Effects of water viscosity and tongue ingestion site on tongue pressure during food bolus propulsion.

The purpose of this study was to help provide data to help to implement effective rehabilitation following surgery for oral cancer by comparing tongue pressure production for water and thickened water from the anterior and posterior parts of the tongue during swallowing. Ten healthy volunteers (7 men, 3 women; age 27.6 ± 1.5 years) participated in the experiments. Tongue pressure during 3 mL water and 3 mL thickened water at the anterior and posterior tongue during swallowing was measured using a sensor sheet system with five measuring points on the hard palate. The sequential order of the points, maximal magnitude and duration of tongue pressure at each point were compared based on water viscosity and tongue ingestion site. There was a common pattern in the sequential order of tongue pressure generation among the two swallowing conditions. The maximal magnitude of tongue pressure was significantly higher when swallowing thickened water than when swallowing water at all points except for the anterior-median and mid-median part. Moreover, the pressure at all sites during posterior ingestions was significantly lower than that during anterior ingestion. The present results provide mean values of tongue pressure during voluntarily triggered swallowing in anterior ingestion and posterior ingestion in young, healthy dentate individuals; these values can be clinically referenced for tongue pressure measurement in the evaluation of patients with dysphagia. The use of reference values may help streamline the diagnosis, treatment and rehabilitation of dysphagia.

Optimal contrast enhancement liquid for dynamic MRI of swallowing.

Several dynamic magnetic resonance imaging (MRI) techniques to observe swallowing and their parameters have been reported. Although these studies used several contrast enhancement liquids, no studies were conducted to investigate the most suitable liquids. The purpose of this study was to identify the optimal contrast enhancement liquid for dynamic MRI of swallowing. MRI was performed using a new sequence consisting of true fast imaging with steady-state precession, generalised auto-calibrating partially parallel acquisition and a keyhole imaging technique. Seven liquids were studied, including pure distilled water, distilled water with thickener at 10, 20 and 30 mg mL(-1) concentrations and oral MRI contrast medium at 1, 2 or 3 mg mL(-1) . Distilled water showed the highest signal intensity. There were statistically significant differences among the following contrast media: distilled water with thickener at 20 mg mL(-1) and the oral MRI contrast medium at 2 mg mL(-1) and 1 mg mL(-1) . It can be concluded that the optimal liquid for dynamic MRI of swallowing is a water-based substance that allows variations in viscosity.

Effects of varying fixed lingual apex positions on tongue pressure during straw drinking.

We investigated the impact of tongue-thrusting on lingual pressure during fluid intake with a straw. In this study, 12 healthy young dentate individuals (two women and 10 men; 19-33 years) were instructed to drink 15 mL of water with a regular drinking straw at 37 °C, when indicated by the investigator. Participants drank after adjusting tongue position to one of the following patterns: (i) Holding the tip of the straw between the lips (Normal Position: NP), (ii) Sticking out the tongue to the vermilion zone of the lower lip and inserting the straw 1 cm past the front teeth (Tongue-thrusting Position: TP). Five recordings were conducted for each participant in a randomised order. To measure tongue pressure during swallowing, a specially designed 0.1-mm thick sensor sheet (Nitta, Osaka, Japan) with a tactile system for measurement of pressure distribution (I-SCAN; Nitta) was used. Duration, maximal magnitude and integrated value of tongue pressure were analysed based on the wave of tongue pressure recorded while water was swallowed. Magnitude, duration and integrated value of tongue pressure were significantly lower in TP than in NP at the median line (Ch1-3). Magnitude and integrated value of tongue pressure at the lateral part of the tongue (Ch5) were significantly lower in TP than in NP. When duration, maximal magnitude and integrated values were compared by channel, no significant differences were observed in NP, but a significant difference was found between Ch3 and the lateral areas Ch4/Ch 5 in TP. When the tongue was thrust forward, movement dynamics of the entire tongue changed and influenced contact between the tongue and palate during liquid intake with a straw. The impact was noticeably weaker on the median line than in lateral areas.

Charge-state-derivation ion detection using a super-conducting nanostructure device for mass spectrometry.

Mass spectrometry (MS) is a method of analyzing ions based on their mass/charge (m/z) ratios. The m/z peak identification requires speculation on the ionic unit-charge states. This problem can be solved by using superconducting junction devices to measure the kinetic energies of single molecules. However, the kinetic energy measurement is followed by the dead time of 1-20 µs, which is fatally slow for modern high-resolution time-of-flight (TOF) analyzers. In this paper, we demonstrate that a superconducting nano-stripline detector (SSLD) composed of a 10-nm-thick and 800-nm-wide NbN strip realizes the charge-state derivation, and furthermore satisfies the ideal MS detector specifications such as a nano-second response, a short recovery time, a wide mass range, and no noise.

Molecular cloning and brain distribution of three types of gonadotropin-releasing hormone from mummichog Fundulus heteroclitus.

Complementary DNAs encoding gonadotropin-releasing hormone (GnRH) precursors were cloned from the mummichog Fundulus heteroclitus brain, showing that this species has three GnRH forms, i.e. medaka Oryzias latipes GnRH (mdGnRH), chicken GnRH-II (cGnRH-II) and Atlantic salmon Salmo salar GnRH (sGnRH). The F. heteroclitus prepro GnRHs have common structural architectures of vertebrate GnRHs, consisting of the signal peptide, 10 amino acids of mature peptide, GKR sequence and GnRH-associated peptide (GAP). Phylogenetic analysis of fish prepro GnRHs showed that F. heteroclitus mdGnRH is a homologue of sbGnRHs and mdGnRHs of other acanthopterygian. Quantitative real-time PCR revealed that mdGnRH was abundantly expressed in the olfactory bulb and in olfactory lobe areas and is expressed in the pituitary. The cGnRH-II was mainly expressed in the midbrain and interbrain areas, and the sGnRH was expressed not only in the olfactory bulb but also in other regions of the brain. These results suggest that the mdGnRH is involved in the stimulation of gonadotrophs in the pituitary, whereas cGnRH-II and sGnRH are involved in neurotransmission and neuromodulation.

Molecular cloning and localization of the luteinizing hormone beta subunit and glycoprotein hormone alpha subunit from Japanese anchovy Engraulis japonicus.

Although Clupeiformes contain many economically important species, there is limited information on their reproductive physiology. To obtain more insight into reproductive mechanisms in clupeiform fishes, molecular cloning of the Japanese anchovy Engraulis japonicus luteinizing hormone beta (LHbeta) and glycoprotein hormone alpha (GPHalpha) subunits, and immunocytochemistry of gonadotrophs in the pituitary using antisera raised against the synthetic peptides for both subunits were carried out. The cDNAs for LHbeta and GPHalpha subunits consisted of 963 and 535 nucleotides encoding 141 and 122 amino acids, respectively. The deduced amino acid sequences of the E. japonicus LHbeta subunit showed a 60% similarity to the Pacific herring Clupea pallasii LHbeta subunit and 24-31% similarities to FSHbeta subunits of other fish species. The E. japonicus GPHalpha subunit showed 52-57% similarities to anguilliform and cypriniform GPHalpha subunits. Both the subunits have typical structural characteristics of each subunit such as N-linked glycosylation sites, conserved cysteine residues and highly conserved short amino acid sequences. These results indicate that cDNAs cloned in this study encode the E. japonicus LHbeta and GPHalpha subunits. Reverse-transcription polymerase chain reaction (RT-PCR) revealed that both the LHbeta and GPHalpha subunit genes were abundantly expressed in the pituitary, and the GPHalpha subunit was observed to be weakly expressed in the extrapituitary tissues. Immunocytochemistry of the E. japonicus pituitary showed that cells that immunoreacted with antiserum against the LHbeta subunit were distributed in the peripheral regions of proximal pars distalis, and these cells were also immunoreactive to antiserum against the GPHalpha subunit. An abundant number of both LHbeta and GPHalpha cells in the pituitary of matured fish were observed, in comparison with immature fish. These results indicate that the E. japonicus LH is involved in the final reproductive maturation as well as those of other teleosts.

Enhanced expression of a glyceraldehyde-3-phosphate dehydrogenase gene in human lung cancers.

We have shown that a Mr 37,000 protein whose expression is strongly enhanced in human lung cancer tissues is the subunit of glyceraldehyde-3-phosphate (GAPDH, EC 1.2.1.12). We have isolated a GAPDH complementary DNA from human lung cancer cells and deduced the complete amino acid sequence of the encoded protein. The structure of the lung cancer GAPDH is identical to that of liver GAPDH. In addition, we have found that GAPDH mRNA expression is markedly increased in human lung cancer tissues. These results disclose a molecular basis of increased glycolysis in cancer cells and reveal an important role of energy creating reaction in cancer cell growth.

Mode of action of a new indolocarbazole anticancer agent, J-107088, targeting topoisomerase I.

J-107088 [6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo[3,4-c]-carb azo le-5,7(6H)-dione] is a new derivative of NB-506, an indolocarbazole antitumor agent. J-107088 induced single-strand DNA cleavage only in the presence of topoisomerase I (top1) more effectively than NB-506 or camptothecin. The preferable sequences of the DNA cleaved by J-107088 were C/T / G as in the case of NB-506. This base-preference of J-107088 in top1-mediated cleavage was different from that of camptothecin, which was T / G/A. top1 poisons stabilize the complex between DNA and top1 (cleavable complex). This cleavable complex is released on addition of a high concentration of monovalent cation or removal of top1 poisons. The complex induced by J-107088 was quite stable; it was scarcely released on the addition of NaCl or dilution of J-107088, contrary to the case with camptothecin and NB-506. J-107088-inducing complexes were also stable in cultured cells, when the compound was added to the culture medium. These unique in vitro activities of J-107088 on top1 that differed from those of camptothecin and NB-506 may be relevant to its more potent in vivo antitumor efficacy in a human tumor xenographted nude mouse model.

Contribution of CD4+ and CD8+ T cells and interferon-gamma to the progress of chronic rejection of kidney allografts: the Th1 response mediates both acute and chronic rejection.

T cells mediating chronic rejection (CR) of human kidney allografts were characterized by comparing them with those mediating acute rejection (AR). Two lines of analysis were performed using biopsy specimens (23 CR and 8 AR). First, the extent of infiltration of CD4+ and CD8+ T cells into allografts was assessed from mRNA expression of CD4 and CD8. The group of CR specimens was not significantly different from the group of AR specimens in terms of the extent of CD4+ and CD8+ T cell infiltration, underlining the importance of the immunological contribution to the progress of CR. Second, Th1/Th2 polarization in infiltrating T cells was investigated by measuring mRNA expression of interferon gamma (IFN-gamma; a Th1 cytokine) and interleukin 4 (IL-4; a Th2 cytokine). IFN-gamma expression was detected in most CR specimens, and was not significantly different between the group of CR specimens and the group of AR specimens. On the other hand, IL-4 expression was detected in only two CR specimens and one AR specimen; from its pathological features, the AR in this last case was concomitant with CR. These results suggest that most cases of CR and of AR are mediated by Th1 mechanisms, although some cases of CR show features of both Th1 and Th2.

A multicenter validation of regional cerebral blood flow quantitation using [123I]iodoamphetamine and single photon emission computed tomography.

Recently, two methods have been proposed for regional cerebral blood flow (rCBF) quantitation using [123I]iodoamphetamine (IMP) and single-photon emission computed tomography (SPECT). The table look-up (TLU) method has been shown to provide both rCBF and volume of distribution, Vd, images from two SPECT scans, while a single-scan autoradiographic (ARG) technique provided rCBF using a fixed and assumed Vd. In both methods, a single blood sample was referred to calibrate the previously determined standard input function. The present multicenter project was designed to evaluate the accuracy of both methods for use as clinical investigative tools. Ten independent institutions performed [123I]IMP-SPECT studies according to both methods in 76 subjects (10 normal volunteers, 32 patients with cerebrovascular disease, and 34 patients with other diseases). Calculated rCBF values were compared with those obtained by the following reference methods available in the participating institutions; [15O] H2O positron emission tomography (PET) (five institutions), [133Xe]SPECT (four institutions), and the [123I]IMP microsphere method (three institutions). Both ARG and TLU methods provided rCBF values that were significantly correlated with those measured by the [15O] H2O PET technique (p < 0.001 for all subjects; overall regression equation, y = 15.14 + 0.54x) and those measured by the [123I]IMP-microsphere method (p < 0.001 for all subjects: y = 2.0 + 0.80x). Significant correlation (p < 0.05) was observed in 18 of 24 subjects studied with the [133Xe] SPECT reference technique (overall regression equation, y = 15.0 + 0.55x). Mean cortical gray matter rCBF in a group of normal subject was 43.9 +/- 3.3 and 43.4 +/- 2.0 ml/min/100 g for the ARG and TLU methods, respectively. Regional Vd of [123I]IMP estimated by the TLU method was 45 ml/ml +/- 20% in the normal cortical region. Close agreement between ARG and TLU rCBF values was observed (y = -3.21 + 1.07x, r = 0.97), confirming the validity of assuming a fixed Vd in the ARG method. Results of this study demonstrate that both the ARG and TLU methods accurately and reliably estimate rCBF in a variety of clinical settings.

Elevation of cerebral lactate detected by localized 1H-magnetic resonance spectroscopy in migraine during the interictal period.

We used localized 1H-magnetic resonance spectroscopy (MRS) to study the metabolic changes in the brains of patients with migraine during the interictal period. Measurement of metabolite levels in the occipital visual cortex in six normal subjects and six patients disclosed high lactate levels in the five patients who had experienced a migraine attack within the previous 2 months. One patient who had not experienced a migraine attack in the previous 4 years did not show a lactate peak. We speculate that anaerobic glycolysis occurs in the brains of patients with migraine during the interictal period, and a long attack-free period may normalize the subclinical metabolic disturbance.

Mitochondrial encephalomyopathy: elevated visual cortex lactate unresponsive to photic stimulation--a localized 1H-MRS study.

We used localized H-magnetic resonance spectroscopy (MRS) to study the metabolic changes in the visual cortex of patients with mitochondrial encephalomyopathy. Measurement of metabolite levels in the occipital visual cortex obtained in the dark with seven normal subjects and with four patients (all four of whom had Kearns-Sayre syndrome [KSS]) showed high lactate levels in the patients. Photic stimulation (PS) in four normal volunteers showed that lactate increased immediately after the start of PS and that it decreased to the baseline level with continued PS. Lactate in the resting state was higher in the KSS patients than in the controls, and, unlike the controls, the KSS patients showed no significant elevation of lactate with PS.

Substitution at the F-ring N-imide of the indolocarbazole antitumor drug NB-506 increases the cytotoxicity, DNA binding, and topoisomerase I inhibition activities.

The antitumor drug NB-506, which is currently undergoing phase I/II clinical trials, contains a DNA-intercalating indolocarbazole chromophore substituted with a glucose residue. In addition to interacting with DNA, the drug stabilizes the topoisomerase I-DNA covalent complex. To reinforce the DNA binding and anti-topoisomerase I activities of NB-506, an analogue containing a new substituent on the naphthalimide ring F was synthesized. The N-formylamino group of NB-506 has been replaced with a more hydrophilic group, N-bis(hydroxymethyl)methylamino. In this study we show that the incorporation of a longer substituent on the N6 position effectively reinforces both the interaction with DNA and the capacity of the drug to maintain the integrity of the topoisomerase I-DNA covalent complexes. The strength and the mode of binding of the drugs to DNA were studied by complementary biophysical techniques including absorption, fluorescence, and circular and linear dichroism. Various biochemical procedures were applied to investigate the effects on human topoisomerase I using plasmid DNA as well as restriction fragments. The drug binding sites and the positions of the topoisomerase I-mediated cleavage sites were mapped with nucleotide resolution using footprinting and sequencing techniques. Cytotoxicity measurements performed with various human cancer cell lines (HCT-116, DLD-1, MKN-45) indicate that the newly designed drug is 3 to 4 times more toxic to colon and gastric cancer cells than NB-506. Therefore, the results suggest that the antitumor activity of indolocarbazole-based drugs can be enhanced by incorporating DNA and/or topoisomerase I reactive groups. They also support the hypothesis that the substituent on the imide nitrogen on the F ring of NB-506 has direct interaction with the molecular target. The study helps to define the structure-activity relationships in the indolocarbazole series of antitumor agents targeting topoisomerase I.

T-cell receptor variable gene analysis of renal allograft-infiltrating cells in biopsy specimens using a nonradioisotopic micromethod.

BACKGROUND: A sensitive micromethod for T-cell receptor (TCR) analysis is needed for clonality analysis of renal allograft-infiltrating T cells (RAITs) obtained by needle biopsy. METHODS: TCR cDNA was amplified by the anchored polymerase chain reaction and was hybridized with 28 different TCR beta variable (TCRBV) genes fixed on nylon membranes, and the percentage of each TCRBV gene was measured spectrophotometrically. RESULTS: The specificity and linearity of the hybridization technique and the constancy of the TCRBV percentages over a wide range of sample amounts were demonstrated by control experiments. Analysis of RAITs of biopsy specimens from four patients showed broad or skewed TCRBV usage, indicating the presence of polyclonal and oligoclonal RAIT populations, respectively. In one patient who received OKT3 immunosuppressive treatment, the TCRBV skewness was dramatically reduced after the treatment. CONCLUSION: We have established a powerful method for analyzing RAIT clonality, which is especially useful for monitoring RAIT dynamics after immunosuppression therapy.

A comparative study of simple methods to measure regional cerebral blood flow using iodine-123-IMP SPECT.

UNLABELLED: The aim of this study was to compare the accuracy and reliability of simple methods of quantifying regional cerebral blood flow (rCBF) with 123I-labeled N-isopropyl-p-iodoamphetamine (IMP) and SPECT and to determine which method was best. METHODS: Four methods were examined: (a) the microsphere method with continuous withdrawal of arterial blood, which was based on a microsphere model using the SPECT image obtained 5 min after tracer injection, (b) the microsphere method with one-point sampling, which was the same as the first method except that one-point sampling was used instead of continuous withdrawal, (c) the modified microsphere method with one-point sampling, which was the same as the second method except that a later SPECT image (30-min postinjection) with correction was used and (d) a table look-up method based on a two-compartment model with one-point arterial blood sampling and two SPECT scans obtained 40- and 180-min postinjection. The accuracy of these methods was validated by comparing the rCBF values with those obtained by nonlinear least squares fitting analysis based on the two-compartment model in 15 subjects. RESULTS: Regional cerebral blood flow values obtained by the first method correlated most closely with those obtained by nonlinear least squares fitting analysis (error, 6.8%). The second method estimated rCBF with a mean error of 10.4%. The third method estimated rCBF with a mean error of 13.1%, even though it tended to slightly overestimate rCBF. The fourth method was inclined to underestimate rCBF with a mean error of 17.1%, and it greatly overestimated regional distribution volume. CONCLUSION: The first method was the most accurate and reliable. For less invasiveness, the first method should be combined with one-point sampling instead of continuous withdrawal, which was used in the second method. When using a delayed SPECT image with a conventional SPECT scanner, the third method was considered to be superior to the fourth method.

Quantification of cerebral blood flow and partition coefficient using iodine-123-iodoamphetamine.

UNLABELLED: The aim of this study was to develop a simple, noninvasive method for quantifying both regional cerebral blood flow (rCBF) and the partition coefficient (lambda) using N-isopropyl-p[123I]iodoamphetamine and SPECT. METHODS: By employing a two-compartment model (influx, K1: outflux, k2), a new method was introduced that requires two serial SPECT scans at 30 min and 60 min, and a single arterial sample 5 min after tracer injection. The integral of the arterial input function is inferred from the sample by using the correlation obtained from 25 subjects. Two original mathematical functions, phi for K1 and gamma for lambda (= K1/k2), were obtained from the input functions of 12 subjects. The values of K1 and lambda are determined from the two scans and the single arterial sample by using these functions. The values obtained for K1 (= rCBF) and lambda were compared with those obtained by nonlinear least-squares fitting analysis and the 133Xe inhalation SPECT method. RESULTS: K1 and lambda were in good agreement with the values obtained by nonlinear least-squares fitting analysis (r = 0.873 in K1 and r = 0.825 in lambda), and rCBF values were closely correlated with those obtained by the 133Xe method (r = 0.843). CONCLUSION: The proposed method has three advantages: (a) accurate, simultaneous quantification of both rCBF and the partition coefficient; (b) simplicity and noninvasiveness; and (c) a relatively short period (approximately 70 min) for the study.

Noninvasive quantification of cerebral blood flow using 99mTc-ECD and SPECT.

UNLABELLED: The aim of this study was to develop a simple, noninvasive method for quantifying regional cerebral blood flow (rCBF) using 99mTc-ethyl cysteinate dimer (ECD) by a single SPECT scan and single venous sampling. METHODS: Using a three-compartment model, we introduced the regional brain fractionation index (BFI), Cb(Ts)/integral of 0-Ts Ca(tau)dtau [Ca(t), arterial input; Cb(t), brain activity]. Regional BFI obtained at the optimum time Ts (min) was converted to rCBF using an exponential function, which was obtained by analyzing the relationship between regional BFI and rCBF (= F) obtained by the standard 133Xe inhalation SPECT method. The integral of the concentration of 99mTc-ECD in arterial blood corrected for physical decay [Ca(t)] in BFI was estimated from a single venous blood sample obtained at the optimum time Tv using the regression line obtained by analyzing the relationship between the integral of Ca(t) and venous sample data. The data come from three groups of patients. The first group of patients (n = 16) underwent a complete 99mTc-ECD BFI study with measurement of Ca(t) and dynamic SPECT scanning, as well as a 133Xe inhalation study to measure rCBF The results were used to analyze the relationship between regional BFI and rCBF (obtained with 133Xe) and to determine the optimum time Ts for obtaining BFI. Data from the second group of patients (n = 15) were used to analyze the relationship between the integral of Ca(t) and venous sample data and to determine the optimum time Tv for one-point venous blood sampling. Finally, the third group of patients (8 patients, 10 studies) was used to validate the current method by comparing the results with 133Xe inhalation SPECT. RESULTS: Regional BFI obtained at time Ts = 20 min showed good agreement (r = 0.907; a = 0.552, b = 0.962) with rCBF. The venous sample data obtained at time Tv = 6 min showed a good correlation (r = 0.988) with BFI. In comparing rCBF values thus obtained and those obtained by the 133Xe method, we found a good correlation (r = 0.917, slope = 1.01). CONCLUSION: The proposed method has three advantages: (a) accurate quantification of rCBF without underestimation in the high flow range, (b) simplicity and noninvasiveness and (c) the ability to use any type of SPECT camera for the study.

Sequence analysis and oligonucleotide genotyping of HLA-DR"JX6", a DR"blank" haplotype found in the Japanese population.

We analyzed one of the HLA-DR"blank" haplotypes found in the Japanese population using serologic studies, sequence determination, and genotyping with sequence-specific oligonucleotide (SSO) probes. The DR"blank" haplotype, designated DR"JX6", segregated in a family in association with the DRw52 and the DQw7 specificities. The cDNA and genomic DNA of the DRB1 gene originating from the DR"JX6" haplotype were amplified enzymatically and sequenced after cloning into a plasmid vector. The amino acid sequence of the first domain in the DR beta 1 chain of the DR"JX6" haplotype was different from those of other DR haplotypes sequenced so far, but in the first hypervariable region, the sequence was identical to those of the DRw11, DRw13, DRw14, and DRw17 haplotypes. SSO probes were synthesized on the basis of the DR"JX6" haplotype sequence as well as known sequences of the DRB1, DRB3, and DRB4 genes of other DR haplotypes. These SSO probes were used for the genotyping of Japanese donors whose DRB genes were amplified enzymatically and found to show a hybridization profile that was consistent with the results of serologic studies on the DR"JX6" haplotype.

Increase of nicotinamide methyltransferase and N1-methyl-nicotinamide oxidase activities in the livers of the rats administered alkylating agents.

Twenty four hours after intraperitoneal injection of alkylating agents, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), N-methyl-N-nitrosourea (MNU) and methyl methanesulfonate (MMS), into rats, an increase in nicotinamide (Nmd) methyltransferase and N1-methylnicotinamide (1-CH3Nmd) oxidase activities in the liver was found. Since activities of these enzymes in the liver extracts were not stimulated directly by these agents in vitro, it is postulated that the increases in these enzyme activities are due to the induction of each enzyme.

Behavioral studies on FR115427, a novel selective N-methyl-D-aspartate antagonist.

Behavioral and in vitro receptor binding methods were used to evaluate and compare the effects of FR115427 ((+)-l-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride) with those of MK801, a non-competitive NMDA antagonist. FR115427 inhibited NMDA-induced convulsions in mice by intracerebroventrical(ICV) and systematic injection. FR115427 was found to be about ten times less potent than MK801. Furthermore, the inhibitory effect of FR115427 and MK801 on NMDA-induced convulsions was evaluated in time course studies in mice. MK801 exhibited a more sustained anticonvulsive activity than FR115427. In addition, PCP-like behaviors were examined in mice after ICV injection of these compounds. At the lowest dose FR115427 significantly increased locomotor activity, although the effect of this compound was about hundred times less potent than that of MK801. At higher dose a more complex pattern of behavior, e.g. head-movement and eventually ataxia was observed. In binding assays with rat brain membranes, FR115427 inhibited the binding of (3H)TCP (IC50 = 0.249 microM) and (3H)MK801 (IC50 = 0.312 microM) but did not inhibit the binding of (3H)CPP or (3H)glycine. These results suggest that FR115427 is a novel non-competitive NMDA antagonist that acts on a binding site located within the NMDA receptor associated ion channel.