authors.affiliation: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Naruoka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakahara
authors.forename: Yo
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kurauchi
authors.forename: Asami
authors.initials: A
authors.lastname: Mori
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Nishihira
authors.forename: Kunio
authors.initials: K
authors.lastname: Ishii
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D007555:Isoxazoles / Q000494:pharmacology*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008297:Male; D016202:N-Methylaspartate / Q000009:adverse effects*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012164:Retinal Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D016202:N-Methylaspartate
keywords: Amacrine cells; Excitotoxicity; Glutamate; Macrophage migration inhibitory factor; Neuronal cells