Histological protection by cilnidipine, a dual L/N-type Ca2+ channel blocker, against neurotoxicity induced by ischemia–reperfusion in rat retina

Although a blockade or lack of N-type Ca2+ 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 Ca2+ channel blocker, cilnidipine. We histologically examined the effects of cilnidipine on neuronal injury induced by ischemia–reperfusion, intravitreous N-methyl-d-aspartate (NMDA) (200 nmol/eye) and intravitreous NOC12 (400 nmol/eye), an nitric oxide donor, in the rat retina, and compared its effects with those of ω-conotoxin MV IIA, an N-type Ca2+ channel blocker and amlodipine, an L-type Ca2+ channel blocker. Morphometric evaluation at 7 days after ischemia–reperfusion showed that treatment with cilnidipine (100 μg/kg, i.v. or 0.5 pmol/eye, intravitreous injection) prior to ischemia dramatically reduced the retinal damage. Treatment with ω-conotoxin MV IIA before ischemia (0.1 pmol/eye, intravitreous injection) significantly reduced the retinal damage. However, amlodipine (30–100 μg/kg, i.v. or 0.1–1 pmol/eye, intravitreous injection) did not show any protective effects. Treatment with cilnidipine (100 μg/kg, i.v.) reduced the retinal damage induced by intravitreous NMDA, but not NOC12. These results suggest that cilnidipine reduces Ca2+ influx via N-type Ca2+ 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.