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PubMed1996

Role of protein kinases in regulating sheep erythrocyte K-Cl cotransport.

K-Cl cotransport in sheep erythrocytes can be activated by treatment either with A-23187 and EDTA to reduce concentration of internal ionized Mg [Mg]i) to submicromolar levels, with staurosporine, a potent kinase inhibitor, or with N-ethylmaleimide (NEM). Activation by these maneuvers is prevented and reversed by genistein [inhibition constant (Ki) of 15 microM], which inhibits tyrosine kinases (TK). The related glycosidated compound genistin, which does not inhibit TK, does not inhibit transport, whereas another TK inhibitor, tyrphostin B46, inhibits both basal and stimulated transport (Ki of 28 microM). Cotransport activation by NEM is prevented and reversed by the phosphatase inhibitor, calyculin A, and activation by staurosporine occurs only if cells contain ATP. Increasing [Mg]i inhibits cotransport in the presence of calyculin A whether or not staurosporine is present as well. Our work suggests that genistein inhibits cotransport through a TK and that staurosporine and NEM activate cotransport, probably through inhibition of other kinases, causing stimulation through dephosphorylation of a protein (possibly the transporter itself) be a serine/threonine phosphatase. [Mg]i inhibits cotransport by activating a kinase (concentration for half-maximal activation of 10 microM) that phosphorylates this protein.

Adenosine Triphosphate↗
PubMed2003

16-(4-Cyanobenzylidene)-17-oxoandrost-5-en-3beta-ol.

In the title compound, 4-(3beta-hydroxy-17-oxoandrost-5-en-16-ylidenemethyl)benzonitrile, C(27)H(31)NO(2), rings A and C of the steroid nucleus are in chair conformations. The central six-membered ring B is in an 8beta,9alpha-half-chair conformation, while the five-membered ring D adopts a 13beta,14alpha-half-chair conformation. The cyanobenzylidene moiety has an E configuration with respect to the carbonyl group at position C17. The dihedral angle between the planes of the steroid nucleus and the cyanobenzylidene moiety is 22.61 (15) degrees. Intermolecular O-H.N hydrogen bonds formed between the hydroxyl group of the steroid and the N atom of the cyanobenzylidene moiety of symmetry-related molecules link the steroid molecules into chains which run parallel to the b axis.

Androstenols↗
PubMed1994

Inhibition of Moloney murine leukemia virus replication by tyrphostins, tyrosine kinase inhibitors.

We have previously shown that topoisomerase I (topo I) antagonist inhibited retrovirus replication. Since tyrphostins, synthetic compounds and protein tyrosine kinases (PTKs) blockers, inhibited topo I activity (manuscript in preparation) we examined their ability to inhibit Moloney murine leukemia virus (Mo-MuLV) replication. We found that non-cytotoxic doses of tyrphostin derivatives (AG-555, AG-18) blocked or substantially reduced Mo-MuLV replication in acute or chronically infected NIH/3T3 cells. Our experiments suggest that the antiviral effect of these tyrphostin derivatives was not the result of antiproliferative activity. However, the tyrphostin derivatives used in our present investigation differ in their ability to inhibit Mo-MuLV replication. Furthermore, as expected from stereospecific competitive inhibitors, the antiviral effect is not a general characteristic of all tyrphostin derivatives, since AG-213 does not affect Mo-MuLV replication. Our results indicate that these tyrphostin derivatives may represent a novel class of antiretroviral drugs.

3T3 Cells↗
PubMed1997

Involvement of spinal cord delta opiate receptors in the antinociception of gestation and its hormonal simulation.

Physiological as well as hormone-simulated pregnancy (HSP) is associated with opioid-mediated elevations in maternal nociceptive thresholds. Previous reports from this laboratory have demonstrated the involvement of spinal cord kappa opiate receptors in this phenomenon. The present study was undertaken in order to determine the exclusivity of this mediation. Intrathecal (i.t.) administration of the delta opiate receptor-selective antagonists naltrindole (NTI), 7-benzylidenenaltrexone (BNTX) or naltriben (NTB) substantially reduces nociceptive thresholds of gestation (day 20) and HSP (day 19). Hyperalgesic actions of these compounds following i.t. administration are not observed in non-pregnant or vehicle-treated control animals. These data indicate that delta opiate receptor activity is a prerequisite for the manifestation of a substantial portion of gestational and HSP analgesia. In contrast, i.t. application of the micro-selective antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) has no effect on nociceptive thresholds of gestational day 20, as was previously demonstrated for HSP-induced antinociception. Thus, the potent spinal mu analgesic system does not participate in gestational or HSP analgesia. During physiological pregnancy, less robust constituents of intrinsic opioid pain-attenuating systems in the spinal cord (delta and kappa opioid systems) are recruited to mediate the maternal antinociception of gestation. Furthermore, the ability of estrogen and progesterone to modulate spinal opioid antinociceptive activity emphasizes potential differences between men and women in their response to pain medication.

Animals↗
PubMed2004

A novel bis-benzylidenecyclopentanone derivative, BPR0Y007, inducing a rapid caspase activation involving upregulation of Fas (CD95/APO-1) and wild-type p53 in human oral epidermoid carcinoma cells.

BPR0Y007, a bis-benzylidenecyclopentanone derivative (2,5-bis- (4-hydroxy-3-methoxybenzylidene) cyclopentanone), was identified in our laboratory as a novel antineoplastic agent with a broad spectrum of antitumor activity against many human cancer cells. A previous study showed that BPR0Y007 inhibited DNA topoisomerase I (Top 1) activity and prevented tubulin polymerization. Notably, no cross-resistance with BPR0Y007 was observed in camptothecin-, VP-16- or vincristine-resistant cell lines. In this study, we further investigated the cellular and molecular events underlying the antitumoral function of this compound in human oral epidermoid carcinoma KB cells, focusing on the early cytotoxic effect. Treatment of KB cells with BPR0Y007-induced G(2)/M phase arrest followed by sub-G(1) phase accumulation. Annexin-V-propidium iodide (PI) binding assay and DNA fragmentation assay further indicated that BPR0Y007-induced cell death proceeded through an apoptotic pathway as opposed to via necrosis. This compound produced a time-dependent activation of caspases-3 and -8, however, another caspase-3 initiator, caspase-9, was only marginally activated at later time point. We further demonstrated that the activation of the caspases cascade and nuclear fragmentation was not associated with inactivated Bcl-2 and perturbed mitochondrial membrane potential by BPR0Y007. The finding that BPR0Y007-induced apoptosis through a membrane-mediated mechanism was supported by up-regulated expression of Fas (CD95/APO-1), but not Fas-L. Furthermore, up-regulation of p53 and its affected gene, MDM2, in KB cells was found after BPR0Y007 exposure. Overall, our results demonstrated that the BPR0Y007 could induce an early cytotoxic apoptosis through a caspase-8-dependent but mitochondrial-caspase-9 independent pathway, and involving upregulation of p53.

Antineoplastic Agents↗
PubMed1995

Antiproliferative effects of tyrosine kinase inhibitors (tyrphostins) on human bladder and renal carcinoma cells.

Growth factor receptors with tyrosine kinase activity mediate paracrine and autocrine growth regulation of normal and malignant cells. The epidermal growth factor receptor (EGF-R) is a tyrosine kinase transmembrane protein that is overexpressed by many epithelial malignancies, including transitional cell and renal cell carcinoma. Ligand-induced stimulation of cell growth depends on activation of the tyrosine kinase activity of the EGF-R. Tyrphostins are small molecular weight compounds that have been shown to preferentially inhibit the EGF-R tyrosine kinase and thus may inhibit EGF-R-dependent cell growth. We examined the effect of two tyrphostins, RG14620 and AG555, on the proliferation of three transitional cell carcinoma lines (RT4, J82, and T24) and three renal cell carcinoma lines (A-198, Caki-1, and Caki-2). Both tyrphostins inhibited proliferation of all six cell lines in a dose-dependent fashion. They were equally effective with IC50s ranging between 3 and 16 microM. Complete inhibition of growth was achieved at tyrphostin concentrations between 10 and 30 microM. Although both tyrphostins inhibited proliferation of T24 transitional carcinoma cells in growth assays, only RG14620 but not AG555 was found to specifically inhibit EGF-R autophosphorylation in this cell line. These results suggest that other intracellular targets in addition to the EGF-R are affected by these agents. In summary, tyrphostins are potent growth inhibitors for urological malignancies.

Adult↗
PubMed1992

Agonistic effects of tyrphostins on human peripheral mononuclear cells.

Tyrosine kinases of the src family, p56lck and p59fyn, were implicated in the transduction of signals via the T-cell receptor complex. These kinases are negatively regulated by phosphorylation of a carboxyl-terminal tyrosine residue. Tyrphostins are synthetic low molecular weight compounds that selectively inhibit different protein tyrosine kinases. We report here on the agonistic and antagonistic effects of tyrphostins on human peripheral blood mononuclear cells (PBM). At low concentration, the tyrphostins enhanced glucose uptake and maximal stimulation was attained at a concentration characteristic for each of the tyrphostins used. Higher concentrations were less effective. The tyrphostins AG126 and AG183 were also found to enhance IL-2-induced cytotoxicity in human PBM in a biphasic manner. In contrast, the tyrphostin AG17 markedly inhibited IL-2-induced cytotoxicity at low AG17 concentration and no stimulation was observed. The tyrphostins tested had selective effects on [3H]thymidine incorporation induced by the mixed lymphocyte culture and different agents. The most potent inhibitor was AG17. Tyrphostins also affect cytokine secretion by human PBM. AG126 and AG183 enhanced TNF-alpha secretion and this effect was more prominent in the presence of IL-2. AG126 enhanced IFN-gamma, IL-1, and IL-6 production in PBM that were costimulated with the stress stimuli heat shock and phenylarsine oxide. The stimulatory effects of the tyrphostins on cytokine secretion and induction of cytotoxicity might be interrelated. The agonistic and antagonistic effects of tyrphostins on lymphocyte functions may have therapeutic potential.

Benzylidene Compounds↗
PubMed2003

In vivo antitumor activity of a novel sulfonamide, HMN-214, against human tumor xenografts in mice and the spectrum of cytotoxicity of its active metabolite, HMN-176.

The cytotoxic effects of HMN-176 ((E)-4-[[2-N-[4-methoxybenzenesulfonyl] amino] stilbazole] 1-oxide; a newly synthesized compound, were evaluated and compared with those of the clinically used antitumor agents cis-platinum, adriamycin, etoposide, taxol, and vincristine in 22 human tumor cell lines isolated from various organs. HMN-176 exhibited potent cytotoxicity with IC(50) values in the nM range, and the variance of its cytotoxic efficacy was remarkably small. Drug-resistant cell lines also showed low cross-resistance to HMN-176 corresponding to overall resistance indices of less than 14.3. HMN-214 was synthesized as an oral prodrug because of the poor oral absorption of HMN-176 itself. Pharmacokinetic studies showed that HMN-214 was an acceptable oral prodrug of HMN-176. In the in vivo analysis of the schedule-dependency of HMN-214, the repeated administration for over 5 days elicited potent antitumor activity, as expected from the exposure-dependency of the cytotoxicity of HMN-176 and from the cytometric studies. The antitumor activity of HMN-214 against human tumor xenografts was equal or superior to that of clinically available agents, including cis-platinum, adriamycin, vincristine, and UFT without severe toxicity such as neurotoxicity. Because of its good activity in preclinical trials, HMN-214 has entered Phase I clinical trials in the USA.

Animals↗
PubMed1993

Involvement of protein kinase C and protein tyrosine kinase pathways in tumor necrosis factor-alpha-induced clustering of ovarian theca-interstitial cells.

Tumor necrosis factor-alpha (TNF) induces clustering of theca-interstitial cells (TIC) isolated from immature, hypophysectomized rats, while inhibiting luteinizing hormone (LH)-stimulated androstenedione in vitro. Stimulators of PKC, 1-oleoyl-2-acetyl-sn-glycerol (OAG, 50 and 100 microM) and phorbol-12-myristate-13-acetate (PMA, 50 nM), caused TIC clustering by 6 days in vitro. Clustering induced by these compounds resembled that induced by TNF. The protein kinase inhibitor, staurosporine at 1 and 10 nM, impaired TNF-induced TIC clustering for 6 days, as did the protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperizine dihydrochloride (H-7); conversely, the protein kinase inhibitor, chelerythrine chloride (0.1, 1.0 or 10 microM), did not attenuate TNF-directed clustering. The protein kinase inhibitors did not reverse the suppression of LH-stimulated androstenedione by TNF. Inhibitors of the EGF receptor PTK, A23 (10, 50, or 100 microM) and A46 (0.1, 1.0, 10, or 50 microM), impaired TNF-induced TIC clustering, while TNF suppression of LH-directed androstenedione was unaffected. EGF-induced TIC clustering was also impaired by A46, while A23 was less effective. Both A23 and A46 blocked EGF attenuation of LH-directed androstenedione after 4 days. When challenged with TNF (1 ng/ml) or PMA (50 nM), PKC activity increased in TIC. A23 (50 microM) and A46 (10 microM) each alone blocked the TNF-associated increase in PKC activity; however, PKC activity attributable to PMA was unaffected by A46. Together, these results suggest that TNF-induced TIC clustering involves activation of PTK which directs subsequent increases in PKC activity; however, mechanisms by which TNF inhibits LH-stimulated steroidogenesis remains elusive.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2003

Cytotoxic and inhibitory effects of 4,4'-dihydroxy chalcone (RVC-588) on proliferation of human leukemic HL-60 cells.

Chalcones have been identified as interesting compounds with cytotoxic and tumor reducing properties. In the present study, the biological activity of synthetic chalcones on myeloid leukemic cells was investigated. Human myeloid HL-60 leukemia cells were exposed to 1-20 micro M chemicals for 0-96h. The viability of the cells was measured using trypan blue dye exclusion method. 4,4'-Dihydroxy chalcone (RVC-588) was selected for further experiments to determine characteristics of cytotoxicity among other compounds. The data show that cell viability decreased after treatment and IC(50) value was approximately 2 micro M for RVC-588. Cell differentiation was analyzed with cytofluorometry by changes in expression of glicoprotein surface markers CD11b/Mac-1, CD11c and CD14 together with morphological analysis. A maximum level of expression changes was determined at 72h but these changes were not statistically significant to show the differentiation of HL-60 cells to mature myeloid and/or monocytoid cells. Apoptotic DNA degradation was evaluated and quantitated using sensitive enzyme-linked immunoabsorbant (ELISA) method. Using this technique, a maximum level of apoptosis 1.2-fold higher than control was observed in cultures exposed for 48h to 2 micro M RVC-588. The DNA ladder assay was subsequently used to determine DNA breaks qualitatively. After 24h, the cells exposed to 2 micro M RVC-588 was shown to have cytotoxic-late apoptotic ladder pattern compared to control cells. These data demonstrate that RVC-588 has a high cytotoxic and antitumor activity in HL-60 cells among other chemicals we synthesized. Although the mechanism by which RVC-588 initiated cell death in these cells is presently not known and apoptotic mechanisms are likely to play less role compared to other chalcone analogues reported previously.

Acetophenones↗
PubMed1998

Pharmacokinetics and urinary excretion of DMXBA (GTS-21), a compound enhancing cognition.

DMXBA (3-(2,4-dimethoxybenzylidene)-anabaseine, also known as GTS-21) is currently being tested as a possible pharmacological treatment of cognitive dysfunction in Alzheimer's disease. In this study, plasma and brain pharmacokinetics as well as urinary excretion of this compound have been evaluated in adult rats. DMXBA concentrations were determined by HPLC. Following a 5 mg kg-1 iv dose, DMXBA plasma concentration declined bi-exponentially with mean (+/- SE) absorption and elimination half-lives of 0.71 +/- 0.28 and 3.71 +/- 1.12 h, respectively. The apparent steady state volume of distribution was 2150 +/- 433 mL kg-1, total body clearance was 1480 +/- 273 mL h-1 kg-1, and AUC0-infinity was 3790 +/- 630 ng h mL-1. Orally administered DMXBA was rapidly absorbed. After oral administration of 10 mg kg-1, a peak plasma concentration of 1010 +/- 212 ng mL-1 was observed at 10 min after dosing. Elimination half-life was 1.740 +/- 0.34 h, and AUC0-infinity was 1440 +/- 358 ng h mL-1. DMXBA peak brain concentration after oral administration was 664 +/- 103 ng g-1 tissue, with an essentially constant brain-plasma concentration ratio of 2.61 +/- 0.34, which indicates that the drug readily passes across the blood-brain barrier. Serum protein binding was 80.3 +/- 1.1%. Apparent oral bioavailability was 19%. Renal clearance (21.8 mL h-1 kg-1) was less than 2% of the total clearance (1480 +/- 273 mL h-1 kg-1); urinary excretion of unchanged DMXBA over a 96 h period accounted for only 0.28 +/- 0.03% of the total orally administered dose. Our data indicates that DMXBA oral bioavailability is primarily limited by hepatic metabolism.

Animals↗
PubMed2000

Communication between multiple drug binding sites on P-glycoprotein.

P-glycoprotein, a member of the ATP-binding cassette transporter family, is able to confer resistance on tumors against a large number of functionally and chemically distinct cytotoxic compounds. Several recent investigations suggest that P-glycoprotein contains multiple drug binding sites rather than a single site of broad substrate specificity. In the present study, radioligand-binding techniques were used to directly characterize drug interaction sites on P-glycoprotein and how these multiple sites interact. The drugs used were classified as either 1) substrates, which are known to be transported by P-glycoprotein (e.g., vinblastine) or 2) modulators, which alter P-glycoprotein function but are not themselves transported by the protein (e.g., XR9576). Drug interactions with P-glycoprotein were either competitive, at a common site, or noncompetitive, and therefore at distinct sites. Based on these data, we can assign a minimum of four drug binding sites on P-glycoprotein. These sites fall into two categories: transport, at which translocation of drug across the membrane can occur, and regulatory sites, which modify P-glycoprotein function. Intriguingly, however, some modulators interact with P-glycoprotein at a transport site rather than a regulatory site. The pharmacological data also demonstrate that both transport and regulatory sites are able to switch between high- and low-affinity conformations. The multiple sites on P-glycoprotein display complex allosteric interactions through which interaction of drug at one site switches other sites between high- or low-affinity conformations. The data are discussed in terms of a model for the mechanism of transport by P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo.

(2.4)-Dimethoxybenzylidene anabaseine dihydrochloride (GTS-21), a compound that interacts with rat neuronal nicotinic acetylcholine receptors (nAChRs), was evaluated using human recombinant nAChRs in vitro and various pharmacokinetic and behavioral models in rodents, dogs and monkeys. GTS-21 bound to human alpha 4 beta 2 nAChR (K1-20 nM) 100-fold more potently than to human alpha 7 nAChR, and was 18- and 2-fold less potent than (-)-nicotine at human alpha 4 beta 2 and alpha 7 nAChR, respectively. Functionally. GTS-21 stimulated [5H]dopamine release from rat striatal slices with an EC50 of 10 +/- 2 microM (250-fold less potent and 70% as efficacious as (-)-nicotine), an effect blocked by the nAChR antagonist dihydro-beta-erythroidine. However, GTS-21 did not stimulate human alpha 4 beta 2 nor human ganglionic nAChRs significantly. In vivo, GTS-21 had no adverse effect on dog blood pressure (< or = 2.5 micromol/kg i.v. bolus infusion), in marked contrast with (-)-nicotine, GTS-21 (-62 micromol/kg.s.e.) also did not cross-discriminate significantly with (-)-nicotine in rats and did not reduce temperature or locomotion in mice. Neither was it active in the elevated plus maze anxiety model (0.19-6.2 micromol/kg.IP) in normal mice. However, GTS-21 did improve learning performance of monkeys in the delayed matching-to-sample task (32-130 nmol/kg.i.m.).

Animals↗
PubMed2005

ARD-353 [4-((2R,5S)-4-(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-ylmethyl)benzoic acid], a novel nonpeptide delta receptor agonist, reduces myocardial infarct size without central effects.

A novel delta-receptor selective compound, ARD-353 [4-((2R,5S)-4-(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2, 5-dimethylpiperazin-1-ylmethyl)benzoic acid], was evaluated for activity on infarct size in a rat model of acute myocardial infarction. ARD-353 was characterized as having delta receptor selectivity using radioligand binding and had no apparent selectivity between delta receptor subtypes as determined by [(3)H] cyclic [D-Pen(2),D-Pen(5)]enkephalin (delta(1)) and [(3)H]Deltorphin II (delta(2)) competition binding. ARD-353 also showed selective delta receptor agonist activity in mouse-isolated vas deferens. There was no evidence of any seizure-like convulsions when ARD-353 was administered to mice either i.v. or p.o., implying minimal penetration of the blood-brain barrier. ARD-353 decreased infarct size in a left anterior descending coronary artery (LAD) occlusion model of myocardial infarction. In animals pretreated with ARD-353 (i.v.) and then subjected to 30 min of LAD occlusion followed by 90 min of reperfusion, infarct size was reduced in a dose-dependent manner compared with vehicle-treated controls. The effects of ARD-353 on infarct size were blocked by the delta(1)-opioid selective antagonist 7-benzylidenenaltrexone, indicating a significant role for the delta(1)-opioid receptor in the cardioprotective mechanism of ARD-353. ARD-353 (0.3 mg/kg i.v.) produced significant protection when administered 5 min and 12 and 48 h before ischemic insult or when given immediately after the ischemic insult (at the start of reperfusion). Given the lack of central nervous system effects and beneficial efficacy in the rat model of myocardial ischemia, it is felt that ARD-353 is the first nonpeptide delta-receptor agonist with true potential for clinical use before surgically induced ischemia or in an emergency setting.

Animals↗
PubMed2006

Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia.

CONTEXT: The alpha7 nicotinic acetylcholine receptor gene, CHRNA7, is associated with genetic transmission of schizophrenia and related cognitive and neurophysiological sensory gating deficits. Cognitive dysfunction is responsible for significant psychosocial disability in schizophrenia. Nicotine, a low-potency agonist at the alpha7 receptor, has some positive effects on neurophysiological and neurocognitive deficits associated with schizophrenia, which suggests that more effective receptor activation might meaningfully enhance cognition in schizophrenia. OBJECTIVES: To determine if 3-[(2,4-dimethoxy)benzylidene]anabaseine (DMXB-A), a natural alkaloid derivative and a partial alpha7 nicotinic cholinergic agonist, significantly improves neurocognition, and to assess, by effects on P50 auditory evoked potential inhibition, whether its neurobiological actions are consistent with activation of alpha7 nicotinic receptors. DESIGN: Randomized, double-blind crossover trial of 2 drug doses and 1 placebo. SETTING: General clinical research center. PATIENTS: Twelve persons with schizophrenia who did not smoke and were concurrently treated with antipsychotic drugs. One person was withdrawn because of a transient decrease in white blood cell count. INTERVENTION: Administration of DMXB-A. MAIN OUTCOME MEASURES: Total scale score of the Repeatable Battery for the Assessment of Neuropsychological Status and P50 inhibitory gating. RESULTS: Significant neurocognitive improvement was found on the Repeatable Battery for the Assessment of Neuropsychological Status total scale score, particularly for the lower DMXB-A dose compared with placebo. Effects were greater than those of nicotine in a similar study. Significant improvement in P50 inhibition also occurred. Patients generally tolerated the drug well. CONCLUSIONS: An alpha7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia. Longer trials are needed to determine the clinical utility of this novel treatment strategy.

Adult↗
PubMed1997

Nicotinic receptor stimulation protects neurons against beta-amyloid toxicity.

beta-Amyloid (A beta), a major constituent of senile plaques in Alzheimer's disease (AD), is thought to contribute to the neurodegeneration. We examined the effects of nicotinic receptor agonists on A beta cytotoxicity in cultured rat cortical neurons. The number of viable neurons decreased significantly when cultures were exposed to synthetic A beta peptides (25-35). Concomitant administration of nicotine with A beta markedly reduced the number of dead cells. This nicotine-induced neuroprotection was dependent on the concentration. When hexamethonium or mecamylamine, nicotinic antagonist, was added, neuroprotective effect of nicotine was blocked, which indicates that effect of nicotine was mediated by nicotinic receptors. In addition, a selective alpha7-receptor antagonist, alpha-bungarotoxin (alpha-BTX), blocked the neuroprotective effect of nicotine. Furthermore, incubation with 3-(2,4)-dimethoxybenzylidene anabaseine (DMXB), a selective alpha7-receptor agonist, protected against A beta-induced neuronal death. These results suggest that alpha7-receptor activation plays an important role in neuroprotection against A beta cytotoxicity. This study suggests that nicotinic receptor stimulation, especially alpha7-receptor activation, may be able to protect neurons from degeneration induced by A beta and may have effects that counter the progress of AD.

Amyloid beta-Peptides↗