Phenytoin, an antiepileptic drug, competitively blocked non-NMDA receptors produced by Xenopus oocytes

Kawano, Hideki; Sashihara, Shunsuke; Morita, Takashi; Ohno, Kiyoshi; Kawamura, Masaru; Yoshii, Kentaro

doi:10.1016/0304-3940(94)90481-2

Cited by 21 publications

(14 citation statements)

References 12 publications

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“…PHT appears to shift the LDH efflux curve to right. This shift agrees with our previous results that PHT competitively blocked electrical responses of non-NMDA receptors produced by brain mRNA-injected Xenopus oocytes (Kawano et al, 1994). Further experiments will clarify the relations between the extent of the block and the protection.…”

Section: Resultssupporting

confidence: 90%

“…Further experiments will clarify the relations between the extent of the block and the protection. Figure 3 shows the protective effect of different concentrations of PHT against the neurotoxicity induced with 100/~M kainate, the Kd value of kainate on the non-NMDA receptors (Kawano et al, 1994). The protective control -7 -6 -5 -4 log PHT (M) Fig.…”

Section: Resultsmentioning

confidence: 98%

“…3). That is, 10ktM PHT significantly protects neurons when a half of non-NMDA receptors there are activated, since the Kd value of kainate on non-NMDA receptors were close to 100ktM (Kawano et al, 1994). As an anticonvulsant, PHT is clinically used at -10#M in CSF without serious neurological side effects (Rogawski and Porter, 1990).…”

Section: Discussionmentioning

confidence: 97%

“…Recently we found that PHT, at clinical concentrations, competitively blocked the non-NMDA receptors, a glutamate receptor subtype, produced by Xenopus oocytes injected with ddY-strain mice whole brain mRNA (Kawano et al, 1994). These results imply that PHT is clinically effective against the excitotoxicity.…”

Section: Introductionmentioning

confidence: 89%

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Phenytoin protected mouse cortical cell cultures against neurotoxicity induced by kainate but not by NMDA

et al. 1997

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Summary. Phenytoin (PHT) protected cultured mouse cortex neurons against kainate-induced excitotoxicity, but failed to protect against the Nmethyl-D-aspartate (NMDA)-induced excitotoxicity. The voltage-clamp experiments showed that PHT significantly blocked kainate-induced currents but did not block NMDA-induced currents in the cultured neurons. These results indicate that PHT protects the cultures by blocking non-NMDA receptors and suggest that PHT has clinical efficacy against neuronal cell death through the excessive stimulation of non-NMDA receptors.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 89%

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Phenytoin protected mouse cortical cell cultures against neurotoxicity induced by kainate but not by NMDA

et al. 1997

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“…Phenytoin is an anticonvulsant whose mechanism of action includes blocking cellular responses to excitatory amino acids (Wamil and Mclean, 1993;Kawano et al, 1994). Moreover, calciummediated cellular functions (protein phosphorylation, neurotransmitter release) and calcium-dependent depolarization, both associated with neuronal death, have been shown to be arrested by phenytoin (De Lorenzo, 1977;Gage et al, 1980).…”

mentioning

confidence: 97%

Effects of phenytoin on memory, cognition and brain structure in post-traumatic stress disorder: a pilot study

et al. 2005

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Phenytoin (Dilantin) is an anticonvulsant used in the treatment of epilepsy. It is believed to act by modulation of glutamatergic transmission. Because the neurobiology of post-traumatic stress disorder (PTSD) has been hypothesized to involve alterations in glutamatergic transmission with subsequention neurotoxicity, we assessed the effects of phenytoin on cognition and brain structure in PTSD patients. Phenytoin was administered in an open label fashion for 3 months to nine adult patients with PTSD related to a variety of traumas, including early abuse, combat and car accidents. Subjects underwent magnetic resonance imaging for measurement of whole brain and hippocampal volume, and neuropsychological testing of memory and cognition, before and after treatment. Phenytoin treatment resulted in a significant 6% increase in right brain volume (p < 0.05). Increased hippocampal volume was correlated with reductions in symptom severity as measured by the Clinician Administered PTSD Scale and improvements in executive function as measured by the Trails test. However, treatment associated improvements in memory and cognition did not achieve statistical significance. These findings suggest that phenytoin treatment may be associated with changes in brain structure in patients with PTSD.

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Open channel block of NMDA receptors by conformationally restricted analogs of milnacipran and their protective effect against NMDA-induced neurotoxicity

Noguchi

Ishii

Ohtubo

et al. 1999

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We investigated the blocking effect of the conformationally restricted analogs of milnacipran on NMDA receptors by recording the whole-cell currents of Xenopus oocytes injected with rat brain mRNA and the single channel currents of cultured hippocampal neurons under voltage-clamp conditions. Their protective effect against excitotoxicity was also investigated on cultured cortex neurons. All conformationally restricted analogs examined blocked activated NMDA receptors, though their structures were quite different from known NMDA receptor blockers. The analogs with a (1S, 2R, 1'S)-configuration such as PPDC ((1S, 2R)-1-phenyl-2[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide+ ++) had lower IC50 values than those with other configurations. The empirical Hill coefficients for each compound were close to unity, indicating a 1:1 stoichiometry for the block. PPDC decreased the maximum responses to both N-methyl D-aspartate (NMDA) and glycine without altering their dissociation constants. The blocking effect was enhanced on hyperpolarization. PPDC had no effects on other glutamate receptor subtypes (AMPA, kainate, and metabotropic glutamate receptors) or other neurotransmitter receptors (GABA(A), 5HT2C, and AChM1 receptors) produced by the oocytes. PPDC decreased the mean open time of NMDA receptors without decreasing their elementary conductance. The microscopic blocking rate constant was 2.8x10(7) M(-1)s(-1). The macroscopic unblocking rate constant of PPDC was much faster than that of MK-801. Only the analogs with the (1S, 2R, 1'S)-configuration protected the cultures against NMDA-induced neurotoxicity, though they failed to protect against kainate-induced neurotoxicity. These results show that conformationally restricted analogs, at least PPDC, selectively blocked open channels of NMDA receptors.

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Phenytoin, an antiepileptic drug, competitively blocked non-NMDA receptors produced by Xenopus oocytes

Cited by 21 publications

References 12 publications

Phenytoin protected mouse cortical cell cultures against neurotoxicity induced by kainate but not by NMDA

Phenytoin protected mouse cortical cell cultures against neurotoxicity induced by kainate but not by NMDA

Effects of phenytoin on memory, cognition and brain structure in post-traumatic stress disorder: a pilot study

Open channel block of NMDA receptors by conformationally restricted analogs of milnacipran and their protective effect against NMDA-induced neurotoxicity

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