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J C Huang

Publications and source records attributed to J C Huang.

At least 37 records · Page 2Linked to original sources
PubMed2000

Morphologic preservation and variability of human donor retina.

PURPOSE: To facilitate studies of human retina and utilization of human retinal tissue for treatment of retinal diseases, we studied morphologic preservation in postmortem human retina. METHODS: Morphology of retinas from thirty-one human eyes was examined using light and electron microscopy. The inner and outer retina, rod and cone photoreceptor cells, and central and peripheral retina were compared with regard to morphologic preservation. Possible factors affecting survival were analyzed. RESULTS: The earliest postmortem change was vacuolation of the nerve fiber layer within a few hours postmortem, followed by vacuolation and cytoplasmic swelling of the inner retina. As compared with the inner retina, outer retinal structure was better preserved, i.e., the photoreceptor cells maintained better morphology. Rod cell morphology was better preserved than cone cell morphology, with good preservation of the rod outer segment disc membranes and the inner segment mitochondrial membranes. Thus, well-preserved rod photoreceptor cells were evident in specimens at least 48-hours postmortem. Peripheral retina was better preserved than the central retina including the fovea and perifovea. Factors affecting anatomical integrity included the total time postmortem and, more importantly, the time between death and enucleation. Other factors, including age and sex, did not appear to affect morphological preservation in the present study. CONCLUSIONS: Human retina postmortem remained morphologically intact for a relatively long period of time, with differential preservation among different geographic areas and cell types. This morphologic evidence is consistent with previous findings of functional preservation (e.g. , photoresponses) in such tissue. This study may shed some light on understanding of human retina and its utilization for retinal transplantation.

Adolescent↗
PubMed1999

Characterization of two subclasses of PR-10 transcripts in lily anthers and induction of their genes through separate signal transduction pathways.

The lily PR-10 belongs to a family of intracellular pathogenesis-related (IPR) proteins. Genomic Southern analysis indicates that the PR-10 is encoded by a family of multiple genes. Seven heterogeneous cDNA clones encoding lily PR-10 from Lilium longiflorum are divided into two subclasses based on sequence comparison and Southern hybridization. A 82% overall sequence similarity was found between the two subclasses (represented by PR-10c and d). The two cDNAs include an open reading frame of 474 bp encoding 157 amino acids. 5'- and 3'-untranslated regions exhibit low similarity, but similarity is high in the coding region. The lily PR-10 genes are induced by abscisic acid (ABA) and methyl jasmonate (MeJA) in the anther and various other organs of lily plants. The induction of PR-10 genes by ABA and MeJA in lily anthers occurs by two separate signal transduction pathways. The protein phosphatase inhibitor okadaic acid inhibits the MeJA-induced expression of PR-10 genes downstream of MeJA. In addition, the protein kinase inhibitor staurosporine inhibits the MeJA-induced expression of PR-10 genes, implying that an activity of staurosporine-sensitive protein kinases exists downstream of MeJA in the anther. However, okadaic acid does not inhibit the ABA-induced expression of PR-10 genes whereas staurosporine does. These observations suggest that, in addition to the known pathway that ABA induces gene expression by activating JA or MeJA, a MeJA-independent pathway of ABA induction exists in the anther. The alternative pathway of ABA induction involves a staurosporine-sensitive protein kinase activity downstream of ABA.

Abscisic Acid↗
PubMed1999

CD5- small B-cell leukemias are rarely classifiable as chronic lymphocytic leukemia.

Expression of the CD5 antigen by neoplastic cells often is considered a diagnostic criterion for B-cell chronic lymphocytic leukemia (B-CLL). However, published series frequently include a number of CD5- cases. We studied the spectrum of CD5- B-cell lymphoproliferative disorders presenting with leukemia involvement and reassessed the prevalence of CD5- B-CLL. We immunophenotyped 192 cases of clonal, small lymphocytic, B-cell disorders involving peripheral blood or bone marrow. Of these, 41 CD5- cases were further analyzed, correlating the immunophenotypic findings with pathologic material and clinical data. Only 3 CD5- cases were classified as CD5- B-CLL. These 3 cases had features unusual for B-CLL, including bright surface immunoglobulin expression, bright CD20 expression, and absence of CD23 expression (2 cases) or Richter syndrome (1 case). The remainder of the CD5- cases consisted of hairy cell leukemia, hairy cell variant, prolymphocytic leukemia, follicular center cell lymphoma, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma (SMZL), small lymphocytic lymphoma with marrow fibrosis, and lymphoma, not further classified. Eight cases remained unclassified, but some displayed features of SMZL. CD5- lymphoproliferative disorders of peripheral blood or bone marrow are unlikely to be CLL and often are classified more appropriately as non-Hodgkin lymphoma in the leukemia phase.

Adult↗
PubMed1998

Repetitive transcranial magnetic stimulation activates specific regions in rat brain.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique to induce electric currents in the brain. Although rTMS is being evaluated as a possible alternative to electroconvulsive therapy for the treatment of refractory depression, little is known about the pattern of activation induced in the brain by rTMS. We have compared immediate early gene expression in rat brain after rTMS and electroconvulsive stimulation, a well-established animal model for electroconvulsive therapy. Our result shows that rTMS applied in conditions effective in animal models of depression induces different patterns of immediate-early gene expression than does electroconvulsive stimulation. In particular, rTMS evokes strong neural responses in the paraventricular nucleus of the thalamus (PVT) and in other regions involved in the regulation of circadian rhythms. The response in PVT is independent of the orientation of the stimulation probe relative to the head. Part of this response is likely because of direct activation, as repetitive magnetic stimulation also activates PVT neurons in brain slices.

Animals↗
PubMed1998

Specific agrin isoforms induce cAMP response element binding protein phosphorylation in hippocampal neurons.

The synaptic basal lamina protein agrin is essential for the formation of neuromuscular junctions. Agrin mediates the postsynaptic clustering of acetylcholine receptors and regulates transcription in muscles. Agrin expression is not restricted to motor neurons but can be demonstrated throughout the CNS. The functional significance of agrin expression in neurons other than motor neurons is unknown. To test whether agrin triggers responses in neurons that lead to the activation of transcription factors, we have analyzed phosphorylation of the transcriptional regulatory site serine 133 of the transcription factor CREB (cAMP response element binding protein) in primary hippocampal neurons. Our results indicate that the neuronal (Ag4,8), but not the non-neuronal (Ag0,0), isoform of agrin induces CREB phosphorylation in hippocampal neurons. The kinetics of agrin- and BDNF-induced CREB phosphorylation are similar: peak levels are reached in minutes and are strongly reduced 2 hr later. Neuronal responses to agrin require extracellular calcium, and, in contrast to tyrosine kinase inhibitors, the specific inhibition of protein kinase A (PKA) does not affect agrin-evoked CREB phosphorylation. Our results show that hippocampal neurons specifically respond to neuronal agrin in a Ca2+-dependent manner and via the activation of tyrosine kinases.

Agrin↗
PubMed1998

Structure-activity relationships for a series of bis(phenylalkyl)amines: potent subtype-selective inhibitors of N-methyl-D-aspartate receptors.

A series of bis(phenylalkyl)amines, structural analogues of ifenprodil and nylidrin, were synthesized and tested for antagonism of N-methyl-D-aspartate (NMDA) receptors. Potency and subunit selectivity were assayed by electrical recordings in Xenopus oocytes expressing three binary combinations of cloned rat NMDA receptor subunits: NR1A expressed in combination with either NR2A, NR2B, or NR2C. The bis(phenylalkyl)amines were selective antagonists of NR1A/2B receptors. Assayed under steady-state conditions, the most potent of these, N-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentylamine hydrochloride (20), has an IC50 value of 8 nM and >1000-fold selectivity with respect to NR1A/2A and NR1A/2C receptors. The structure-activity relationship of the bis(phenylalkyl)amine series indicates that the piperidine ring and alkyl chain substitutions common to NR2B-selective antagonists such as ifenprodil, CP 101,606, and Ro 25-6981 are not necessary to generate potent and selective ligands. The primary determinants of potency are the phenolic OH group, acting as a hydrogen bond donor, the distance between the two rings, and an electrostatic interaction between the receptor and the basic nitrogen atom. This study provides a framework for designing structurally novel NR2B-selective antagonists which may be useful for treatment of a variety of neurological disorders.

Animals↗
PubMed1998

Gene transfer to cultured human endometrial stromal cells: a model to study cyclooxygenase-2 gene regulation.

OBJECTIVE: To compare and optimize conditions for gene transfer to human endometrial stromal cells derived from primary culture and to determine the effect of interleukin-1beta (IL-1beta) and phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator. on the promoter activity of the human cyclooxygenase-2 (COX-2) gene. DESIGN: Prospective controlled study. SETTING: Academic research laboratory. PATIENT(S): Women undergoing benign gynecologic surgery for indications other than endometrial diseases. INTERVENTION(S): Endometrial stromal cells were used for transient transfection study. MAIN OUTCOME MEASURE(S): Luciferase activity in transfected endometrial stromal cells. RESULT(S): Gene transfer mediated by cationic lipid was more efficient and more consistent. Lipofectamine, a polycationic lipid, yielded the highest efficiency. Phorbol 12-myristate 13-acetate (30 nM) and IL-1beta (100 ng/mL) increased COX-2 promoter activity by 2.6-fold and 2.2-fold, respectively. CONCLUSION(S): Induction of COX-2 by IL-1beta and PMA suggests that COX-2 and prostaglandin have important roles in the growth and differentiation of endometrial stromal cells. This model can be used to explore the roles of different promoter regulatory elements in COX-2 gene activation.

Analysis of Variance↗
PubMed1998

Information and risk perception: a dynamic adjustment process.

It is common in catastrophic food-contamination events that consumers fail to adjust instantaneously to a normal consumption level. One explanation is that consumers only gradually accept new positive information as being trustworthy. The gradual establishment of the trustworthiness of the released information depends on both positive and negative media coverage over time. We examine the individual "trust" effects by extending the prospective reference theory (Viscusi, 1989) to include a dynamic adjustment process of risk perception. Conditions that allow aggregation of changes in risk perceptions across individuals are described. The proposed model describes a general updating process of risk perceptions to media coverage and can be applied to explain the temporal impact of media coverage on consumption of a broad range of goods (food or nonfood). A case study of milk contamination is conducted to demonstrate consumer demand adjustment process to a temporarily unfavorable shock. The results suggest that effects of positive and negative information to adjustment of consumption and risk perception are asymmetric over time.

Animals↗
PubMed1998

The expression of vascular endothelial growth factor isoforms in cultured human endometrial stromal cells and its regulation by 17beta-oestradiol.

Angiogenesis or formation of new blood vessels is required for regeneration of the endometrium after its breakdown during each menstruation. Vascular endothelial growth factor (VEGF), a family of recently discovered angiogenic factors, may be involved in the repair and growth of the endometrium. In this study reverse transcription-polymerase chain reaction (PCR) was used to confirm the presence of VEGF mRNA and restriction enzyme digestion to confirm the identity of PCR products generated from different VEGF isoforms in cultured human endometrial stromal cells. The shortest isoform, VEGF 121, was the most abundant in quiescent stromal cells. It was about one-and-a-half times that of VEGF 165. The longest isoform, VEGF 206, was not detected; only a relatively weak signal for VEGF 189 was detectable. The mRNA for VEGF increased 2-fold after stimulation by 17beta-oestradiol (10 nM) for 30 min. A further increase to 3-fold above baseline occurred after 2 h incubation and remained steady at 6 h incubation, but decreased to 2-fold of baseline after 15 h. There was no differential stimulation of mRNA for VEGF isoforms: the ratio of VEGF 121 to 165 remained constant at 3:2 during the course of the incubation, with the exception at 15 h incubation when the ratio was 2:1. The VEGF protein, determined by specific enzyme immunoassay, increased from undetectable at baseline to 79.8 +/- 18.9 pg/ml (n = 4, mean +/- SD, 9.6 cm2/well/ml) after 2 h, with a further significant increase to 249.5 +/- 27.3 pg/ml after 15 h and 695.0 +/- 41.4 pg/well after 39 h. At 15 h incubation, the specific oestradiol antagonist ICI 182,780 (1 microM) significantly reduced VEGF secretion by 25% from 249.5 +/- 27.3 to 189.0 +/- 26.6 pg/ml. Thus, VEGF showed specific patterns of isoform expression in the human endometrial stromal cells; oestradiol (10 microM) stimulated, but not differentially, the mRNA for VEGF isoforms.

Cells, Cultured↗
PubMed1998

Characterization of a desiccation-related protein in lily pollen during development and stress.

This work characterizes a lily (Lilium longiflorum Thunb. cv. Snow Queen) anther (LLA) protein associated with desiccation. Peptide mapping analysis revealed that the abundant LLA-23 doublet contained similar polypeptides, having an isoelectric point of 6.1. Immunoblots of pollen protein from developing anther/pollen confirmed that the LLA-23 protein accumulated only at the later stage of pollen maturation and that the levels remained steady in mature and vital pollen. The accumulation of LLA-23 proteins was correlated with desiccation that naturally occurred in pollen. Subcellular fractionation of pollen proteins revealed that the protein was located in the cytoplasmic fraction. Premature drying of developing pollen confirmed that the concomitant accumulation of LLA-23 was associated with desiccation. Peptide sequence analysis demonstrates similarities between the lily LLA-23 and a family of water-deficit/ripening-induced proteins including LP3 of pine, DS2 of potato, and Asr of tomato and pummelo. In addition, the concomitant accumulation of LLA-23 can be experimentally manipulated by methyl jasmonate (Me-JA) and salicylic acid (SA) as well as by mannitol and methyl viologen. The LLA-23 represents a novel member of the water-deficit/ripening-induced proteins.

Acetates↗
PubMed1998

Age-related immunogenicity of meningococcal polysaccharide vaccine in aboriginal children and adolescents living in a Northern Manitoba reserve community.

OBJECTIVE: To determine the total and functional serogroup C antibody response to a quadrivalent meningococcal polysaccharide vaccine in a group of aboriginal infants, children and adolescents. A secondary objective was to determine their prevalence of meningococcal carriage. DESIGN: Open prospective, before and after intervention study. SUBJECTS: Aboriginal children ages 0.5 to 19.9 years, living in a single Northern community and eligible for a public health immunization campaign conducted in all Manitoba native reserve communities to control a meningococcal serogroup C, electrophoretic type (ET) 15 outbreak. No outbreak cases had occurred in the community at the time of the study. METHODS: Total serogroup C capsular polysaccharide antibody (CPA) and functional bactericidal antibody (BA) responses were measured by enzyme-linked immunosorbent assay and bactericidal assay, respectively. RESULTS: Neisseria meningitidis was recovered from the oropharynx of 13 (5.2%) of 249 aboriginal children including 4 (1.6%) serogroup C isolates, all with the designation C:2a:P1.2,5 ET15. Paired sera from 152 children were available for assay. For CPA the geometric mean concentrations and proportions with > or =2 microg/ml before and after immunization were 0.69, 18% and 12.3, 96%, respectively. A significant increase in serum CPA was achieved by children of all ages, with the greatest response occurring after age 11 years. Among infants < lyear old 89% achieved concentrations of > or =2 microg/ml. For BA the pre- and post-vaccine geometric mean titers were 1.02 and 45.9. The response was significantly associated with age. BA titers > or =1:8 were present, before and after immunization, respectively, in 0 and 0% of infants <1 year old, 0 and 20% of 1- to 1.4-year-olds, 0 and 50% of 1.5- to 1.9-year-olds and 1 and 100% of > or =2-year-olds. CONCLUSION: The age-related total and functional group C meningococcal antibody response after quadrivalent polysaccharide vaccine among aboriginals is similar to that reported for Caucasian children. After age 2 all children made excellent CPA and BA responses. In the younger age groups the BA response was blunted but 82 to 95% achieved CPA titers of > or =2 microg/ml.

Adolescent↗
PubMed1998

Interleukin-1 beta induces cyclooxygenase-2 gene expression in cultured endometrial stromal cells.

Increasing evidence indicates that PGs may play an obligatory role in blastocyst implantation. Cyclooxygenase (also known as PGH synthase) isozymes 1 and 2 catalyze the rate limiting steps in the biosynthesis of PGs. The ubiquitous cyclooxygenase-1 (COX-1) subserves housekeeping functions, whereas the inducible cyclooxygenase-2 (COX-2) is expressed by limited cell types and tightly controlled. Here we report the induction of COX-2 gene expression by interleukin-1 beta (IL-1 beta) in cultured human endometrial stromal cells. COX-2 activity was induced by IL-1 beta (1 ng/mL); conversion of exogenous arachidonic acid to PGF2 alpha increased from 2.6 +/- 0.6 ng/well (mean +/- SEM; n = 6) to 22.2 +/- 5.6 ng, but was completely blocked (2.8 +/- 0.7 ng/well) by NS-398, a specific COX-2 inhibitor. Undetectable in quiescent stromal cells, messenger ribonucleic acid for COX-2 was induced 30 min after IL-1 beta treatment, reached a maximum at 4 h, and decreased after 15 h. Protein synthesis was not required for induction of the COX-2 gene, as it was blocked by actinomycin D but not by cycloheximide. The 70-kDa COX-2 protein was not detected in quiescent cells, became detectable 6 h after IL-1 beta treatment, and remained detectable even after 15 h. IL-1 beta (0.1-100 ng/mL) increased the luciferase activity in promoterless luciferase reporter containing the 900-bp 5'-flanking sequence (-891 to +9) of the COX-2 gene in a dose-dependent manner, with an ED50 of 0.1-1 ng/mL.

Arachidonic Acid↗
PubMed1998

Enamel specific protein kinases and state of phosphorylation of purified amelogenins.

Ameloblastic tissue samples from unerupted bone molars were used to prepare subcellular enamel protein kinase preparations, nuclear + plasma membrane, cytosolic and microsomal, and used in in vitro phosphorylation of purified 20 kDa bovine amelogenin in the presence of 32P-ATP. Both cytosolic and microsomal preparations can phosphorylate purified native amelogenins, the addition of Ca2+ slightly increased the microsomal enzyme activity or at least did not inhibit the activity, whereas the presence of Ca2+ substantially decreased the cytosolic kinase activity towards phosphorylation of amelogenins. A comparative analysis using the enamel microsomal kinase against osteopontin, dephosphorylated casein and bone sialoprotein showed no phosphorylation of the first two proteins, and only minor phosphorylation of the bone sialoprotein. Overall, the present work demonstrates for the first time that the protein kinase responsible for the phosphorylation of amelogenins is a novel kinase, which is not inhibited by Ca2+, unlike the microsomal protein kinase (casein kinase type-II) of bone which phosphorylates secretory proteins osteopontin and bone sialoprotein and is strongly CaZ+ inhibited. The direct phosphoserine analysis on the purified bovine 20 kDa amelogenin indicated the presence of 0.8 moles of phosphoserine/mole protein naturally occurring, consistent with the quantitative analysis of 14C-radiolabeling of phosphoserines by conversion to dehydroalanine and in situ reaction with the thiol agent, 14C-mercaptoethanol, 0.64 moles 14C-incorporated/mole 20 kDa amelogenin. The purified low Mramelogenins 5.3 kDa E4 (TRAP) and 7.2 kDa E3 (LRAP), were also derivatized by 14C-mercaptoethanol, providing 0.46 and 0.88 moles 14C-incorporated/mole respectively. Further studies of the 14C-radiolabeled E4 amelogenin by sequence analysis confirmed one site of label to be at position 16 from the N-terminal and hence provided a direct evidence for the naturally occurring phosphoserine residue at this position.

Amelogenin↗
PubMed1998

Preparation and transplantation of photoreceptor sheets.

PURPOSE: Photoreceptor (PR) transplantation may be a treatment for blindness secondary to PR degeneration. We studied different technical aspects of PR-sheet preparation. METHODS: Geographic variation in the thickness of the cat PR layer (from the outer segments to the outer plexiform layer) and inner retina (width of the remainder of the retina) was studied. PR sheets (cat and human) were prepared through gelatin embedding and subsequent vibratoming or excimer laser ablation. Cat PR sheets were evaluated after transplantation. RESULTS: The thickness of the cat PR layer and inner retina varied in different regions. The superior central retina, including the area centralis, was thickest (PR layer: 115-123 microm, entire retina: 225-230 microm, in fixed tissue). The peripheral retina was approximately 40% thinner than the center. Fresh retina was approximately 7.9% thicker than the fixed retina. Both vibratomy and excimer laser ablation removed the inner retina, leaving a PR-layer sheet with good morphology. To produce good quality PR sheets with vibratomy, use of different gelatin concentrations (2% to 35%) at various stages of sheet preparation was crucial. To produce PR sheets of uniform thickness with excimer laser ablation, control of fluid on the retinal surface was critical. Twenty-four hours after PR transplantation surgery, donor PR cells were well oriented and in close contact with host retinal pigment epithelial cells. Gelatin supporting the transplant dissolved as early as 100 min after surgery. CONCLUSIONS: We confirmed and expanded the work of previous investigators and showed that cat and human PR sheets can be manufactured using vibratomy or excimer laser ablation. This preparation provides a well oriented and organized PR cell layer after transplantation.

Animals↗
PubMed1998

Usefulness of an immunohistochemical panel in paraffin-embedded tissues for the differentiation of B-cell non-Hodgkin's lymphomas of small lymphocytes.

Diagnosis of small B-cell lymphomas is sometimes difficult without fresh tissue for flow cytometry (FC) or immunohistochemistry (IHC). Therefore, we examined the usefulness of a paraffin section IHC panel consisting of antibodies to CD5, CD10, CD20, CD23, CD43, and cyclin D1. We tested 55 formalin-fixed small B-cell lymphomas, including 16 small lymphocytic lymphomas (SLLs), 10 mantle cell lymphomas (MCLs), 25 follicle center lymphomas (FCLs), and 4 mantle zone lymphomas (MZLs). Seventeen cases had B5-fixed sections that were stained in the same manner. The findings were correlated with FC immunophenotyping when available. All of the SLLs and 90% of the MCLs expressed CD5 by IHC, with occasional weak expression in some MCLs. All of the FCLs and MZLs lacked CD5 expression. These results were comparable to those obtained by FC. CD43 expression was seen in 100% of the SLLs, 90% of the MCLs, and 75% of the MZLs. CD23 expression was seen in 94% of the SLL; of these, 100% also showed expression of CD23 by FC. Cyclin D1 was detected in all of the MCLs by IHC but also in 3 of the 16 SLLs. CD23 was absent in all of the MCLs. CD10 expression was present in 21 (95%) of 22 FCLs. All of the 17 cases fixed in B5 showed a decreased immunoreactivity for CD5 in the neoplastic cells. In contrast, CD10 immunoreactivity was judged better in B5-fixed sections. We concluded, therefore, that anti-CD5 and -CD10 were useful tools in the differential diagnosis of B-cell lymphomas of small lymphocytes and that a paraffin-section IHC panel consisting of antibodies to CD5, CD10, CD20, CD23, CD43, and cyclin D1 was a useful ancillary technique that compared favorably with FC.

Antigens, CD↗
PubMed1997

5-(N-oxyaza)-7-substituted-1,4-dihydroquinoxaline-2,3-diones: novel, systemically active and broad spectrum antagonists for NMDA/glycine, AMPA, and kainate receptors.

A group of 5-aza-7-substituted-1,4-dihydroquinoxaline-2,3-diones (QXs) and the corresponding 5-(N-oxyaza)-7-substituted QXs were prepared and evaluated as antagonists of ionotropic glutamate receptors. The in vitro potency of these QXs was determined by inhibition of [3H]-5,7-dichlorokynurenic acid ([3H]DCKA) binding to N-methyl-D-aspartate (NMDA)/glycine receptors, [3H]-(S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA) binding to AMPA receptors, and [3H]kainate ([3H]KA) binding to KA receptors in rat brain membranes. 5-(N-Oxyaza)-QXs 12a-e all have low micromolar or submicromolar potency for NMDA/glycine receptors and low micromolar potencies for AMPA and KA receptors. QXs 12a-e display 2-12-fold selectivity for NMDA/glycine receptors compared to AMPA receptors, and approximately 2-fold difference between AMPA and KA potency. In contrast to other QXs that either show high selectivity for NMDA (such as ACEA 1021) or AMPA (such as NBQX) receptors, these molecules are broad spectrum antagonists of ionotropic glutamate receptors. 7-Nitro-5-(N-oxyaza)-QX (12e) is the most potent inhibitor among 12a-e, having IC50 values of 0.69, 1.3, and 2.4 microM at NMDA, AMPA, and KA receptors, respectively. In functional assays on glutamate receptors expressed in oocytes by rat cerebral cortex poly(A+) RNA, 7-chloro-5-(N-oxyaza)-QX (12a) and 7-nitro-5-(N-oxyaza)-QX (12e) have Kb values of 0.63 and 0.31 microM for NMDA/glycine receptors, and are 6- and 4-fold selective for NMDA over AMPA receptors, respectively. 5-(N-Oxyaza)-7-substituted-QXs 12a-e all have surprisingly high in vivo potency as anticonvulsants in a mouse maximal electroshock-induced seizure (MES) model. 7-Chloro-5-(N-oxyaza)-QX (12a), 7-bromo-5-(N-oxyaza)-QX (12b), and 7-methyl-5-(N-oxyaza)-QX (12c) have ED50 values of 0.82, 0.87, and 0.97 mg/kg i.v., respectively. The high in vivo potency of QXs 12a-e is particularly surprising given their low log P values (approximately -2.7). Separate studies indicate that QXs 12a and 12e are also active in vivo as neuroprotectants and also have antinociceptive activity in animal pain models. In terms of in vivo activity, these 5-(N-oxyaza)-7-substituted-QXs are among the most potent broad spectrum ionotropic glutamate antagonists reported.

Animals↗