Direct Inhibition of N-Methyl-D-Aspartate (NMDA)-Receptor Function by Antiglaucomatous β-Antagonists

Nagata, Tatsuo; Ueno, S.; Morita, Hirofumi; Kubota, Toshiaki; Toyohira, Yumiko; Tsutsui, Masato; Tawara, Akihiko; Yanagihara, Nobuyuki

doi:10.1254/jphs.fp0071776

Cited by 9 publications

(5 citation statements)

References 41 publications

(33 reference statements)

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“…Receptor-specific currents were activated by the coagonists glutamate and glycine, which had EC 50 values are in a similar range as those reported previously for human NMDA receptors (Hess et al 1996;Nagata et al 2008;Hedegaard et al 2011). As expected, the non-competitive antagonists (+)MK-801, PCP, ketamine and memantine showed potent voltage-dependent block at receptors composed of the NR1 and the NR2A or the NR2B subunit.…”

Section: Discussionsupporting

confidence: 85%

Potencies and unblocking kinetic properties of antagonists at recombinant human NMDA receptors in a Xenopus oocytes model

Heusler

Tourette

Cussac

2015

Naunyn-Schmiedeberg's Arch Pharmacol

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N-methyl-D-aspartate (NMDA) receptor channels are implicated in a wide range of physiological and pathophysiological processes, and a large number of pharmacological agents have been introduced that target the receptor via diverse mechanisms of action. Amongst others, subunit selectivity (in particular for the NR2B receptor subunit) and rapid unblocking kinetics have been put forward as favourable pharmacological properties of NMDA receptor-targeting drugs. Here, we describe a pharmacological characterization of human recombinant NMDA receptors expressed in Xenopus oocytes in an electrophysiological set-up. Using this approach, we compare inhibitor potencies of several known NMDA receptor ligands as well as unblocking kinetic properties of selected compounds. All compounds tested had similar potencies at receptors containing NR2A or NR2B receptors with the exception of traxoprodil, which was selective for NR2B. The rank order of potency was (+)MK-801 > phencyclidine (PCP) ≈ traxoprodil > memantine ≈ ketamine > duloxetine. In line with its proposed rapid dissociation properties, the relatively well-tolerated drug memantine exhibits markedly faster unblocking than ketamine and PCP, similar to the low-affinity compound, duloxetine. Electrophysiological recording in Xenopus oocytes thus allows a relatively convenient comparison of key pharmacological parameters at recombinant human NMDA receptors.

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Section: Discussionsupporting

confidence: 85%

Potencies and unblocking kinetic properties of antagonists at recombinant human NMDA receptors in a Xenopus oocytes model

Heusler

Tourette

Cussac

2015

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Lowering IOP is the current main treatment for glaucoma, yet disease progression continues to occur even in patients with significant IOP reduction[17]. Therefore lowering IOP is inadequate for glaucoma patients [12,18]. Efforts have been made to attempt to discover appropriate drugs or chemicals (neuroprotectants) that can be taken orally to slow down retinal ganglion cell death and have negligible side-effects [19].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effects of bis(7)-tacrine against glutamate-induced retinal ganglion cells damage

Fang

Wang

et al. 2010

BMC Neurosci

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BackgroundGlutamate-mediated excitotoxicity, primarily through N-methyl-D-aspartate (NMDA) receptors, may be an important cause of retinal ganglion cells (RGCs) death in glaucoma and several other retinal diseases. Bis(7)-tacrine is a noncompetitive NMDA receptors antagonist that can prevent glutamate-induced hippocampal neurons damage. We tested the effects of bis(7)-tacrine against glutamate-induced rat RGCs damage in vitro and in vivo.ResultsIn cultured neonatal rats RGCs, the MTT assay showed that glutamate induced a concentration- and time-dependent toxicity. Bis(7)-tacrine and memantine prevented glutamate-induced cell death in a concentration-dependent manner with IC50 values of 0.028 μM and 0.834 μM, respectively. The anti-apoptosis effects of bis(7)-tacrine were confirmed by annexin V-FITC/PI staining. In vivo, TUNEL analysis and retrograde labeling analysis found that pretreatment with bis(7)-tacrine(0.2 mg/kg) induced a significant neuroprotective effect against glutamate-induced RGCs damage.ConclusionsOur results showed that bis(7)-tacrine had neuroprotective effects against glutamate-induced RGCs damage in vitro and in vivo, possibly through the drug's anti-NMDA receptor effects. These findings make bis(7)-tacrine potentially useful for treating a variety of ischemic or traumatic retinopathies inclusive of glaucoma.

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“…Interstingly, betaxolol (β-adrenoceptor antagonist) has been known to attenuate the N-methyl-D-aspartate (NMDA) induced Ca +2 influx by calcium channel blocking. It also interacts with NMDA receptors [94]. The result is reduction of Ca +2 influx and IOP lowering.…”

Section: Glaucoma Inhibitorsmentioning

confidence: 99%

Discovery of novel inhibitors for the treatment of glaucoma

Cholkar

Trinh

Pal

et al. 2015

Expert Opinion on Drug Discovery

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Introduction Glaucoma is a neurodegenerative disease with heterogeneous causes that result in retinal ganglionic cell death (RGC). The discovery of ocular anti-hypertensives has shifted glaucoma therapy, largely, from surgery to medical intervention. Indeed, several intraocular pressure (IOP) lowering drugs, with different mechanisms of action and RGC protective property, have been developed. Areas covered In this review, the authors discuss the main new class of kinase inhibitors used as glaucoma treatments, which lower IOP by enhancing drainage and/or lowering production of aqueous humor. The authors include novel inhibitors under preclinical evaluation and investigation for their anti-glaucoma treatment. Additionally, the authors look at treatments that are in clinics now and which may be available in the near future. Expert opinion Treatment of glaucoma remains challenging because the exact cause is yet to be delineated. Neuroprotection to the optic nerve head is undisputable. The novel ROCK inhibitors have the capacity to lower IOP and provide optic nerve and RGC protection. In particular, the S-isomer of roscovitine has the capacity to lower IOP and provide neuroprotection. Combinations of selected drugs, which can provide maximal and sustained IOP lowering effects as well as neuroprotection, are paramount to the prevention of glaucoma progression. In the near future, microRNA intervention may be considered as a potential therapeutic target.

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Direct Inhibition of N-Methyl-D-Aspartate (NMDA)-Receptor Function by Antiglaucomatous β-Antagonists

Cited by 9 publications

References 41 publications

Potencies and unblocking kinetic properties of antagonists at recombinant human NMDA receptors in a Xenopus oocytes model

Potencies and unblocking kinetic properties of antagonists at recombinant human NMDA receptors in a Xenopus oocytes model

Neuroprotective effects of bis(7)-tacrine against glutamate-induced retinal ganglion cells damage

Discovery of novel inhibitors for the treatment of glaucoma

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