Histological Protection by Nilvadipine against Neurotoxicity Induced by NOC12, a Nitric Oxide Donor, in the Rat Retina

Abstract

In the present study, we histologically examined the effects of nilvadipine on neuronal injury induced by intravitreal (i.v.) N-methyl-D-aspartate (NMDA) (200 nmol/eye) and intravitreal NOC12 (400 nmol/eye), a nitric oxide donor, in the rat retina. Morphometric evaluation at 7 d after injection of NMDA or NOC12 showed that treatment with nilvadipine (1 mg/kg, i.v.) 15 min prior to injection of NMDA or NOC12 dramatically reduced the retinal damage. These results suggest that nilvadipine protects neurons against excitotoxic injury in the rat retina in vivo at least in part via an antioxidative effect. 1-3)Glutamate is the principal excitatory neurotransmitter in the central nervous system, including retina. 4,5) However, stimulation of some of the glutamate receptor by excess amount of glutamate under pathologic conditions such as hypoxia 6) and ischemia-reperfusion 1) is toxic to neuronal cells. The activation of the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptor, 7,8) followed by excess Ca 2+ influx via NMDA receptor-operated channels is thought to be involved in the predominant mechanism of neuronal excitotoxicity. In fact, excitotoxicity caused by the elevation of glutamate concentration in the retinal extracellular space near the glutamate receptor channels is thought to be one of the mechanisms of neuronal cell death induced by glaucoma. 9) MK-801, an NMDA receptor channel blocker, has been reported to prevent retinal damage induced by retinal ischemia-reperfusion. 10,11) Activation of NMDA receptors depolarizes neurons and subsequently activates voltage-dependent Ca 2+ channels (VDCCs).12,13) We previously reported that cilnidipine, a dual L/N-type Ca 2+ channel blocker, has a beneficial effect on retinal ischemia-reperfusion injury.14) Therefore, activation of VDCCs after stimulation of NMDA receptor is likely involved in the mechanism of retinal excitotoxic injury.Nilvadipine, a dihydropyridine L-type VDCC blocker, has selective and long-lasting effects on cerebral arteries compared with other calcium channel blockers such as nicardipine, nifedipine and diltiazem.15) Nilvadipine was effective in several experimental models of cerebral ischemia. 16,17) In addition, nilvadipine has been reported to inhibit glutamate-induced apoptotic cell death by blocking Ca 2+ influx via L-type VDCC in the purified retinal ganglion cells, 18) and to have beneficial effects on the retinal ischemia-reperfusion injury.19) Nilvadipine increases blood velocity and blood flow in the optic nerve head, choroid and retina of rabbits, and had little effect on systemic blood pressure in subjects without hypertension. 20)In contrast to cilnidipine and nilvadipine, we previously reported that amlodipine, another dihydropyridine L-type VDCC blocker, did not inhibit retinal injury induced by ischemia-reperfusion, 14) suggesting that other mechanism than blocking Ca 2+ influx via L-type VDCC may be important for retinal neuroprotection against excitotoxiciity by L-type VDCC blockers. In fact, clinidipine blocks no...

Combination of Lanosterol and Nilvadipine Nanosuspensions Rescues Lens Opacification in Selenite-Induced Cataractic Rats

“…In the cataract model, the enhanced Ca 2+ in the lens promotes the aggregation of α-crystallin through the activation of calpain, and it has been reported that NIL, an anti-hypertensive lipophilic dihydropyridine-type calcium channel blocker, attenuates the enhanced intracellular Ca 2+ contents, resulting in alleviation of the calpain activation and α-crystallin aggregation [ 17 ]. Furthermore, Kuroki et al have also shown that treatment with NIL protected against toxicity through an anti-oxidative effect [ 37 ]. From these findings, we investigated whether combination with NIL-ONSs supports the anti-cataractogenic activity of LAN-ONSs.…”