Protective effects of ifenprodil against glutamate-induced neurotoxicity in cultured retinal neurons

Zhang, Shen; Kashii, Satoshi; Yasuyoshi, Hiroki; Kikuchi, Masashi; Honda, Yoshio; Kaneda, Katsuyuki; Sato, Sati; Akaike, Akinori

doi:10.1007/s004170000185

Cited by 6 publications

(7 citation statements)

References 14 publications

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“…Our assays confirmed that glutamate promotes an extensive cell death (77% of total cells) after incubation for 8 h compared with control without glutamate. Interestingly, both compounds 2a and 2b protected the neurons from the glutamate effect (from 77% to 27% and 45%, respectively), values close to that detected for Ifenprodil, in this assay and in the literature (Figure 4) (29,30). No significant effect was observed when incubating these compounds with the neuron cultures without adding glutamate suggesting a safe profile.…”

Section: Resultssupporting

confidence: 86%

“…An earlier work showed that incubation of avian retinal neurons cultures with glutamate (1 m m ) for 8 h promoted an intense cell death (28) that could be prevented by previous culture treatment with 10 μ m ifenprodil (29). Thus, triazolyl‐amidines 2a and 2b were tested for their neuroprotective potential profile by pre‐incubating the purified cultures of avian retinal neurons, prepared as described elsewhere (28), with 100 n m of the compounds solubilized in dimethyl sulfoxide (DMSO) for 48 h in the same culture medium.…”

Section: Methodsmentioning

confidence: 99%

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Molecular Modeling of a Phenyl‐Amidine Class of NMDA Receptor Antagonists and the Rational Design of New Triazolyl‐Amidine Derivatives

et al. 2012

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Recently, many efforts have been made to develop N-methyl-D-aspartic acid receptor antagonists for treating different pathological conditions such as thrombo-embolic stroke, traumatic head injury, Huntington's, Parkinson's, and Alzheimer's diseases). However, as side-effects limit the use of most antagonists, new drugs are still required. In this work, we performed a (quantitative) structure-activity relationship analysis of 17 phenyl-amidine derivatives (1a-1q), reported as N-methyl-D-aspartic acid receptor antagonists, and used this data to rationally design the triazolyl-amidines. The best (quantitative) structure-activity relationship model constructed by multiple linear regression analysis presented high data fitting (R = 0.914) was able to explain 83.6% of the biological data variance (R(2) = 0.836), presented a satisfactory internal predictive ability (Q(2) = 0.609) and contained the descriptors (E(HOMO), Ovality and cLogP). Our assays confirmed that glutamate promotes an extensive cell death in avian neurons (77%) and 2a and 2b protected the neurons from the glutamate effect (from 77% to 27% and 45%, respectively). The results of neurotoxicity and cytotoxicity on Vero cells suggested the favorable profile of 2a and 2b. Also, the molecular modeling used to predict the activity, the interaction with the receptor and the pharmacokinetic and toxicity of the triazolyl-amidines pointed them as a promising class for further exploration as N-methyl-D-aspartic acid receptor antagonists.

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Section: Resultssupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Molecular Modeling of a Phenyl‐Amidine Class of NMDA Receptor Antagonists and the Rational Design of New Triazolyl‐Amidine Derivatives

et al. 2012

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“…However, the neuroprotective effect promoted by ifenprodil was significantly less than that produced by MK‐801. A previous study showed that ifenprodil was equally effective as MK‐801 in protecting embryonic retinal cells in vitro exposed to glutamate (Zhang et al. 2000), suggesting that excitotoxicity was mostly mediated by polyamine binding to NMDA receptors.…”

Section: Discussionmentioning

confidence: 99%

A role for polyamines in retinal ganglion cell excitotoxic death

Pernet¹,

Bourgeois²,

Polo³

2007

Journal of Neurochemistry

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Neuronal death due to excessive activation of N-methyl-D-aspartate (NMDA) receptors is a hallmark of neurodegenerative diseases. The polyamines: putrescine, spermine, and spermidine, bind to specific sites on the NMDA receptor and promote its activation, but their role in NMDA-induced neuronal death is ill defined. In this study, we characterized the role of polyamines in excitotoxic death of retinal ganglion cells (RGCs), a population of central neurons susceptible to NMDAinduced damage. Our data show that endogenous arginase I, the rate limiting enzyme for polyamine biosynthesis, is expressed in the intact, adult retina. Intraocular injection of NMDA visibly increased arginase I expression in Mü ller cells, the predominant glial cell-type in the mammalian retina. Inhibition of polyamine synthesis using di-fluoro-methyl-ornithine (DFMO) was markedly neuroprotective, while injection of exogenous polyamines in conjunction with NMDA exacerbated RGC death. Blockade of the polyamine binding sites on NMDA receptors using the non-competitive antagonist ifenprodil was neuroprotective, suggesting that polyamines contribute to excitotoxic death, at least partly, by binding to NMDA receptors. Importantly, we also demonstrate that NMDA leads to activation of both the Erk1/2 and PI3 K/Akt pathways, but only the PI3 K/Akt kinase was required for di-fluoro-methylornithine-induced RGC survival. In summary, our study reveals that polyamines modulate neuronal death in the retina via different mechanisms that potentiate NMDA-triggered excitotoxicity.

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“…Ifenprodil is known to bind specifically to the NR2B subunit of NMDA receptors (see Supplementary Fig. S2) 28 , and its neuroprotective effect was also reported to be suppressed by spermidine 29 . In contrast, MK-801 binds to the site within the channel pore of the NR1/NR2 receptor complex (see Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Whether pentamidine has a neuroprotective effect in the retina and whether this effect is modified by spermidine is unknown at present. However, it was reported that spermidine suppressed the neuroprotective effect of ifenprodil in rat cultured retinal neurons 29 . The inhibitory effect of ifenprodil on MK-801 binding was also attenuated by spermidine 38 , as also seen with pentamidine.…”

Section: Discussionmentioning

confidence: 97%

Nafamostat and sepimostat identified as novel neuroprotective agents via NR2B N-methyl-D-aspartate receptor antagonism using a rat retinal excitotoxicity model

Fuwa¹,

Kageyama²,

Ohashi³

et al. 2019

Sci Rep

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In addition to its role in the treatment of pancreatitis, the serine protease inhibitor nafamostat exhibits a retinal protective effect. However, the exact mechanisms underlying this effect are unknown. In this study, the neuroprotective effects of nafamostat and its orally active derivative sepimostat against excitotoxicity were further characterised in vitro and in vivo. In primary rat cortical neurons, nafamostat completely suppressed N-methyl-D-aspartate (NMDA)-induced cell death. Intravitreal injection of nafamostat and sepimostat protected the rat retina against NMDA-induced degeneration, whereas the structurally related compounds, gabexate and camostat, did not. The neuroprotective effects of nafamostat and the NR2B antagonist ifenprodil were remarkably suppressed by spermidine, a naturally occurring polyamine that modulates the NR2B subunit. Both nafamostat and sepimostat inhibited [3H]ifenprodil binding to fractionated rat brain membranes. Thus, nafamostat and sepimostat may exert neuroprotective effects against excitotoxic retinal degeneration through NMDA receptor antagonism at the ifenprodil-binding site of the NR2B subunit.

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Protective effects of ifenprodil against glutamate-induced neurotoxicity in cultured retinal neurons

Abstract: The findings suggest that ifenprodil protected the cultured retinal cells we used in this study against glutamate neurotoxicity by its inhibitory action on the polyamine modulatory site of the NMDA receptor.

Cited by 6 publications

References 14 publications

Molecular Modeling of a Phenyl‐Amidine Class of NMDA Receptor Antagonists and the Rational Design of New Triazolyl‐Amidine Derivatives

Molecular Modeling of a Phenyl‐Amidine Class of NMDA Receptor Antagonists and the Rational Design of New Triazolyl‐Amidine Derivatives

A role for polyamines in retinal ganglion cell excitotoxic death

Nafamostat and sepimostat identified as novel neuroprotective agents via NR2B N-methyl-D-aspartate receptor antagonism using a rat retinal excitotoxicity model

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