May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Direct Inhibition of the Function of N-methyl-D-aspartate (NMDA) Receptors by Antiglaucoma Drugs: A Possible Therapeutic Benefit for the Treatment of Glaucoma
Author Affiliations & Notes
  • N. Tatsuo
    Univ of Occup and Environ Health, Kitakyusyu, Japan
    Ophtalmol,
  • S. Ueno
    Univ of Occup and Environ Health, Kitakyusyu, Japan
    Pharmacol,
  • H. Morita
    Univ of Occup and Environ Health, Kitakyusyu, Japan
    Ophtalmol,
  • T. Kubota
    Univ of Occup and Environ Health, Kitakyusyu, Japan
    Ophtalmol,
  • N. Yanagihara
    Univ of Occup and Environ Health, Kitakyusyu, Japan
    Pharmacol,
  • A. Tawara
    Univ of Occup and Environ Health, Kitakyusyu, Japan
    Ophtalmol,
  • Footnotes
    Commercial Relationships N. Tatsuo, None; S. Ueno, None; H. Morita, None; T. Kubota, None; N. Yanagihara, None; A. Tawara, None.
  • Footnotes
    Support This work was supported in part by grant-in-Aid #16591777 for Scientific Research from the Ministry of Education, Science, Sports and Culture of the Japanease Government.
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 3944. doi:
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      N. Tatsuo, S. Ueno, H. Morita, T. Kubota, N. Yanagihara, A. Tawara; Direct Inhibition of the Function of N-methyl-D-aspartate (NMDA) Receptors by Antiglaucoma Drugs: A Possible Therapeutic Benefit for the Treatment of Glaucoma. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3944.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose:: It has been suggested that neurodegeneration in glaucoma depends on apoptosis of retinal ganglion cells, which is partly related to glutamate overactivation of NMDA receptors. Therefore, antiglaucoma drugs that can produce an inhibitory effect on NMDA receptor activation, in addition to the lowering effect of intraocular pressure, would be more useful for preventing progression of glaucoma. In the present study, we investigated the effects of antiglaucoma drugs on NMDA recepotor function, and on cell death induced by NMDA receptor overactivation.

Methods:: We expressed human wild-type or mutant NR1a together with wild-type NR2A NMDA receptor subunits in Xenopus oocytes, and studied the direct effects of antiglaucoma drugs (timolol, betaxolol, pilocarpine and latanoprost) on glutamate-induced currents using two-electrode voltage clamp technique. For some of drugs we also examined the protective effect against the death of NR1a/NR2A-expressing oocytes induced by glutamate activation.

Results:: At NR1a/NR2A receptors, timolol and betaxolol significantly inhibited glutamate-evoked currents (up to 55% of the control), whereas less inhibition (up to 83%) was obtained by pilocarpine, at the concentrations from 10 to 100 µM. No significant effect was observed by latanoprost (from 1 nM to 1 µM). Moreover, the death of oocytes expressing NR1a/NR2A was induced by the addition of glutamate into the oocyte medium (28% of viability after 24 hr), and the viability was significantly improved (58% after 24 hr) in the presence of timolol or betaxolol. On the other hand, this inhibitory effect of timolol and betaxolol was noncompetitive with respect to glutamate, and the mutations that changed Asn616 of NR1a subunit, a critical residue for Mg2+ block of NMDA receptors, to Arg (N616R) or Gln (N616Q) almost eliminated the effects of timolol and betaxolol, as well as the blocking effect of Mg2+.

Conclusions:: These results suggest an additional effect of timolol and betaxolol that directly inhibits NMDA receptor function possibly via N616 at NR1a subunit, resulting in producing a protective effect against cell death induced by NMDA receptor overactivation. Our findings could be of use for the protection from retinal ganglion cell death in glaucoma.

Keywords: receptors: pharmacology/physiology • drug toxicity/drug effects • neuroprotection 
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