Effect of MCI-9042, a 5-HT2 receptor antagonist, on retinal ganglion cell death and retinal ischemia.
The neuroprotective effect of MCI-9042 (Mitsubishi Pharma Corporation) was investigated on glutamate-induced retinal ganglion cell (RGC) death in vitro and on rat retinal ischemia in vivo. RGCs were purified from retinal cells isolated from 6-day-old Wistar rats and cultured in serum-free media. After application of 25 microM glutamate, the viability of RGCs treated with or without several serotonin 2 (5-HT(2)) receptor antagonists: MCI-9042, M-1 (a major metabolite of MCI-9042), ketanserin, and LY-53857; was evaluated by calcein-acetoxymethyl ester staining. Retinal ischemia was induced by intraocular pressure (IOP) elevation (130 mmHg, 50 min). Rats were intraperitoneally injected with MCI-9042 at a dose of 3, 30 mg/kg or base at 30 min before and just after ischemia-reperfusion. Retinal damages were evaluated by histology, morphometric analysis and electroretinograms (ERGs) recordings at 7 days after ischemia-reperfusion. 25 microM glutamate decreased the number of viable RGCs to about 60 to 65% of untreated RGCs. MCI-9042, M-1, ketanserin, and LY-53857 significantly reduced glutamate-induced RGC death at concentrations of more than 100 nM, 1 nM, 1 microM and 100 nM, respectively. Ischemia-reperfusion caused thinning of the thickness between the inner plexiform layer and the outer plexiform layer and attenuation of a-and b-waves in ERG recordings. The intraperitoneal injection of MCI-9042 significantly reduced morphological and functional damages in retinal ischemia. Our data demonstrate that 5-HT(2) receptor antagonists including MCI-9042 and M-1 have the neuroprotective effects in cultured RGCs and that MCI-9042 protects against ischemic retinal diseases.
Inoue-Matsuhisa
Eri
E
Research Division, EI Research Institute Co., Ltd, c/o Osaka Kasei Corporation, 2-6-11 Nakajima, Nishiyodogawaku, Osaka 555-0041, Japan. eriinoueei@aol.com
Sogo
Shunji
S
Mizota
Atsushi
A
Taniai
Mariko
M
Takenaka
Hisashi
H
Mano
Tomiya
T
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009798:Ocular Hypertension / Q000150:complications; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D012171:Retinal Vessels / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D013386:Succinates / Q000494:pharmacology* / Q000627:therapeutic use
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D012702:Serotonin Antagonists; D013386:Succinates; C064294:sarpogrelate; D018698:Glutamic Acid