Protective Effects of Flunarizine on Ischemic Injury in the Rat Retina

Takahashi, Kanji; Lam, Tsun Ip; Edward, Deepak P.; Büchi, Ernst R.; Tso, Mark O.M.

doi:10.1001/archopht.1992.01080180134041

Cited by 103 publications

(65 citation statements)

References 30 publications

(1 reference statement)

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“…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. It has been shown that dual T-and L-type VDCC blockers, such as flunarizine 30) and lomerizine, 31) pre- vented death of retinal neurons in a transient retinal ischemia model and glutamate-induced neurotoxicity in vitro. 31) Recently, nilvadipine was reported to block both T-and L-type VDCCs in isolated rat hippocampal CA1 pyramidal neurons.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…Isso pode ser feito através da utilização de drogas que ajam em uma ou mais etapas da cascata que leva ao aumento extracelular de glutamato. Algumas delas já vem sendo estudadas há algum tempo, como é o caso dos redutores de radicais livres (21) , substâncias que agem no receptor de glutamato (22) , antagonistas dos receptores opiói-des (23) , agentes dopaminérgicos (24) , agentes adrenosinérgi-cos (25) ou antagonistas do cálcio (26) . A possibilidade de proteção neuro-retiniana quando da utilização de substitutos do humor vítreo já é alvo de investigações pelos autores.…”

Section: Discussionunclassified

Toxicidade retiniana do gás hexafluoreto de enxofre, líquido perfluorocarbono, ar e solução salina balanceada em olhos de coelhos

Souza¹,

Aihara²,

Souza³

et al. 2005

Arq. Bras. Oftalmol.

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Descritores: Retina/lesões; Descolamento retiniano/cirurgia; Corpo vítreo/efeito de drogas; Hexafluoreto de enxofre/toxicidade; Líquido perfluorocarbono/toxicidade; Ácido glutâmico/ toxicidade; Coelhos INTRODUÇÃONos últimos 50 anos, grandes avanços ocorreram para a elucidação da patogênese e tratamento do descolamento de retina (DR), principalmente depois que Schepens (1) desenvolveu e popularizou o uso da oftalmoscopia binocular indireta. Desde então houve uma revolução nas formas de tratamento do DR com o aprimoramento de técnicas já existentes e o aparecimento de outras (2)(3)(4) . Juntamente com estes incrementos, novas substâncias foram adicionadas ao arsenal cirúrgico do DR. O gás hexafluoreto de enxoToxicidade retiniana do gás hexafluoreto de enxofre, líquido perfluorocarbono, ar e solução salina balanceada em olhos de coelhos Objetivo: Determinar a toxicidade retiniana do gás hexafluoreto de enxofre, líquido perfluorocarbono e solução salina balanceada em olhos de coelhos. Métodos: Foram analisados 22 olhos de 16 coelhos albinos da raça Nova Zelândia divididos em grupos: solução salina balanceada (7 olhos); hexafluoreto de enxofre (4 olhos), líquido perfluorocarbono (5 olhos) e controle (6 olhos). Após aspiração de 0,3 ml de humor vítreo, foi injetado a mesma quantidade de solução salina balanceada ou hexafluoreto de enxofre a 100% ou líquido perfluorocarbono na cavidade vítrea. O grupo controle não foi submetido a nenhum procedimento. Três semanas depois o humor vítreo foi coletado para análise bioquímica e o olho enucleado para análise histológica. Resultados: Os olhos dos animais que receberam injeção de hexafluoreto de enxofre e líquido perfluorocarbono mostraram significativo aumento da concentração vítrea de glutamato quando comparado aos grupos solução salina balanceada e controle (p<0,05). A análise histológica confirmou os achados bioquímicos mostrando alterações como disrupção do segmento externo dos fotorreceptores, afilamento das camadas plexiforme interna e externa, diminuição do número de núcleos na camada ganglionar e nuclear interna, edema e presença de macrófagos nas camadas superficiais. Estas alterações foram mais acentuadas no grupo líquido de perfluorocarbono em relação ao grupo hexafluoreto de enxofre. Não foram observadas alterações histológicas retinianas significativas nos grupos solução salina balanceada e controle. Conclusão: A presença de gás hexafluoreto de enxofre e líquido perfluorocarbono na câmara vítrea se mostrou potencialmente tóxica para a retina de coelhos quando comparado ao grupo controle e solução salina balanceada.

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“…Flunarizine, an intracellular calcium overload blocker, partially protects against ischemic neuronal cell death. The same drug also reduces photoreceptor cell death in light induced retinal degeneration (Takahashi et al, 1992). Treatment with aurintricarboxylic acid also reduces the degeneration (Lam et al, 1995).…”

Section: Apoptosis Of the Retina Induced By Ischemia-reperfusion Leamentioning

confidence: 95%

Apoptosis of the mammalian retina and lens

Papermaster

1997

Cell Death Differ

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Although retinal neurons usually last the entire lifetime of an individual, many innate genetic and developmental errors and external stimuli can reduce their longevity leading to loss of visual acuity or blindness. Similarly, the lens, largely composed of denucleated fiber cells must remain transparent for life if vision is to remain clear. Apoptosis of retinal neurons and newly generated lens fiber cells contributes to retinal degeneration and cataract formation, respectively, in both humans and experimental mammals. The apoptosis is triggered by many stimuli in addition to inherited mutations and may be amenable to pharmacologic amelioration. These studies not only provide new clinical insights but also the opportunity to investigate the molecular pathways leading to apoptosis in an organ that is not required for survival. The eye, becomes, therefore, an important organ for evaluation of theories of apoptosis in vivo.

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Protective Effects of Flunarizine on Ischemic Injury in the Rat Retina

Cited by 103 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

Toxicidade retiniana do gás hexafluoreto de enxofre, líquido perfluorocarbono, ar e solução salina balanceada em olhos de coelhos

Apoptosis of the mammalian retina and lens

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