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Potentiation
Kinds of Potentiation Selected AbstractsEcotoxicologic impacts of agricultural drain water in the Salinas River, California, USAENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2003Brian S. Anderson Abstract The Salinas River is the largest of the three rivers that drain into the Monterey Bay National Marine Sanctuary in central California (USA). Large areas of this watershed are cultivated year-round in row crops, and previous laboratory studies have demonstrated that acute toxicity of agricultural drain water to Ceriodaphnia dubia is caused by the organophosphate (OP) pesticides chlorpyrifos and diazinon. We investigated chemical contamination and toxicity in waters and sediments in the river downstream of an agricultural drain water input. Ecological impacts of drain water were investigated by using bioassessments of macroinvertebrate community structure. Toxicity identification evaluations were used to characterize chemicals responsible for toxicity. Salinas River water downstream of the agricultural drain was acutely toxic to the cladoceran Ceriodaphnia dubia, and toxicity to C. dubia was highly correlated with combined toxic units (TUs) of chlorpyrifos and diazinon. Laboratory tests were used to demonstrate that sediments in this system were acutely toxic to the amphipod Hyalella azteca, a resident invertebrate. Toxicity identification evaluations (TIEs) conducted on sediment pore water suggested that toxicity to amphipods was due in part to OP pesticides; concentrations of chlorpyrifos in pore water sometimes exceeded the 10-d mean lethal concentration (LC50) for H. azteca. Potentiation of toxicity with addition of the metabolic inhibitor piperonyl butoxide suggested that sediment toxicity also was due to other non,metabolically activated compounds. Macroinvertebrate community structure was highly impacted downstream of the agricultural drain input, and a number of macroinvertebrate community metrics were negatively correlated with combined TUs of chlorpyrifos and diazinon, as well as turbidity associated with the drain water. Some macroinvertebrate metrics were also correlated with bank vegetation cover. This study suggests that pesticide pollution is the likely cause of ecological damage in the Salinas River, and this factor may interact with other stressors associated with agricultural drain water to impact the macroinvertebrate community in the system. [source] Potentiation of glycine responses by dideoxyforskolin and tamoxifen in rat spinal neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2003Dominique Chesnoy-Marchais Abstract Dideoxyforskolin, a forskolin analogue unable to stimulate adenylate cyclase, and tamoxifen, an antioestrogen widely used against breast cancer, are both known to block some Cl, channels. Their effects on Cl, responses to glycine or GABA have been tested here by using whole-cell recording from cultured spinal neurons. Dideoxyforskolin (4 or 16 µm) and tamoxifen (0.2,5 µm) both potentiate responses to low glycine concentrations. They also induce blocking effects, predominant at high glycine concentrations. At 5 µm, tamoxifen increased responses to 15 µm glycine by a factor >4.5, reaching 20 in some neurons. Potentiation by extracellular dideoxyforskolin or tamoxifen persisted after intracellular application of the modulator and was not due to Zn2+ contamination. Potentiation by tamoxifen also persisted in a Ca2+ -free extracellular solution, after intracellular Ca2+ buffering and protein kinase C blockade. Thus, the critical sites of action are not intracellular. The EC50 for glycine was lowered 6.6-fold by 5 µm tamoxifen. The kinetics and voltage-dependence of the effects of tamoxifen on glycine responses support the idea that this hydrophobic drug may act from a site located within the membrane. Tamoxifen (5 µm) also increased responses to 2 µm GABA by a factor of 3.5, but barely affected peak responses to 20 µm GABA. The demonstration that tamoxifen affects some of the main inhibitory receptors should be useful for better evaluating its neurological effects. Furthermore, the results identify a new class of molecules that potentiate glycine receptor function. [source] Potentiation of 3-hydroxyglutarate neurotoxicity following induction of astrocytic iNOS in neonatal rat hippocampal culturesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2001Stefan Kölker Abstract Neuronal damage in glutaryl-CoA dehydrogenase deficiency (GDD) has previously been addressed to N- methyl- d -aspartate (NMDA) receptor-mediated neurotoxicity of the accumulating neurotoxic metabolite 3-hydroxyglutarate. However, acute encephalopathic crises in GDD patients are typically precipitated by febrile illness or even routine vaccinations, suggesting a potentiating role of inflammatory cytokines. In the present study we investigated the effect of interleukin-1, and interferon-, on 3-hydroxyglutarate toxicity in rat cortical astrocyte cultures and neonatal rat hippocampal cultures. A cotreatment of both culture systems with interleukin-1, and interferon-, induced the protein expression of astrocytic inducible nitric oxide synthase (iNOS), resulting in increased nitric oxide (NO) production. Cytokine pretreatment alone had no effect on cell viability but potentiated 3-hydroxyglutarate neurotoxicity. NOS inhibition by aminoguanidine and L-NAME prevented an iNOS-mediated potentiation of 3-hydroxyglutarate neurotoxicity but failed to protect neurons against 3-hydroxyglutarate alone. In contrast, superoxide dismutase/catalase as well as MK-801 prevented toxicity of 3-hydroxyglutarate alone as well as its potentiation by iNOS, supporting a central role of NMDA receptor stimulation with subsequently increased superoxide anion production. It is concluded that the potentiation of 3-hydroxyglutarate neurotoxicity is most probably due to an induction of astrocytic iNOS and concomitantly increased NO production, enabling enhanced peroxynitrite formation. Thus, we provide evidence for a neuroimmunological approach to the precipitation of acute encephalopathic crises in GDD by inflammatory cytokines. [source] Potentiation of isoniazid-induced liver toxicity by rifampicin in a combinational therapy of antitubercular drugs (rifampicin, isoniazid and pyrazinamide) in Wistar rats: A toxicity profile studyHEPATOLOGY RESEARCH, Issue 10 2007Sheikh Abdullah Tasduq Aim:, Biochemical characterization of long-term toxic manifestations of anti-tubercular (anti-TB) drugs , rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) , individually and in two combinations: (i) RIF + INH, and (ii) RIF + INH + PZA in Wistar rats. Methods:, Animals received anti-TB drugs , alone or in combination , once daily p.o. for up to 90 days (doses, in mg/kg: RIF, 250; INH, 50; PZA, 100). Assays for alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin (serum) and lipid peroxidation (LPO), glutathione (GSH), glutathione peroxidase (GPx), catalase, Na+K+-ATPase and CYP 2E1 (liver) were performed to assess liver toxicity. Clinical biochemistry was done by commercial kits. Determinations were made at 0, 15, 30 and 90 days of treatment schedule. Results:, Anti-TB drugs-treated animals showed abnormal rises or falls (>1.5,2 fold) in the serum/liver parameters. Mild hyperlipidemia, hypercholesterolemia and hyperuricemia were the other pathologies. Of all the treated groups, INHalone or in combination with other drugs produced a progressive enhancement of toxicity over 15,90 days. The in vivo results were further supported by in vitro results (MTT assay, GSH and LPO) in primary cultures of rat hepatocyte. Results indicated that anti-TB drugs in combination: (i) caused membrane damage resulting in leakage of ALT, ALP and bilirubin; (ii) caused imbalance in endogenous enzymatic oxidant,antioxidant defense via increased lipid peroxidation and in glutathione homeostasis; and (iii) enhanced the CYP 2E1-mediated bioactivation mechanism. Conclusion:, Toxicity manifestations seemed to be heptocytic injury targeted at hepatocytes, bile ducts or sinusoidal cells related to hepatitis and primary biliary cholestasis. [source] Role of Endothelium/Nitric Oxide and Cyclic AMP in Isoproterenol Potentiation of 17ß-Estradiol-Mediated VasorelaxationJOURNAL OF CARDIAC SURGERY, Issue 6 2002HY Chan Estrogen exerts vasorelaxation and cardiac protection via multiple cellular mechanisms. Estrogen modifies vasodilatation induced by certain relaxants such as ß-adrenoceptor agonists. However, little is known whether low concentrations of ß-adrenoceptor agonists would also influence the acute relaxant response to estrogen. The present study was designed to investigate the synergistic interaction between isoproterenol and 17ß-estradiol, and to study the role of endothelium and cyclic AMP-dependent pathway in this interaction. Changes in vessel tone of the isolated rat mesenteric artery rings were measured by force-displacement Grass transducer. In 9,11-dideoxy-11,, 9,-epoxy-methanoprostaglandin F2, - preconstricted endothelium-intact rings, 17ß-estradiol induced concentration-dependent relaxation with pD2 of 5.074 ± 0.043. Pretreatment of endothelium-intact rings with isoproterenol (1-3 × 10 -9 M, 1-h incubation time) significantly enhanced 17,-estradiol-induced relaxation. Longer incubation (2.5 h) did not produce further amplifying effect. This effect was inhibited by Rp-cGMPS triethylamine (3 × 10 -6 M), and disappeared in the presence of 3 × 10 -5 M NG -nitro-L-arginine methyl ester or in the endothelium-denuded rings. The effect of isoproterenol was partially antagonized by propranolol (3 × 10 -6 M), ICI 118,551 (3 × 10 -6 M) but not by atenolol (10 -5 M). None of three ,-adrenoceptor antagonists affected 17ß-estradiol-induced relaxation in the absence of isoproterenol. Rp-cAMPS triethylamine (3 × 10 -6 M) abolished the effect of isoproterenol. Besides, exposure to 3 × 10 -9 M forskolin for 1 h also potentiated the relaxant response to 17,-estradiol. In summary, this isoproterenol enhancement was dependent on the presence of endothelium and abolished by L-NAME via a ,2 -adrenoceptor-mediated cyclic AMP-dependent mechanism. These data also indicate the possible existence of cyclic AMP-dependent nitric oxide-producing pathway in the regulation of the vascular response to vasodilators. (supported by UPGC Direct Grant) [source] Potentiation of angiogenic response by ischemic and hypoxic reconditioning of the heartJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2002Nilanjana Maulik Abstract This review is intended to discuss the newly discovered role of preconditioning which should make it an attractive therapeutic stimulus for repairing the injured myocardium. We recently found that apart from rendering the myocardium tolerant to ischemic reperfusion injury, preconditioning also potentiates angiogenesis. Our study demonstrated for the first time that both ischemic and hypoxic preconditioning triggered myocardial angiogenesis at the capillary and arteriolar levels which nicely corroborated with the improved myocardial contractile function.Hypoxic preconditioning resulted in the stimulation of VEGF, the most potent angiogenic factor known to date. In concert, endothelial cell specific tyrosine kinase receptors, Tie 1, Tie 2 and Flt-1 and Flk-1 were also significantly enhanced in the preconditioned myocardium. The redox-regulated transcription factor NFkB was found to play an essential role in the preconditioning regulation of angiogenesis [source] Essential role of PSM/SH2-B variants in insulin receptor catalytic activation and the resulting cellular responsesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2008Manchao Zhang Abstract The positive regulatory role of PSM/SH2-B downstream of various mitogenic receptor tyrosine kinases or gene disruption experiments in mice support a role of PSM in the regulation of insulin action. Here, four alternative PSM splice variants and individual functional domains were compared for their role in the regulation of specific metabolic insulin responses. We found that individual PSM variants in 3T3-L1 adipocytes potentiated insulin-mediated glucose and amino acid transport, glycogenesis, lipogenesis, and key components in the metabolic insulin response including p70 S6 kinase, glycogen synthase, glycogen synthase kinase 3 (GSK3), Akt, Cbl, and IRS-1. Highest activity was consistently observed for PSM alpha, followed by beta, delta, and gamma with decreasing activity. In contrast, dominant-negative peptide mimetics of the PSM Pro-rich, pleckstrin homology (PH), or src homology 2 (SH2) domains inhibited any tested insulin response. Potentiation of the insulin response originated at the insulin receptor (IR) kinase level by PSM variant-specific regulation of the Km (ATP) whereas the Vmax remained unaffected. IR catalytic activation was inhibited by peptide mimetics of the PSM SH2 or dimerization domain (DD). Either peptide should disrupt the complex of a PSM dimer linked to IR via SH2 domains as proposed for PSM activation of tyrosine kinase JAK2. Either peptide abolished downstream insulin responses indistinguishable from PSM siRNA knockdown. Our results implicate an essential role of the PSM variants in the activation of the IR kinase and the resulting metabolic insulin response. PSM variants act as internal IR ligands that in addition to potentiating the insulin response stimulate IR catalytic activation even in the absence of insulin. J. Cell. Biochem. 103: 162,181, 2008. © 2007 Wiley-Liss, Inc. [source] Regions of the amino terminus of the P2X1 receptor required for modification by phorbol ester and mGluR1, receptorsJOURNAL OF NEUROCHEMISTRY, Issue 2 2009Hairuo Wen Abstract The potentiation of P2X1 receptor currents by phorbol ester (PMA) treatment and stimulation of mGluR1, receptors was sensitive to inhibition of novel forms of protein kinase C. Potentiation was also reduced by co-expression of an amino terminal P2X1 receptor minigene. Cysteine point mutants of residues Tyr16 -Gly30 were expressed in Xenopus oocytes. Peak current amplitudes to ATP for Y16C, T18C and R20C mutants were reduced, however this did not result from a decrease in surface expression of the channels. The majority of the mutants showed changes in the time-course of desensitization of ATP evoked currents indicating the important role of this region in regulation of channel properties. PMA and mGluR1, potentiation was abolished for the mutants Y16C, T18C, R20C, K27C and G30C. Minigenes incorporating either Y16C, K27C, V29C or G30C still inhibited PMA responses. However D17C, T18C or R20C mutant minigenes were no longer effective suggesting that these residues are important for interaction with regulatory factors. These results demonstrate that the conserved YXTXK/R sequence and a region with a conserved glycine residue close to the first transmembrane segment contribute to PMA and GPCR regulation of P2X1 receptors. [source] Potentiation of PGE2 -mediated cAMP production during neuronal differentiation of human neuroblastoma SK-N-BE(2)C cellsJOURNAL OF NEUROCHEMISTRY, Issue 2 2001Se-Young Choi The prostaglandin-evoked cAMP production was studied in human neuroblastoma SK-N-BE(2)C cells during neuronal differentiation induced by all- trans retinoic acid. The incubation with 5 µm all- trans retinoic acid for 4,6 days promoted neurite outgrowth of cells. After differentiation, prostaglandin E2 (PGE2)-induced cAMP production was dramatically increased, whereas forskolin- and AlF -induced cAMP productions were not changed. The increase reached maximum after 4-days of incubation with all- trans retinoic acid. The differentiation caused an increase in the maximal response and a decrease in the half-maximal effective concentration of the PGE2 -induced cAMP production. In addition, the binding of [3H]PGE2 to membrane receptors was enhanced in differentiated cells. However, the order of potency of the various prostaglandins (PGE1 = PGE2 > PGD2 = PGF2, = PGI2) in cAMP production did not change during the differentiation, suggesting that mainly E-prostanoid (EP) receptors were involved. Butaprost, an EP2 receptor specific agonist, increased the cAMP level in a concentration dependent manner and had a similar potentiating effect on cAMP production as PGE2 upon differentiation. Northern blot analysis using the human cDNA probes shows that the EP2 mRNA level was about seven times higher in differentiated cells, while the dopamine ,-hydroxylase (DBH) mRNA completely disappeared. Our results, thus, suggest that elevated gene expression of the prostanoid EP2 receptor results in an increase in the PGE2 -evoked cAMP production in SK-N-BE(2)C cells during neuronal differentiation. [source] Involvement of ,, Subunits of Gq/11 in Muscarinic M1 Receptor Potentiation of Corticotropin-Releasing Hormone-Stimulated Adenylyl Cyclase Activity in Rat Frontal CortexJOURNAL OF NEUROCHEMISTRY, Issue 1 2000Maria C. Olianas Abstract : In the present study, we investigated the involvement of ,, subunits of Gq/11 in the muscarinic M1 receptor-induced potentiation of corticotropin-releasing hormone (CRH)-stimulated adenylyl cyclase activity in membranes of rat frontal cortex. Tissue exposure to either one of two ,, scavengers, the QEHA fragment type II adenylyl cyclase and the GDP-bound form of the , subunit of transducin, inhibited the muscarinic M1 facilitatory effect. Moreover, like acetylcholine (ACh), exogenously added ,, subunits of transducin potentiated the CRH-stimulated adenylyl cyclase activity, and this effect was not additive with that elicited by ACh. Western blot analysis indicated the expression in frontal cortex of both type II and type IV adenylyl cyclases, two isoforms stimulated by ,, subunits in synergism with activated Gs. The M1 receptor-induced enhancement of the adenylyl cyclase response to CRH was counteracted by the Gq/11 antagonist GpAnt-2A but not by GpAnt-2, a preferential Gi/o antagonist. In addition, the muscarinic facilitatory effect was inhibited by membrane preincubation with antiserum directed against the C terminus of the , subunit of Gq/11, whereas the same treatment with antiserum against either Gi1/2 or Go was without effect. These data indicate that in membranes of rat frontal cortex, activation of muscarinic M1 receptors potentiates CRH-stimulated adenylyl cyclase activity through ,, subunits of Gq/11. [source] Ethanol Acutely Inhibits Ionotropic Glutamate Receptor-Mediated Responses and Long-Term Potentiation in the Developing CA1 HippocampusALCOHOLISM, Issue 4 2010Michael P. Puglia Background:, Developmental ethanol (EtOH) exposure damages the hippocampus, causing long-lasting alterations in learning and memory. Alterations in glutamatergic synaptic transmission and plasticity may play a role in the mechanism of action of EtOH. This signaling is fundamental for synaptogenesis, which occurs during the third trimester of human pregnancy (first 12 days of life in rats). Methods:, Acute coronal brain slices were prepared from 7- to 9-day-old rats. Extracellular and patch-clamp electrophysiological recording techniques were used to characterize the acute effects of EtOH on ,-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR)- and N -methyl- d -aspartate receptor (NMDAR)-mediated responses and long-term potentiation (LTP) in the CA1 hippocampal region. Results:, Ethanol (40 and 80 mM) inhibited AMPAR- and NMDAR-mediated field excitatory postsynaptic potentials (fEPSPs). EtOH (80 mM) also reduced AMPAR-mediated fEPSPs in the presence of an inhibitor of Ca2+ permeable AMPARs. The effect of 80 mM EtOH on NMDAR-mediated fEPSPs was significantly greater in the presence of Mg2+. EtOH (80 mM) neither affected the paired-pulse ratio of AMPAR-mediated fEPSPs nor the presynaptic volley. The paired-pulse ratio of AMPAR-mediated excitatory postsynaptic currents was not affected either, and the amplitude of these currents was inhibited to a lesser extent than that of fEPSPs. EtOH (80 mM) inhibited LTP of AMPAR-mediated fEPSPs. Conclusions:, Acute EtOH exposure during the third-trimester equivalent of human pregnancy inhibits hippocampal glutamatergic transmission and LTP induction, which could alter synapse refinement and ultimately contribute to the pathophysiology of fetal alcohol spectrum disorder. [source] Ethanol Potentiation of Glycine Receptors Expressed in Xenopus Oocytes Antagonized by Increased Atmospheric PressureALCOHOLISM, Issue 5 2003Daryl L. Davies Background: Behavioral and biochemical studies indicate that exposure to 12 times normal atmospheric pressure (12 ATA) of helium-oxygen gas (heliox) is a direct, selective ethanol antagonist. The current study begins to test the hypothesis that ethanol acts by a common mechanism on ligand-gated ion channels by expanding previous hyperbaric investigations on ,-aminobutyric acid type A (GABAA) receptors (GABAARs) at the biochemical level to ,1glycine (GlyRs) expressed in Xenopus oocytes. Methods: Oocytes expressing wild-type ,1 homomeric GlyRs were voltage-clamped (,70 mV) and tested in the presence of glycine (EC2) ± ethanol (50,200 mM) under 1 ATA control and 3 to 12 ATA heliox conditions. Glycine concentration response curves, strychnine/glycine interactions, and zinc (Zn2+) modulation of GlyR function was also tested. Results: Pressure reversibly antagonized the action of ethanol. The degree of antagonism increased as pressure increased. Pressure did not significantly alter the effects of glycine, strychnine, or Zn2+, indicating that ethanol antagonism by pressure cannot be attributed to alterations by pressure of normal GlyR function. The antagonism did not reflect tolerance to ethanol, receptor desensitization, or receptor rundown. Conclusion: This is the first use of hyperbarics to investigate the mechanism of action of ethanol in recombinant receptors. The findings indicate that pressure directly and selectively antagonizes ethanol potentiation of ,1GlyR function in a reversible and concentration- and pressure-dependent manner. The sensitivity of ethanol potentiation of GlyR function to pressure antagonism indicates that ethanol acts by a common, pressure-antagonism,sensitive mechanism in GlyRs and GABAARs. The findings also support the hypothesis that ethanol potentiation of GlyR function plays a role in mediating the sedative-hypnotic effects of ethanol. [source] Length Dependent Potentiation in Electrically Stimulated Human Ankle Dorsiflexor MusclesNEUROMODULATION, Issue 2 2002Petra Mela PhD Abstract The purpose of this study was to investigate the short-term history effect of a decreasing frequency train on force and the influence of joint angle on such effect in human dorsiflexor muscles. Six able-bodied and three spinal cord injured (SCI) subjects took part in the study. Their isometric left dorsiflexor muscles were stimulated with two-second bursts at three ankle joint positions and movements at the ankle were measured. Trains with constant stimulation frequencies (CSF: 50, 25, 20, 16, 12, 8 Hz) and with decreasing stimulation frequencies (DSF1,2) were used. Each DSF tetanus consisted of four 0.5 second bursts of different frequencies (DSF1: 50, 25, 16, 8 Hz; DSF2: 50, 20, 12, 8 Hz). To evaluate the effect of preceding higher stimulation frequencies (DSF), the average moment at corresponding time intervals in the DSF and CSF trials were compared for 25, 20, 16, 12, 8 Hz. Preceding higher stimulation frequencies caused increase of the moment elicited by a given frequency. This was true for all the subjects at dorsiflexed positions, but the effect is highly dependent on joint ankle. At plantar flexed positions moment enhancement was seen only in SCI subjects. We conclude that effects of joint angle as well as individual muscle properties should be taken into account when optimizing muscle force by means of frequency modulation. [source] NMDA potentiation by visible light in the presence of a fluorescent neurosteroid analogueTHE JOURNAL OF PHYSIOLOGY, Issue 12 2009Lawrence N. Eisenman N -Methyl- d -aspartate (NMDA) receptors are widely studied because of their importance in synaptic plasticity and excitotoxic cell death. Here we report a novel method of potentiating NMDA receptors with fluorescence excited by blue (480 nm) light. In the presence of 300 nm of a (7-nitro-2,1,3-benzoxadiazol-4-yl) amino (NBD)-tagged neuroactive steroid carrier C2-NBD-(3,,5,)-3-hydroxypregnan-20-one (C2-NBD 3,5,P), responses of cultured hippocampal neurons to 10 ,m NMDA were potentiated to 219.2 ± 9.2% of the baseline response (100%) by a 30 s exposure to 480 nm light. The potentiation decayed back to baseline with a time constant of 80.6 s. Responses to 1 ,m and 100 ,m NMDA were potentiated to 147.9 ± 9.6% and 174.1 ± 15.6% of baseline, respectively, suggesting that visible-light potentiation is relatively insensitive to NMDA concentration. Peak autaptic NMDA responses were potentiated to 178.9 ± 22.4% of baseline. Similar potentiation was seen with 10 ,m NBD-lysine, suggesting that visible-light potentiation is not a steroid effect. Potentiation was also seen with a steroid analogue in which the NBD was replaced with fluorescein, suggesting that NBD is not the only fluorophore capable of supporting visible-light potentiation. UV light and redox potentiation of NMDA receptors largely occluded subsequent blue light potentiation (127.7 ± 7.4% and 120.2 ± 6.2% of baseline, respectively). The NR1a(C744A,C798A) mutant that is insensitive to redox and UV potentiation was also largely unaffected by visible-light potentiation (135.0 ± 10.0% of baseline). Finally, we found that the singlet oxygen scavenger furfuryl alcohol decreased visible-light potentiation. Collectively, these data suggest that visible-light potentiation of NMDA receptors by fluorescence excitation shares mechanisms with UV and redox potentiation and may involve singlet oxygen production. [source] Potentiation of mouse vagal afferent mechanosensitivity by ionotropic and metabotropic glutamate receptorsTHE JOURNAL OF PHYSIOLOGY, Issue 1 2006James A. Slattery Glutamate acts at central synapses via ionotropic (iGluR , NMDA, AMPA and kainate) and metabotropic glutamate receptors (mGluRs). Group I mGluRs are excitatory whilst group II and III are inhibitory. Inhibitory mGluRs also modulate peripherally the mechanosensitivity of gastro-oesophageal vagal afferents. Here we determined the potential of excitatory GluRs to play an opposing role in modulating vagal afferent mechanosensitivity, and investigated expression of receptor subunit mRNA within the nodose ganglion. The responses of mouse gastro-oesophageal vagal afferents to graded mechanical stimuli were investigated before and during application of selective GluR ligands to their peripheral endings. Two types of vagal afferents were tested: tension receptors, which respond to circumferential tension, and mucosal receptors, which respond only to mucosal stroking. The selective iGluR agonists NMDA and AMPA concentration-dependently potentiated afferent responses. Their corresponding antagonists AP-5 and NBQX alone attenuated mechanosensory responses as did the non-selective antagonist kynurenate. The kainate selective agonist SYM-2081 had minor effects on mechanosensitivity, and the antagonist UBP 302 was ineffective. The mGluR5 antagonist MTEP concentration-dependently inhibited mechanosensitivity. Efficacy of agonists and antagonists differed on mucosal and tension receptors. We conclude that excitatory modulation of afferent mechanosensitivity occurs mainly via NMDA, AMPA and mGlu5 receptors, and the role of each differs according to afferent subtypes. PCR data indicated that all NMDA, kainate and AMPA receptor subunits plus mGluR5 are expressed, and are therefore candidates for the neuromodulation we observed. [source] ORIGINAL ARTICLE: Effect of Maternal Immunopotentiation on Apoptosis-Associated Molecules Expression in Teratogen-Treated EmbryosAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2009Shoshana Savion Problem, Potentiation of the maternal immune system was shown by us to affect the embryonic response to teratogenic insults. In order to understand better the mechanisms underlying that phenomenon, we explored the effect of maternal immunopotentiation by rat splenocytes on the early stages of the embryonic response to cyclophosphamide (CP). Method of study, Immunopotentiated CP-treated embryos were analysed for cell cycle changes by flow cytometry, while cell proliferation and apoptosis were assessed by 5,-bromo-2,-deoxyuridine (BrdU) incorporation and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) respectively. The expression of the p65 subunit of NF-,B, I,B,, Bax, bcl-2 and p53 was assessed by flow cytometry. Results, Exposure to CP resulted in significant growth retardation and in the appearance of cellular damage, a reduction in cell proliferation and the appearance of apoptotic cells, which were all found to be delayed in immunopotentiated embryos. In parallel, CP-treated embryos demonstrated a reduction in the percentage of p65- or I,B,-positive cells, while the percentage of bcl-2- or p53-positive cells increased initially and decreased later. Those changes were normalized by maternal immunopotentiation when tested at 24 hrs after exposure to the teratogen. Conclusion, Our data implicate maternal immunopotentiation to protect the embryo against teratogenic insults, possibly through its effect on the expression of p65, bcl-2 or p53. [source] Beta2 -glycoprotein I protects thrombin from inhibition by heparin cofactor II: Potentiation of this effect in the presence of anti,,2 -glycoprotein I autoantibodiesARTHRITIS & RHEUMATISM, Issue 4 2008Soheila Rahgozar Objective Beta2 -glycoprotein I (,2GPI) is an important autoantigen in the antiphospholipid syndrome (APS). In vitro studies suggest that it may have multifaceted physiologic functions, since it displays both anticoagulant and procoagulant properties. We have previously reported that ,2GPI can directly bind thrombin, a key serine protease in the coagulation pathway. The present study was undertaken to examine the influence of ,2GPI on thrombin inactivation by the serpin heparin cofactor II (HCII). The effect of anti-,2GPI antibodies was also examined. Methods HCII inactivation of thrombin was assessed using chromogenic and various platelet functional assays. The influence of intact and proteolytically cleaved ,2GPI and anti-,2GPI antibodies was determined in these systems. Results ,2GPI protected thrombin against inactivation by HCII/heparin. Cleavage of ,2GPI at Lys317,Thr318 abrogated its protective effect. Patient polyclonal IgG and murine monoclonal anti-,2GPI antibodies potentiated the procoagulant influence of ,2GPI in this system. Conclusion These novel findings suggest that ,2GPI may regulate thrombin inactivation by HCII/heparin. The observation that anti-,2GPI antibodies potentiate the protective effect of ,2GPI on thrombin in this system, thereby promoting a procoagulant response, may potentially delineate one of the pathophysiologic mechanisms contributing to the prothrombotic tendency in patients with APS. [source] Potentiation of Histamine Release by Microfungal (1,3)- and (1,6)-,-D-GlucansBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2007Peter Holck The mechanisms by which they induce these effects are, however, not clear. In the present study, mediator release and its potentiation by the (1,3)-,-D-glucan as well as by the (1,6)-,-D-glucan found in yeast and other fungi were therefore examined. Blood leucocytes from healthy volunteers and from patients allergic to house dust mite were incubated with (1,3)-,-D-glucans with increasing 1,6-branchings: curdlan [a linear (1,3)-,-D-glucan], laminarin and scleroglucan, and furthermore with pustulan, a linear (1,6)-,-D-glucan. Histamine release was not observed on exposure to the glucans only, but in the presence of anti-immunoglobulin E (IgE) antibody or specific antigens, all the glucans investigated led to an enhancement of the IgE-mediated histamine release. The glucans induced a significant potentiation of the mediator release when present at concentrations in the range of 2,5 × 10,5 M. These results suggest that (1,3)-,-D-glucan as well as (1,6)-,-D-glucan aggravates IgE-mediated histamine release. Knowledge concerning the effects of glucans on immune responses may be of importance for understanding and treating inflammatory and allergic diseases. [source] Potentiation of domperidone-induced catalepsy by a P-glycoprotein inhibitor, cyclosporin ABIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2003Kenji Tsujikawa Abstract The distribution of domperidone (DOM), a peripheral dopamine D2 receptor antagonist, to the brain is restricted by P-glycoprotein (P-gp) at the blood,brain barrier (BBB) and for this reason, DOM rarely causes parkinsonian symptoms, such as extrapyramidal side effects (EPS), unlike other dopamine D2 antagonists. In this study, we aimed to investigate whether cyclosporin A (CsA), a P-gp inhibitor, potentiates EPS induced by DOM. The intensity of EPS was assessed in terms of the duration of catalepsy in mice. D1, D2 and mACh receptor occupancies at the striatum were measured in vivo and in vitro. Moreover, the distribution of DOM to the brain was investigated by using an in situ brain perfusion technique. The intensity of DOM-induced catalepsy was significantly potentiated by the coadministration of CsA. The in vivo occupancies of D1, D2 and mACh receptors, as well as the brain distribution of DOM, were increased by CsA. These results suggest that CsA increases the brain distribution of DOM by inhibiting P-gp at the BBB, and potentiates catalepsy by increasing the occupancies of the D1 and D2 receptors. The risk of DOM-induced parkinsonism may be enhanced by the coadministration of CsA. Copyright © 2003 John Wiley & Sons, Ltd. [source] Potentiation of E-4031-induced torsade de pointes by HMR1556 or ATX-II is not predicted by action potential short-term variability or triangulationBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2007G Michael Background and purpose: Torsade de pointes (TdP) can be induced by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether IKs blockade or enhancement of INa could potentiate TdP induced by IKr blockade and to investigate whether short-term variability (STV) or triangulation of action potentials preceded TdP. Experimental approach: Experiments were performed in open-chest, pentobarbital-anaesthetized, ,1 -adrenoceptor-stimulated, male New Zealand White rabbits, which received three consecutive i.v. infusions of either the IKr blocker E-4031 (1, 3 and 10 nmol kg,1 min,1), the IKs blocker HMR1556 (25, 75 and 250 nmol kg,1 min,1) or E-4031 and HMR1556 combined. In a second study rabbits received either the same doses of E-4031, the INa enhancer, ATX-II (0.4, 1.2 and 4.0 nmol kg,1) or both of these drugs. ECGs and epicardial monophasic action potentials were recorded. Key results: HMR1556 alone did not cause TdP but increased E-4031-induced TdP from 25 to 80%. ATX-II alone caused TdP in 38% of rabbits, as did E-4031; 75% of rabbits receiving both drugs had TdP. QT intervals were prolonged by all drugs but the extent of QT prolongation was not related to the occurrence of TdP. No changes in STV were detected and triangulation was only increased after TdP occurred. Conclusions and implications: Giving modulators of ion channels in combination substantially increased TdP but, in this model, neither STV nor triangulation of action potentials could predict TdP. British Journal of Pharmacology (2007) 152, 1215,1227; doi:10.1038/sj.bjp.0707513; published online 29 October 2007 [source] Heterogeneity of the neuropeptide Y (NPY) contractile and relaxing receptors in horse penile small arteriesBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2004Dolores Prieto The distribution of neuropeptide Y (NPY)-immunorective nerves and the receptors involved in the effects of NPY upon electrical field stimulation (EFS)- and noradrenaline (NA)-elicited contractions were investigated in horse penile small arteries. NPY-immunoreactive nerves were widely distributed in the erectile tissues with a particularly high density around penile intracavernous small arteries. In small arteries isolated from the proximal part of the corpora cavernosa, NPY (30 nM) produced a variable modest enhancement of the contractions elicited by both EFS and NA. At the same concentration, the NPY Y1 receptor agonist, [Leu31, Pro34]NPY, markedly potentiated responses to EFS and NA, whereas the NPY Y2 receptor agonist, NPY(13,36), enhanced exogenous NA-induced contractions. In arteries precontracted with NA, NPY, peptide YY (PYY), [Leu31, Pro34]NPY and the NPY Y2 receptor agonists, N - acetyl[Leu28,31]NPY (24,36) and NPY(13,36), elicited concentration-dependent contractile responses. Human pancreatic polypeptide (hPP) evoked a biphasic response consisting of a relaxation followed by contraction. NPY(3,36), the compound 1229U91 (Ile-Glu-Pro-Dapa-Tyr-Arg-Leu-Arg-Tyr-NH2, cyclic(2,4,)diamide) and eventually NPY(13,36) relaxed penile small arteries. The selective NPY Y1 receptor antagonist BIBP3226 ((R)- N2 -(diphenacetyl)- N -[(4-hydroxyphenyl)methyl]D -arginineamide) (0.3 ,M) shifted to the right the concentration,response curves to both NPY and [Leu31, Pro34]NPY and inhibited the contractions induced by the highest concentrations of hPP but not the relaxations observed at lower doses. In the presence of the selective NPY Y2 receptor antagonist BIIE0246 ((S)- N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6h)-oxodibenz[b,e]azepin-11-y1]-1-piperazinyl]-2-oxoethyl]cyclo-pentyl- N -[2-[1,2-dihydro,3,5 (4H)-dioxo-1,2-diphenyl-3H -1,2, 4-triazol-4-yl]ethyl]-argininamide) (0.3 ,M), the Y2 receptor agonists NPY(13,36) and N - acetyl[Leu28,31]NPY (24,36) evoked potent slow relaxations in NA-precontracted arteries, under conditions of nitric oxide (NO) synthase blockade. Mechanical removal of the endothelium markedly enhanced contractions of NPY on NA-precontracted arteries, whereas blockade of the neuronal voltage-dependent Ca2+ channels did not alter NPY responses. These results demonstrate that NPY can elicit dual contractile/relaxing responses in penile small arteries through a heterogeneous population of postjunctional NPY receptors. Potentiation of the contractions evoked by NA involve both NPY Y1 and NPY Y2 receptors. An NO-independent relaxation probably mediated by an atypical endothelial NPY receptor is also shown and unmasked in the presence of selective antagonists of the NPY contractile receptors. British Journal of Pharmacology (2004) 143, 976,986. doi:10.1038/sj.bjp.0706005 [source] Potentiation of allergic bronchoconstriction by repeated exposure to formaldehyde in guinea-pigs in vivoCLINICAL & EXPERIMENTAL ALLERGY, Issue 12 2003T. Kita Summary Background Indoor formaldehyde (FA) might worsen allergies and be an underlying factor for the increasing incidence and severity of asthma; the exact mechanism, however, remains unclear. Objective The present study examined the effects of repeated exposure to FA on methacholine- and antigen-induced bronchoconstriction in guinea-pigs in vivo. Methods First, non-sensitized guinea-pigs were transnasally treated with 0.1 or 1.0% FA or saline three times a week for 6 weeks, and increasing concentrations of methacholine (50, 100, and 200 ,g/mL) were inhaled at 5-min intervals. Second, guinea-pigs pre-treated with transnasal administration of FA or saline using the same protocol were passively sensitized with anti-ovalbumin (OA) serum 7 days before antigen challenge. Third, guinea-pigs were actively sensitized with OA and pre-treated with transnasal administration of FA or saline using the same protocol. The lateral pressure of the tracheal tube (Pao) was measured under anesthesia and artificial ventilation. Results The antigen-induced increase in Pao in actively sensitized guinea-pigs was significantly potentiated by FA exposure in a dose-dependent manner. The dose,response curve of the methacholine-induced increase in Pao in non-sensitized guinea-pigs or of the antigen-induced increase in Pao in passively sensitized guinea-pigs was not altered by FA exposure. Transnasal administration of FA significantly increased the serum anti-OA homocytotropic antibody titre (IgG) as measured by the passive cutaneous anaphylaxis reaction in actively sensitized guinea-pigs. Conclusion The results suggest that repeated exposure to FA worsens allergic bronchoconstriction through enhancing antigen sensitization. [source] Tonic Potentiation And Attenuation Produced By Membrane Depolarization In Guinea-Pig TrachealisCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2000Kenichi Yamaki SUMMARY 1. We studied how membrane depolarization directly affected intracellular Ca2+ signalling when voltage-operated Ca2+ channels (VOCC) were not available in guinea-pig tracheal smooth muscle. To block VOCC, we used 3 ,mol/L verapamil, which completely abolished high K+ (20,60 mmol/L)-induced contraction, and elevation of fura-2 signal. 2. Muscle tone was generated by adding Ca2+ to the extracellular Ca2+ -free solution containing prostaglandin (PG)E2 (100 nmol/L) after abolishing basal tone with indomethacin (1 ,mol/L). 3. In the absence of verapamil, high K+ (20,60 mmol/L) solution potentiated 2.4 mmol/L Ca2+ -induced sustained contractions. Even in the presence of 3 ,mol/L verapamil, replacement with 20 and 40 mmol/L K+ solution induced tonic potentiation, which was changed to attenuation with a higher K+ solution (60 mmol/L), lower extracellular Ca2+ concentration ([Ca2+]o) and pretreatment with cyclopiazonic acid (10 ,mol/L), a Ca2+ sequestration inhibitor. 4. These results indicate that the balance between depolarization-dependent Ca2+ release and receptor-operated cation channel inhibition may determine whether tonic potentiation or attenuation is manifested, depending on the availability of VOCC, the magnitude of the depolarization, [Ca2+]o and Ca2+ content in the sarcoplasmic reticulum. [source] Prostaglandin I2 sensory input into the enteric nervous system during distension-induced colonic chloride secretion in rat colonACTA PHYSIOLOGICA, Issue 3 2010J. D. Schulzke Abstract Aim:, Intestinal pressure differences or experimental distension induce ion secretion via the enteric nervous system, the sensorial origin of which is only poorly understood. This study aimed to investigate sensorial inputs and the role of afferent and interneurones in mechanically activated submucosal secretory reflex circuits. Methods:, Distension-induced rheogenic chloride secretion was measured as increase in short-circuit current 10 min after distension (,ISC10; distension parameters ± 100 ,L, 2 Hz, 20 s) in partially stripped rat distal colon in the Ussing-chamber in vitro. PGE2 and PGI2 were measured by radioimmunoassay. Results:, ,ISC10 was 2.0 ± 0.2 ,mol h,1 cm,2 and could be attenuated by lobeline, mecamylamine and dimethylphenylpiperazine, indicating an influence of nicotinergic interneurones. Additionally, a contribution of afferent neurones was indicated from the short-term potentiation of ,ISC10 by capsaicin (1 ,m). As evidence for its initial event, indomethacin (1 ,m) inhibited distension-induced secretion and the release of PGI2 was directly detected after distension. Furthermore, serotoninergic mediation was confirmed by granisetron (100 ,m) which was functionally localized distally to PGI2 in this reflex circuit, as granisetron inhibited an iloprost-induced ISC, while indomethacin did not affect serotonin-activated ion secretion. Conclusions:, Distension-induced active electrogenic chloride secretion in rat colon is mediated by a neuronal reflex circuit which includes afferent neurones and nicotinergic interneurones. It is initiated by distension-induced PGI2 release from subepithelial cells triggering this reflex via serotoninergic 5-HT3 receptor transmission. Functionally, this mechanism may help to protect against intestinal stasis but could also contribute to luminal fluid loss, e.g. during intestinal obstruction. [source] Orexins/hypocretins control bistability of hippocampal long-term synaptic plasticity through co-activation of multiple kinasesACTA PHYSIOLOGICA, Issue 3 2010O. Selbach Abstract Aim:, Orexins/hypocretins (OX/Hcrt) are hypothalamic neuropeptides linking sleep,wakefulness, appetite and neuroendocrine control. Their role and mechanisms of action on higher brain functions, such as learning and memory, are not clear. Methods:, We used field recordings of excitatory post-synaptic potentials (fEPSP) in acute mouse brain slice preparations to study the effects of orexins and pharmacological inhibitors of multiple kinases on long-term synaptic plasticity in the hippocampus. Results:, Orexin-A (OX-A) but not orexin-B (OX-B) induces a state-dependent long-term potentiation of synaptic transmission (LTPOX) at Schaffer collateral-CA1 synapses in hippocampal slices from adult (8- to 12-week-old) mice. In contrast, OX-A applied to slices from juvenile (3- to 4-week-old) animals causes a long-term depression (LTDOX) in the same pathway. LTPOX is blocked by pharmacological inhibition of orexin receptor-1 (OX1R) and plasticity-related kinases, including serine/threonine- (CaMKII, PKC, PKA, MAPK), lipid- (PI3K), and receptor tyrosine kinases (Trk). Inhibition of OX1R, CaMKII, PKC, PKA and Trk unmasks LTDOX in adult animals. Conclusion:, Orexins control not only the bistability of arousal states and threshold for appetitive behaviours but, in an age- and kinase-dependent manner, also bidirectional long-term synaptic plasticity in the hippocampus, providing a possible link between behavioural state and memory functions. [source] Circulatory effects of apnoea in elite breath-hold diversACTA PHYSIOLOGICA, Issue 1 2009F. Joulia Abstract Aim:, Voluntary apnoea induces several physiological adaptations, including bradycardia, arterial hypertension and redistribution of regional blood flows. Elite breath-hold divers (BHDs) are able to maintain very long apnoea, inducing severe hypoxaemia without brain injury or black-out. It has thus been hypothesized that they develop protection mechanisms against hypoxia, as well as a decrease in overall oxygen uptake. Methods:, To test this hypothesis, the apnoea response was studied in BHDs and non-divers (NDs) during static and dynamic apnoeas (SA, DA). Heart rate, arterial oxygen saturation (SaO2), and popliteal artery blood flow were recorded to investigate the oxygen-conserving effect of apnoea response, and the internal carotid artery blood flow was used to examine the mechanisms of cerebral protection. Results:, The bradycardia and peripheral vasoconstriction were accentuated in BHDs compared with NDs (P < 0.01), in association with a smaller SaO2 decrease (,2.7% vs. ,4.9% during SA, P < 0.01 and ,6% vs. ,11.3% during DA, P < 0.01). Greater increase in carotid artery blood flow was also measured during apnoea in BHDs than in controls. Conclusion:, These results confirm that elite divers present a potentiation of the well-known apnoea response in both SA and DA conditions. This response is associated with higher brain perfusion which may partly explain the high levels of world apnoea records. [source] Brief exposure to the biological mother "potentiates" the isolation behavior of precocial Guinea pig pupsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 8 2006Michael B. Hennessy Abstract When isolated rat pups are briefly reunited with a lactating female, her subsequent removal leads to a dramatic increase in the emission of ultrasonic vocalizations, but not other behaviors. Whether this socially induced augmentation of isolation behavior (i.e., "potentiation") is characteristic only of altricial rodents is not known. Therefore, we examined precocial guinea pig pups in a potentiation paradigm. Ten-day-old guinea pigs were isolated in a test cage for 10 min, at which time they were then placed into a second cage for 5 min that either contained a companion or, for controls, was empty. Pups were then isolated again in the test cage for a second 10-min period. Control pups showed a significant reduction in vocalizing and locomotor activity from the first to second isolation period. Exposure to the biological mother prevented the decline in both behaviors (Experiment 1), whereas exposure to a familiar littermate (Experiment 2) had no effect, and exposure to an unfamiliar lactating female (Experiment 3) had only a minimal effect on locomotor activity. The results show that potentiation of isolation behaviors is not limited to altricial rodents, and suggest that specific characteristics of the effect (i.e., its magnitude, the specific behaviors affected, and the selectivity of the response to particular social partners) varies with the abilities and requirements of the young, as well as the behavioral ecology of the species in question. © 2006 Wiley Periodicals, Inc. Dev Psychobiol 48: 653,659, 2006. [source] Are CB1 receptor antagonists nootropic or cognitive impairing agents?DRUG DEVELOPMENT RESEARCH, Issue 8 2009Stephen A. Varvel Abstract For more than a decade, a considerable amount of research has examined the effects of rimonabant (SR 141716) and other CB1 receptor antagonists in both in vivo and in vitro models of learning and memory. In addition to its utility in determining whether the effects of drugs are mediated though a CB1 receptor mechanism of action, these antagonists are useful in providing insight into the physiological function of the endogenous cannabinoid system. Several groups have reported that CB1 receptor antagonists enhance memory duration in a variety of spatial and operant paradigms, but not in all paradigms. Conversely, disruption of CB1 receptor signaling also impairs extinction learning in which the animal actively suppresses a learned response when reinforcement has been withheld. These extinction deficits occur in aversively motivated tasks, such as in fear conditioning or escape behavior in the Morris water maze task, but not in appetitively motivated tasks. Similarly, in electrophysiological models, CB1 receptor antagonists elicit a variety of effects, including enhancement of long-term potentiation (LTP), while disrupting long-term depression (LTD) and interfering with transient forms of plasticity, including depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). The collective results of the in vivo and in vitro studies employing CB1 receptor antagonists, demonstrate that these receptors play integral roles in different components of cognitive processing. Functionally, pharmacological blockade of CB1 receptors may strengthen memory duration, but interferes with extinction of learned behaviors that are associated with traumatic or aversive memories. Drug Dev Res 70:555,565, 2009. © 2009 Wiley-Liss, Inc. [source] The brain angiotensin IV/AT4 receptor system as a new target for the treatment of Alzheimer's diseaseDRUG DEVELOPMENT RESEARCH, Issue 7 2009John W. Wright Abstract The brain renin-angiotensin system (RAS) regulates several physiologies including blood pressure, body sodium and water balance, cyclicity of reproductive hormones and related sexual behaviors, and the release of pituitary gland hormones. These physiologies are under the control of the angiotensin II (AngII)/AT1 receptor subtype system. The AngII/AT2 receptor subtype system is expressed during fetal development and is less abundant in the adult. This system appears to oppose growth responses facilitated by activation of the AT1 receptor. There is a growing list of nontraditional physiologies mediated by the most recently discovered angiotensin IV (AngIV)/AT4 receptor subtype system that include the regulation of blood flow, modulation of exploratory behaviors, involvement in stress responses and seizure, and a role in learning and memory acquisition. There is evidence to support an inhibitory influence by AngII, and a facilitory role by AngIV, on neuronal firing rate, long-term potentiation, and associative and spatial learning and memory. These findings suggest an important role for the RAS, and the AT4 receptor in particular, in normal cognitive processing and provide the stimulus for developing drugs that penetrate the blood-brain barrier to interact with this brain receptor in the treatment of dysfunctional memory. Drug Dev Res 70: 472,480, 2009. © 2009 Wiley-Liss, Inc. [source] In vitro and in vivo characterization of TC-1827, a novel brain ,4,2 nicotinic receptor agonist with pro-cognitive activityDRUG DEVELOPMENT RESEARCH, Issue 1 2004Georg Andrees Bohme Abstract Nicotine activates specific receptors that are cation-permeable ionic channels located in the central and autonomous nervous systems, as well as at the neuromuscular junction. Administration of nicotine to animals and humans has been shown to enhance cognitive processes. However, side effects linked to the activation of peripheral nicotinic receptors limit the usefulness of nicotine for the treatment of cognitive disorders such as Alzheimer's disease (AD) or mild cognitive impairments (MCI). The synthesis and properties of TC-1827, a novel metanicotine derivative that activates brain ,4,2 nicotinic receptors is described. TC-1827 has high affinity for nicotine-labeled receptors in the cortex (Ki=34 nM), full-agonist intrinsic activity in ,4,2 -mediated neurotransmitter release studies in synaptosomes, and has no functional activity at nicotinic receptors in ganglionic or muscular cell lines. The compound enhances long-term potentiation in hippocampal slices, a form of synaptic plasticity thought to be involved in information storage at the cellular level. In vivo studies demonstrate that TC-1827 dose-dependently occupies thalamic nicotinic receptors labeled with [3H]-cytisine, increases cortical extracellular acetylcholine levels following oral administration, and enhances cognitive performance in rat and mice behavioral procedures of learning and memory. Pharmacokinetic studies in mice, rats, and monkeys indicated that TC-1827 has good oral absorption with a first pass effect resulting in bioavailabilities of 13,65% across dose/species. Cardiovascular safety studies indicate good cardiovascular tolerability for this compound. The present data demonstrate that TC-1827 is a selective and potent activator of brain ,4,2 nicotinic receptors and is a prototypical member of a new class of compounds with potential utility in the symptomatic treatment of cognitive disorders including AD and MCI. Drug Dev. Res. 62:26,40, 2004. © 2004 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||||||||