title: Histological protection by cilnidipine, a dual L/N-type Ca(2+) channel blocker, against neurotoxicity induced by ischemia-reperfusion in rat retina.
abstract: Although a blockade or lack of N-type Ca(2+) channels has been reported to suppress neuronal injury induced by ischemia-reperfusion in several animal models, information is still limited regarding the neuroprotective effects of a dual L/N-type Ca(2+) channel blocker, cilnidipine. We histologically examined the effects of cilnidipine on neuronal injury induced by ischemia-reperfusion, intravitreous N-methyl-D-aspartate (NMDA) (200nmol/eye) and intravitreous NOC12 (400nmol/eye), an nitric oxide donor, in the rat retina, and compared its effects with those of omega-conotoxin MV IIA, an N-type Ca(2+) channel blocker and amlodipine, an L-type Ca(2+) channel blocker. Morphometric evaluation at 7 days after ischemia-reperfusion showed that treatment with cilnidipine (100microg/kg, i.v. or 0.5pmol/eye, intravitreous injection) prior to ischemia dramatically reduced the retinal damage. Treatment with omega-conotoxin MV IIA before ischemia (0.1pmol/eye, intravitreous injection) significantly reduced the retinal damage. However, amlodipine (30-100microg/kg, i.v. or 0.1-1pmol/eye, intravitreous injection) did not show any protective effects. Treatment with cilnidipine (100microg/kg, i.v.) reduced the retinal damage induced by intravitreous NMDA, but not NOC12. These results suggest that cilnidipine reduces Ca(2+) influx via N-type Ca(2+) channels after NMDA receptors activation and then protects neurons against ischemia-reperfusion injury in the rat retina in vivo. Cilnidipine may be useful as a therapeutic drug against retinal diseases which cause neuronal cell death, such as glaucoma and central retinal vessel occlusion.
authors.affiliation: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Minato-ku, Tokyo, Japan. sakamotok@pharm.kitasato-u.ac.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Takako
authors.initials: T
authors.lastname: Kawakami
authors.forename: Maki
authors.initials: M
authors.lastname: Shimada
authors.forename: Asuwa
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kuwagata
authors.forename: Maki
authors.initials: M
authors.lastname: Saito
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakahara
authors.forename: Kunio
authors.initials: K
authors.lastname: Ishii
mesh_terms: D017311:Amlodipine / Q000627:therapeutic use; D000818:Animals; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000502:physiology; D020864:Calcium Channels, N-Type / Q000502:physiology; D004095:Dihydropyridines / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D020287:In Situ Nick-End Labeling / Q000379:methods; D007267:Injections; D007275:Injections, Intravenous; D008297:Male; D016202:N-Methylaspartate; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009603:Nitroso Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012162:Retinal Degeneration / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D012164:Retinal Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014822:Vitreous Body; D020960:omega-Conotoxins / Q000627:therapeutic use
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D004095:Dihydropyridines; C118603:NOC 12; D018696:Neuroprotective Agents; D009603:Nitroso Compounds; D020960:omega-Conotoxins; D017311:Amlodipine; D016202:N-Methylaspartate; C078452:ziconotide; C065927:cilnidipine