Protective effect of nilvadipine against glutamate neurotoxicity in purified retinal ganglion cells

Otori, Yasumasa; Kusaka, Shunji; Kawasaki, Atsushi; Morimura, Hiroyuki; Miki, Atsuya; Tano, Yasuo

doi:10.1016/s0006-8993(02)03951-3

Cited by 40 publications

(33 citation statements)

References 30 publications

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“…It has been demonstrated that nilvadipine ameliorates glutamateinduced cell death of purified RGCs, although other calcium channel blockers, nifedipine and diltiazem, do not. 18) In addition, increase of the glutamate-evoked intracellular Ca 2+ concentration was significantly reduced by nilvadipine, but not nifedipine and diltiazem, in the purified RGCs. 18) We reported that amlodipine did not inhibit retinal injury induced by ischemia-reperfusion.…”

Section: Discussionmentioning

confidence: 83%

“…18) In addition, increase of the glutamate-evoked intracellular Ca 2+ concentration was significantly reduced by nilvadipine, but not nifedipine and diltiazem, in the purified RGCs. 18) We reported that amlodipine did not inhibit retinal injury induced by ischemia-reperfusion. 14) These data suggest that the blocking effect on Ca 2+ influx via L-type VDCC may not be sufficient for retinal neuroprotection against excitotoxiciity by L-type VDCC blockers.…”

Section: Discussionmentioning

confidence: 83%

“…However, another report demonstrated that nilvadipine (10-100 nM) protected against the glutamate-induced neurotoxicity in the purified retinal ganglion cells. 18) This report suggests that the effect of the drug on hemodynamics is not necessary for its retinal protective effect.…”

Section: Discussionmentioning

confidence: 85%

“…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.…”

Section: -3)mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Kuroki

Mori

Nakahara

et al. 2014

Biological & Pharmaceutical Bulletin

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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...

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 85%

Section: -3)mentioning

confidence: 99%

mentioning

confidence: 99%

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

Kuroki

Mori

Nakahara

et al. 2014

Biological & Pharmaceutical Bulletin

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Dead cell counts during serum cultivation are underestimated by the fluorescent live/dead assay

Zhou

Cui

Urban

2011

Biotechnology Journal

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The live/dead fluorescent assay provides a quick method for assessing the proportion of live and dead cells in cell culture systems or tissues and is widely used. Dead cells are detected by the fluorescence produced when propidium iodide (PI) binds to DNA; PI and similar molecules are excluded from live cells but can penetrate dead cells because of their loss of membrane integrity. Here we investigated the effect of serum in the culture medium on the reliability of the method. We assessed viability of chondrocytes with/without serum using both a live/dead assay kit and also trypan blue staining. We found that after 2 days of culture, the DNA-binding dye PI could no longer detect dead cells if serum was present but they were readily detected in serum-free medium or if an inhibitor to DNase I was added to the serum-containing medium. Dead cells could be detected by trypan blue staining in all cultures. Hence dead cells are no longer detected as the DNase I present in serum degrades their DNA. DNA-binding dyes may thus not give a reliable estimate of the number of dead cells in systems that have been cultured in the presence of serum for several days.

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Localization of inositol 1,4,5‐trisphosphate receptors in mouse retinal ganglion cells

Mafe

Gregg

Medina-Ortiz

et al. 2006

J of Neuroscience Research

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Inositol 1,4,5-trisphosphate receptors (IP(3)R) are ligand-gated intracellular Ca(2+)channels that mediate release of Ca(2+) from intracellular stores into the cytosol on activation by second messenger IP(3.). Similarly, IP(3)R mediated changes in cytosolic Ca(2+) concentrations control neuronal functions ranging from synaptic transmission to differentiation and apoptosis. IP(3)R-generated cytosolic Ca(2+) transients also control intracellular Ca(2+) release and subsequent retinal ganglion cell (RGC) physiology and pathophysiology. The distribution of IP(3)R isotypes in primary adult mouse RGC cultures was determined to identify molecular substrates of IP(3)R mediated signaling in these neurons. Immunocytochemical labeling of IP(3)Rs in retinal sections and cultured RGCs was carried out using isoform specific antibodies and was detected with fluorescence microscopy. RGCs were identified by the use of morphologic criteria and RGC-specific immunocytochemical markers, neurofilament 68 kDa, Thy 1.1, and Thy 1.2. RGC morphology and immunoreactivity to neurofilament 68 kDa and Thy 1.1 or Thy 1.2 were identified in both RGC primary cultures and tissue cryosections. RGCs showed localization on intracellular membranes with a differential distribution of IP(3)R isoforms 1, 2, and 3. IP(3)R Types 1 and 3 were detected intracellularly throughout the cell whereas Type 2 was expressed predominantly in soma. Expression of all three IP(3)Rs by RGCs indicates that all IP(3)R types potentially play a role in Ca(2+) homeostasis and Ca(2+) signaling in these cells. Differential localization of IP(3) receptor subtypes in combination with biophysical properties of IP(3)R types may be an important molecular mechanism by which RGCs organize their cytosolic Ca(2+) signals.

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Protective effect of nilvadipine against glutamate neurotoxicity in purified retinal ganglion cells

Cited by 40 publications

References 30 publications

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

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

Dead cell counts during serum cultivation are underestimated by the fluorescent live/dead assay

Localization of inositol 1,4,5‐trisphosphate receptors in mouse retinal ganglion cells

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