Biomedical subjects

H Sun

Publications and source records attributed to H Sun.

At least 91 records · Page 5Linked to original sources

PubMed2001

Does diabetes target ganglion neurones? Progressive sensory neurone involvement in long-term experimental diabetes.

Targeting of dorsal root ganglia by diabetes could account for the selective sensory abnormalities that patients with early diabetic polyneuropathy develop. In this work, we addressed survival, phenotype and gene expression in sensory neurones in lumbar dorsal root ganglia in a long-term model of experimental streptozotocin-induced diabetes in rats, designed to reflect human disease. Motor and sensory conduction slowing developed early, by the 2-month time point. At 2 months, sensory neurones had no detectable alterations in their calibre or gene expression, assessed using quantitative in situ hybridization studies for mRNA markers that included alpha CGRP, beta CGRP, NFM, t alpha 1-tubulin, SP, VIP, B50 (GAP43), galanin, somatostatin, PACAP, HSP27, c-jun, SNAP 25, p75, TrkA, TrkB and TrkC. By 12 months, however, diabetics had developed neurone perikaryal and distal axon atrophy, accompanied by generalized downregulation of mRNA expression, particularly of CGRP transcripts, PACAP, SP, NFM, p75, trkA and trkC. With the exception of HSP-27, no elevation in mRNAs that increase after injury, such as VIP, galanin, CCK, PACAP, B50 and t alpha 1-tubulin, was observed and constitutive levels, when detectable, trended towards lower rather than increased levels. There was relative preservation of neurone numbers at 12 months; only a non-significant trend towards fewer diabetic neurones was detected using a rigorous and systematic physical dissector counting approach through the entire L5 ganglia. There was no change in the relative populations of CGRP- and SP-immunoreactive neurones. Our findings indicate that even long-term experimental diabetes is associated with relative preservation of sensory neurone populations, but the neurones are atrophic and their gene expression is altered. This pattern of change differs from that following axotomy, implies a degenerative rather than an injury phenotype and has important implications for how such neurones might be rescued.

Animals↗

PubMed2001

Isolation of Cladonema Pax-B genes and studies of the DNA-binding properties of cnidarian Pax paired domains.

Pax genes encode nuclear transcription factors that are involved in developmental control. They contain a conserved DNA-binding domain, the paired domain. The DNA-binding specificity of paired domains is directly related to the gene regulation function of Pax proteins. Pax genes were previously divided into five groups on the basis of a phylogenetic analysis of paired domains. In this study, two highly similar cnidarian Pax-B genes from Cladonema californicum, a jellyfish with eyes, were found and sequenced. In an effort to understand the function of the cnidarian Pax genes isolated in this and a previous study, we characterized the consensus DNA sequences bound by the cnidarian paired domains using a PCR-based method and electrophoretic mobility shift assays. The consensus DNA sequences obtained are very similar to those bound by mammalian Pax proteins. Comparison of known consensus sequences indicates that they are all partially palindromic, but this characteristic is most prominent in cnidarians, which suggests that the DNA sequences bound by the ancestral paired domain could have been palindromic. Also, cnidarian paired domains, like those of Pax-2/5/8, possess a broader binding specificity than other paired domains, which implies that the common ancestor of Pax-2/5/8 and Pax-4/6 paired domains could also have had a similar broad DNA-binding specificity. Thus far, a definitive Pax-6 gene has not been found in several cnidarian species examined, which is consistent with a later origin of the Pax-6 gene and raises two possibilities: the Pax genes of cnidarians are multifunctional and control two or more developmental pathways, including eye development, or they use a Pax-independent pathway for eye development. Whether this pathway does exist and is unique to cnidarians or it whether it represents a true master control under which Pax-6 was later included remains to be determined.

Animals↗

PubMed2001

Enhanced atherosclerosis in Lp(a) WHHL transgenic rabbits.

High lipoprotein(a) [Lp(a)] levels form a major risk factor for the development of atherosclerosis. The risk of elevated Lp(a) concentrations is significantly increased in patients who also have high levels of LDL cholesterol. Although the relation between Lp(a) and atherosclerosis has been reported in numerous studies, little is known about whether Lp(a) would exacerbate the complicated lesion formation in vivo. To test the hypothesis that increased plasma levels of Lp(a) may enhance the development of atherosclerosis in the setting of hypercholesterolemia, we generated WHHL transgenic rabbits expressing human apolipoprotein (a) and compared the atherosclerotic lesions with those of nontransgenic WHHL rabbits.

Animals↗

PubMed2001

Global comparisons between contact and noncontact mapping techniques in the right atrium: role of cavitary probe size.

In the right atrium (RA) we globally investigated: (1) the properties of noncontact electrograms measured by multielectrode cavitary probes, (2) the features of endocardial electrograms computed from the noncontact probe electrograms, and (3) the impact of the probe size on both the noncontact and the computed electrograms. We deployed a custom catheter in the dog RA, which consisted of a cylindrical probe with 64 electrodes on its surface, for measuring noncontact cavitary electrograms, and a concentric endocardial basket carrying an additional array of 64 electrodes, for measuring contact endocardial electrograms (the "gold standard"). Both a 5-mm- and a 10-mm-diam probe (P5 and P10, respectively) were sequentially tested in the same RA of one dog. Unipolar electrograms from both the probe and the basket were simultaneously acquired during normal as well as during paced rhythms (n > or =24 protocols per probe). Boundary element method and numeric regularization were applied to compute endocardial electrograms at the basket electrode locations. We found that noncontact electrograms were attenuated and smoothed, and this effect was exaggerated with the small probe. Computed endocardial electrograms more accurately reconstructed important amplitude distribution and morphological features; peak-to-peak amplitude error, 35% for P5 and 34% for P10. Activation and spatial errors of computed endocardial electrograms were 8.8+/-6.8 ms and 5.1+/-6.1 mm for P5, respectively, and 6.0+/-5.5 ms and 3.2+/-4.4 mm for P10, respectively. In conclusion, global RA activation may be delineated directly from noncontact cavitary electrograms alone, but may be affected by volume attenuation, smoothing, and probe size. Accurate endocardial electrograms, however, can be successfully computed from noncontact electrograms acquired with small probes and be used to reconstruct both electrogram amplitude and detailed morphology.

Animals↗

PubMed2001

Genetic studies of mrp, a locus essential for cellular aggregation and sporulation of Myxococcus xanthus.

Under starvation conditions, Myxococcus xanthus undergoes a complex developmental process which includes cellular aggregation and sporulation. A transposon insertion mutant (the Tn5-Omega280 mutant) with defects in both aggregation and sporulation was analyzed in this study. The Tn5-Omega280 mutant was found to have a disrupted NtrC-like response regulator designated Myxococcus regulatory protein B (mrpB). Further sequencing analyses revealed a histidine kinase homolog (mrpA) immediately upstream of mrpB and a cyclic AMP receptor protein-like transcriptional regulator (mrpC) downstream of mrpB. In-frame deletion analyses revealed that both the mrpB and mrpC genes were required for cellular aggregation and sporulation but that only mrpA was required for sporulation only. Site-specific mutagenesis of the putative phosphorylation site of MrpB, D58, showed that a D58A mutation caused defects in both aggregation and sporulation but that a D58E mutation resulted in only a sporulation defect. Further genetic and molecular analyses with reporter genes and reverse transcription-PCR indicated that mrpA and mrpB are cotranscribed but that mrpC is transcribed independently and that all of these genes are developmentally regulated. In addition, MrpB is essential for transcription of mrpC and MrpC regulates its own transcription. These data indicate that Mrp proteins are important components required for M. xanthus development. The complicated interaction between Mrp proteins may play an important role in regulating developmental gene expression in M. xanthus.

Amino Acid Sequence↗

PubMed2001

Analyses of mrp genes during Myxococcus xanthus development.

Myxococcus xanthus is a gram-negative soil bacterium that undergoes development under starvation conditions. Our previous study identified a new genetic locus, mrp, which is required for both fruiting body formation and sporulation. The locus encodes two transcripts: mrpAB, which consists of a histidine kinase and an NtrC-like response regulator, and mrpC, a cyclic AMP receptor protein family transcription activator. In this study, we used genetic and biochemical analyses to investigate the possible interactions between the mrp genes and other known developmental genes and events. These studies show that the mrp genes possibly function after A-signaling and (p)ppGpp but before C-signaling and that they regulate various early and late developmental genes and events.

Bacterial Proteins↗

PubMed2001

Temporal effect of alcohol consumption on reactivity of pial arterioles: role of oxygen radicals.

Chronic alcohol consumption reduces nitric oxide synthase-dependent responses of pial arterioles via mechanisms that remain uncertain. In addition, the temporal effects of alcohol on pial arterioles is unclear. Thus our goals were to examine the role of oxygen-derived free radicals in alcohol-induced impairment of cerebrovascular reactivity and the temporal effect of alcohol on reactivity of pial arterioles. Sprague-Dawley rats were pair-fed a liquid diet with or without alcohol for 2-3 wk, 2-3 mo, or 5-6 mo. We measured the in vivo diameter of pial arterioles in response to nitric oxide synthase-dependent dilators acetylcholine and ADP and the nitric oxide synthase-independent dilator nitroglycerin. In nonalcohol-fed rats, acetylcholine (1.0 and 10 microM) and ADP (10 and 100 microM) produced dose-related dilatation of pial arterioles. Whereas there was no difference in reactivity of arterioles to the agonists in rats fed the nonalcohol and alcohol diets for a period of 2-3 wk, there was a significant impairment in reactivity of arterioles to acetylcholine and ADP, but not nitroglycerin, in rats fed the alcohol diet for longer durations. We then found that treatment with superoxide dismutase did not alter baseline diameter of pial arterioles in nonalcohol-fed or alcohol-fed rats, but significantly improved impaired nitric oxide synthase-dependent dilatation of pial arterioles in alcohol-fed rats. Thus our findings suggest a temporal relationship in the effects of alcohol on reactivity of pial arterioles and that impaired nitric oxide synthase-dependent cerebral vasodilatation during chronic alcohol consumption may be related, in part, to enhanced release of oxygen-derived free radicals.

Acetylcholine↗

PubMed2001

Tetrahydrobiopterin, a cofactor for NOS, improves endothelial dysfunction during chronic alcohol consumption.

We sought to investigate mechanisms that may account for impaired nitric oxide synthase (NOS)-dependent dilatation of cerebral arterioles during alcohol consumption. Our goals were to examine 1) the effect of exogenous application of a cofactor for NOS, i.e., tetrahydrobiopterin (BH4) on the reactivity of pial arterioles during alcohol consumption; and 2) endothelial NOS (eNOS) protein in nonalcohol-fed and alcohol-fed rats. Sprague-Dawley rats were fed liquid diets with or without alcohol for 2-3 mo. We measured in vivo diameter of pial arterioles in response to NOS-dependent agonists (ACh and ADP) and a NOS-independent agonist (nitroglycerin) before and during application of BH4. Blood vessels were then harvested for Western blot analysis of eNOS protein. In nonalcohol-fed rats, ACh and ADP produced vasodilatation, which was impaired in alcohol-fed rats. Vasodilatation to nitroglycerin was similar in both groups of rats. Application of BH4 did not alter vasodilatation in nonalcohol-fed rats but improved impaired vasodilatation in alcohol-fed rats. Also, eNOS protein in cerebral cortex microvessels, the basilar artery, and aorta was not different between nonalcohol-fed and alcohol-fed rats. Thus impaired NOS-dependent vasodilatation during alcohol consumption does not appear to be related to an alteration in eNOS protein but may be related to a deficiency and/or alteration in the utilization of BH4.

Alcoholism↗

PubMed2001

Intra-operative image updating.

Intraoperative brain shift and deformation pose challenges for image-guided surgery. One strategy to address these problems utilizes computational modeling coupled with intraoperatively acquired information from efficient and economical sources such as ultrasound and the optics of the operating microscope. Calibration algorithms for the accurate integration of these sparse data sources have been implemented. Assessment has been performed in both phantom and pig brain models, and accuracy better than 2 mm has been achieved. Methods of incorporating these data into the computational model are being developed.

Animals↗

PubMed2001

Transgenic rabbits expressing human apolipoprotein(a) develop more extensive atherosclerotic lesions in response to a cholesterol-rich diet.

High lipoprotein(a) [Lp(a)] levels constitute an independent risk factor for the development of atherosclerosis. However, the relationship between Lp(a) and atherosclerosis is not fully understood. To examine the effect of Lp(a) on the development of atherosclerosis, we studied transgenic rabbits expressing human apolipoprotein(a) [apo(a)], which was assembled into Lp(a) in the plasma. Human apo(a) transgenic rabbits fed a 0.3% cholesterol diet for 16 weeks had more extensive atherosclerotic lesions than did nontransgenic rabbits, although the cholesterol levels in the plasma of both groups were similarly elevated. Compared with the lesions in control rabbits, the areas of the atherosclerotic lesions in human apo(a) transgenic rabbits were significantly increased in the aorta, the iliac artery, and the carotid artery. Furthermore, human apo(a) transgenic rabbits on a cholesterol-rich diet had a greater degree of coronary atherosclerosis than did control rabbits. Immunohistochemical analysis revealed that human apo(a) was frequently deposited in the atherosclerotic lesions of transgenic rabbits. We conclude that Lp(a) may have proatherogenic effects in the setting of a cholesterol-rich diet in transgenic rabbits.

Animal Feed↗

PubMed2001

Brightness induction from rods.

Rod modulation of an annular surround can produce brightness contrast in a test field centered at 100 from the fovea. In our research, stimuli originated from a colorimeter that provided 4 primaries in both the circular test and the annular surround fields, and allowed independent modulation of the rods and each of the short (S)-, middle (M)-, and long (L)-wavelength-sensitive cone types. The chromaticity was set so fields had the same appearance as the equal energy spectrum. At 1 photopic troland (td), rod-induced modulation in the test field could be cancelled by either a rod- or a cone-nulling modulation added to the test field. The best cone nulling of rod induction showed residual flicker. Nulling was more effective, though still imperfect, with a cone-nulling stimulus of higher S-cone modulation contrast. Rod induction with square-wave, on-pulse, and off-pulse temporal profiles was closely similar. At higher light levels, 10 and 100 td, rod contrast could not be nulled by rod or cone modulation. The failure to achieve nulls may have been caused by either or both of the following hypotheses: (1) there is a mismatch between the rod and cone temporal waveforms; (2) there is strong rod input to the magnocellular pathway, but negligible rod input to the parvocellular pathway, as shown by single-unit electrophysiological data.

Color Perception↗

PubMed2001

Rod-cone interactions assessed in inferred magnocellular and parvocellular postreceptoral pathways.

Interactions between receptor-isolating rod and long (L)- or middle (M)-wavelength-sensitive cone modulations at 2 Hz and 10 Hz were analyzed in terms of underlying inferred magnocellular (MC) and parvocellular (PC) postreceptoral pathways. Stimuli originated from a colorimeter with 4 primaries in both the center and surround fields. The first experiment employed a phase paradigm in which the thresholds for mixed rod and cone modulations were measured as a function of relative phase. The amplitudes of the rod and cone modulations, equated in threshold units, were varied in tandem. In the second experiment, thresholds for mixed rod and cone modulations were measured as a function of the ratio of the rod and cone modulation amplitudes for 2 fixed phase offsets. Both experiments yielded similar interpretations of rod and L- (or M-) cone interactions. At 1 and 10 troland (td), rod and L- (or M-) cone interactions varied depending on the postreceptoral pathways underlying the detection. When cone thresholds were mediated by the inferred MC pathway, rod and cone thresholds showed almost linear summation. When cone thresholds were mediated by the inferred PC pathway, rod and cone thresholds showed probability summation. Assuming that signals within the same pathway follow linear summation, and signals traveling in different pathways follow probability summation, we concluded that the rod thresholds were mediated by the inferred MC pathway for both the 2-Hz and 10-Hz conditions.

Contrast Sensitivity↗

PubMed2001

Mutational analysis of the PTEN gene in endometrial carcinoma and hyperplasia.

To determine the potential role of PTEN in the process of endometrial carcinogenesis, we examined a series of endometrial carcinoma and hyperplasia of the uterine corpus for the presence of a PTEN mutation. The entire coding region of the gene was screened for the presence of mutations by single-strand conformation polymorphism analysis, and mutations were confirmed by sequencing. We detected mutations in 14 of 57 endometrial carcinomas (13 of 50 endometrioid adenocarcinomas and 1 of 7 nonendometrioid adenocarcinomas) and 7 of 73 endometrial hyperplasias (1 of 24 simple hyperplasias without atypia, none of 16 complex hyperplasias without atypia, and 6 of 33 complex hyperplasias with atypia). Most (88%) mutations were clustered in exons 5, 7, and 8. Of the 24 mutations detected in 21 cases, 12 were frameshifts, 9 were nonsense, 2 were missense, and 1 was a silent mutation. Patients with a PTEN mutation had a better prognosis than those with no PTEN mutation. The presence of PTEN mutations in hyperplasia suggests that PTEN inactivation may occur as an initiating event in endometrial carcinogenesis and is involved in the development of cytologic atypia in hyperplasia.

Carcinoma↗

PubMed2001

Effect of capillary efflux transport inhibition on the determination of probe recovery during in vivo microdialysis in the brain.

Intracerebral microdialysis probe recovery (extraction fraction) may be influenced by several mass transport processes in the brain, including efflux and uptake exchange between brain and blood. Therefore, changes in probe recovery under various experimental conditions can be useful to characterize fundamental drug transport processes. Accordingly, the effect of inhibiting transport on probe recovery was investigated for two capillary efflux transporters with potentially different membrane localization and transport mechanisms, P-glycoprotein and an organic anion transporter. Fluorescein/probenecid and quinidine/LY-335979 were chosen as the substrate/inhibitor combinations for organic anion transport and P-glycoprotein-medicated transport, respectively. Probenecid decreased the probe recovery of fluorescein in frontal cortex, from 0.21 +/- 0.017 to 0.17 +/- 0.020 (p < 0.01). Quantitative microdialysis calculations indicated that probenecid treatment reduced the total brain elimination rate constant by 3-fold from 0.37 to 0.12 (ml/min. ml of extracellular fluid). In contrast, the microdialysis recovery of quinidine, delivered locally to the brain via the probe perfusate, was not sensitive to P-glycoprotein inhibition by systemically administered LY-335979, a potent and specific inhibitor of P-glycoprotein. Recovery of difluorofluorescein, an analog of fluorescein, was also decreased by probenecid in the frontal cortex but not in the ventricle cerebrospinal fluid. These experimental observations are in qualitative agreement with microdialysis theory incorporating mathematical models of transporter kinetics. These studies suggest that only in certain circumstances will efflux inhibition at the blood-brain barrier and blood-cerebrospinal fluid barrier influence the microdialysis probe recovery, and this may depend upon the substrate and inhibitor examined and their routes of administration, the localization and mechanism of the membrane transporter, as well as the microenvironment surrounding the probe.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

[Effects of interferon-alpha on recurrence and metastasis of hepatocellular carcinoma after curative resection in nude mice].

OBJECTIVE: To study the effect of interferon-alpha (IFN-alpha) on the recurrence and metastasis of hepatocellular carcinoma (HCC) in nude mice, and to clarify if there is synergistic effect treated by combination of IFN-alpha and all-trans retinoic acid (ATRA). METHODS: The effect of IFN-alpha and/or ATRA on the proliferation of HCC cell lines was measured in vitro. The metastatic model of human HCC in nude mice LCI-D20 was used in present study. Curative resection was performed at 10th day after implantation in 44 nude mice. Drugs were given at the next day after resection. IFN-alpha was administered subcutaneously at doses of 3+/-10(5) U/day, 6+/-10(5) U/day, respectively. ATRA was administered p.o. at a dose of 20 mg/kg/day, and IFN-alpha 6+/-10(5)U/day combined with ATRA 20 mg/kg/day. The mice were sacrificed 35 days after treatment. The recurrent tumor size was measured and the presence of intrahepatic dissemination and lung metastases were recorded. RESULTS: The effect of IFN-alpha and/or ATRA on the proliferation of HCC cells SMMC7721, BEL-7402, BEL-7405, and MHCC97 was not obvious. The combination of IFN-alpha and ATRA had no synergistic effect in vitro. The lung metastatic rate, the liver recurrent rate, the size of main recurrent lesions, the number of intrahepatic disseminating nodules and the largest disseminating nodule of the controlled group was 100%(12/12), 100%(12/12), (1346.3+/-4.2 ) mm(3), 8.2+/-4.4, 864 mm(3), respectively; whereas it was 0, 87.5%(7/8), (8.7+/-2.9) mm(3), 2.3+/-0.6, and 7.8mm(3), respectively in the IFN-alpha 3+/-10(5) U/day treated group(P<0.05); 0, 12.5%(1/8), 0.5mm(3), 2, 0.5 mm(3) in the IFN-alpha 6+/-10(5)U/day treated group(P<0.05); 0, 12.5%(1/8), 1 mm(3), 2.5+/-0.7, 8 mm(3) in the IFN-alpha 3+/-10(5) U/day and ATRA treated group(P<0.05); 87.5%, 100%, (1472.6+/-5.6) mm(3), 7.3+/-3.8, 768.5 mm(3) in the ATRA treated group (P>0.05). CONCLUSIONS: IFN-alpha has an inhibitory effect on intrahepatic recurrence and lung metastasis of human HCC after curative resection in nude mice, and the effect is enhanced with increasing dose. IFN-alpha and ATRA have no synergistic effect according to in vivo and in vitro test. ATRA has no effect on recurrence and metastasis of HCC.

Animals↗

PubMed2001

[Genetic relationships among six Chinese populations revealed by analysis of 30 autosomal STRs].

30 autosomal STRs of 6 Chinese populations (Bai, Naxi, Tu, Sala, Han in Shandong, She) were amplified by multiplex PCRs using fluerescein-labelled primers. Shriver's Dsw was estimated on the basis of the results of the genescanning and genotyping after running unnatural PAGE of the PCRs' products on ABI 377 sequencer. Phylogenetic trees were constructed by using Neighbor-Joining and UPGMA method based on Dsw, and then the genetic relationships among them were analyzed referring to some relative informations. Our results indicated that the genetic distance between Sala and Tu is near, 0.033. But the distances between Sala and other four populations are far, over 0.12; Tu is close to Naxi and Shandong Han, and the distances are 0.038, 0.063 respectively; The distance between Bai and Han is the nearest, 0.007, but there is a distance, 0.075, between Bai and Naxi, and a far distance, 0.112, between Bai and Tu; The distance between Naxi and Han is 0.100 and the distances between She and other 5 populations are all over 0.12. In both of the NJ and UPGMA phylogenetic trees, Naxi, Tu and Sala is one cluster and Bai and Han is another cluster. She is a single branch. These results, basically consistent with 6 Chinese populations' geographic distribution and histories, can provide some genetic information to comprehensively study their origin, migration, formation and development with their historical records and archaeological evidence.

Asian People↗

PubMed2001

[Measurement of chlorodifluoromethane(HCFC-22) in the atmosphere by using an O2-induced electron capture detector (ECD)].

Chlorodifluoromethane (CHClF2, HCFC-22), a typical substitute of dichlorodifluoromethane(CF2Cl2, CFC-12), which atmospheric concentration was only at 10(-12) V/V level. After preconcentrated air sample, O2-Induced method was used to enhance sensitivity of ECD response to HCFC-22. When O2 concentration in carrier gas was 0.54%, there was the greatest value of S/N(signal to noise) and ECD response increased by about 500 times. With the study of other conditions, such as selection of the ECD temperature, programing of the column oven temperature and carrier gas flow, a practicable analysis method with high sensitivity of ECD was established.

Air↗

PubMed2001

Benzylidene analogs of anabaseine display partial agonist and antagonist properties at the mouse 5-hydroxytryptamine(3A) receptor.

The nicotinic receptor drug candidate, 3-(2,4-dimethoxybenzylidene)-anabaseine (also known as GTS-21; DMXBA), its hydroxy metabolites, and some related analogs were evaluated with the two-electrode voltage-clamp technique in mouse 5-hydroxytryptamine (5-HT)(3A) receptors expressed in Xenopus oocytes. Although DMXBA lacked partial agonist activity, its hydroxy-benzylidene metabolites and related analogs were partial agonists, displaying the following rank order of potency (EC(50)) and apparent efficacy: 5-HT, 0.9 +/- 0.06 microM (100% efficacy) > 3-(2-hydroxy,4-methoxybenzylidene)-anabaseine (2-OH-MBA), 2.0 +/- 0.3 microM (63% efficacy) > 3-(2,4-dihydroxybenzylidene)-anabaseine, 2.6 +/- 0.3 microM (63% efficacy) > 3-(2-methoxy,4-hydroxybenzylidene)-anabaseine, 17.2 +/- 1.0 microM (30% efficacy). To examine the influence of a benzylidene ring hydroxy substituent, the agonist actions of the three possible monohydroxy isomers were examined. The rank order of potency, based on EC(50) determinations, and apparent efficacy was: 3-(2-hydroxybenzylidene)-anabaseine, 20.3 +/- 2.6 microM (63% efficacy) > 3-(4-hydroxybenzylidene)-anabaseine, 32.3 +/- 5.9 microM (14% efficacy) > 3-(3-hydroxybenzylidene)-anabaseine (3-OH-BA) (no agonist activity). Both DMXBA and 3-OH-BA antagonized 5-HT-mediated currents, with IC(50) values of 15.7 +/- 0.9 and 27.5 +/- 4.7 microM, respectively. DMXBA demonstrated both competitive and noncompetitive forms of antagonism over the range of concentrations tested. These results suggest that a hydroxy substituent at the 2' position of the benzene ring is necessary and sufficient for partial agonist activity; substitution at the 4' position with a hydroxy or methoxy group further enhances agonist potency. Because 2-OH-MBA is a primary metabolite of DMXBA, it may contribute to the physiological, biochemical, and behavioral effects of the parent compound when administered in vivo.

Anabasine↗