Effect of MCI-9042, a 5-HT2 receptor antagonist, on retinal ganglion cell death and retinal ischemia.

Abstract

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.

• Authors: Eri Inoue-Matsuhisa, Shunji Sogo, Atsushi Mizota, Mariko Taniai, Hisashi Takenaka, Tomiya Mano
• Journal: Experimental eye research (Exp Eye Res) Vol. 76 Issue 4 Pg. 445-52 (Apr 2003) ISSN: 0014-4835 [Print] England
• PMID: 12634109 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Excitatory Amino Acid Antagonists
• Neuroprotective Agents
• Serotonin Antagonists
• Succinates
• sarpogrelate
• Glutamic Acid

Topics

• Animals
• Cell Death (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Electroretinography
• Excitatory Amino Acid Antagonists (pharmacology)
• Glutamic Acid (pharmacology)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Ocular Hypertension (complications)
• Rats
• Rats, Wistar
• Reperfusion Injury (etiology, prevention & control)
• Retinal Ganglion Cells (drug effects)
• Retinal Vessels (drug effects)
• Serotonin Antagonists (pharmacology, therapeutic use)
• Succinates (pharmacology, therapeutic use)