Lomerizine, a Ca2+ channel blocker, reduces glutamate-induced neurotoxicity and ischemia/reperfusion damage in rat retina.
We examined the effects of a new Ca2+ channel blocker, lomerizine, on the intraocular hypertension-induced ischemia/reperfusion injury in rat retina and on the glutamate-induced neurotoxicity in rat cultured retinal neurons, and compared its effects with those of a Ca2+ channel blocker (flunarizine) and an N-methyl-D-aspartate receptor antagonist (MK-801). Morphometric evaluation at 7 days after ischemia/reperfusion showed that treatment with lomerizine (0.1 and 1 mg kg(-1), i.v.) prior to ischemia and again immediately after reperfusion dose-dependently reduced the retinal damage. Treatment with MK-801 (1 mg kg(-1), i.v.) before ischemia significantly reduced the resulting retinal damage. Flunarizine (0.1 and 1 mg kg(-1), i.v.) tended to reduce the retinal damage, but its effect did not reach statistical significance. In an in vitro study, pretreatment with lomerizine (0.1 and 1 microM) or flunarizine (1 microM) significantly reduced glutamate-induced neurotoxicity, the effects being concentration dependent. Lomerizine (1 microM) also exhibited protective effects against both the N-methyl-D-aspartate and kainate induced types of neurotoxicity. However, lomerizine (1 microM) had little effect on the neurotoxicity induced by ionomycin (1 microM) application. Glutamate-induced neurotoxicity was abolished by removing Ca2+ from the medium. These results indicate that lomerizine protects neuronal cells against retinal neurotoxicity both in vivo and in vitro, and that this Ca2+ channel blocker may be useful as a therapeutic drug against retinal diseases that cause neuronal injury, such as normal tension glaucoma (NTG).
Toriu
N
N
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan. hidehara@tim.hi-ho.ne.jp
Akaike
A
A
Yasuyoshi
H
H
Zhang
S
S
Kashii
S
S
Honda
Y
Y
Shimazawa
M
M
Hara
H
H
D000818:Animals; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005444:Flunarizine / Q000627:therapeutic use; D018698:Glutamic Acid / Q000009:adverse effects*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000209:etiology; D010879:Piperazines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*
D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D010879:Piperazines; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; C052424:lomerizine; D005444:Flunarizine