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Bayard T Storey – One of the best experts on this subject based on the ideXlab platform.

  • calcium influx into mouse spermatozoa activated by solubilized mouse zona pellucida monitored with the calcium fluorescent indicator fluo 3 inhibition of the influx by three inhibitors of the zona pellucida induced acrosome reaction tyrphostin a48 pe
    Molecular Reproduction and Development, 1994
    Co-Authors: Janice L Bailey, Bayard T Storey

    Abstract:

    The fluorescent calcium indicator, fluo-3, was loaded as the membrane permeant tetraacetoxymethyl (AM) ester into cauda epididymal mouse sperm at 25 degrees C for 20 min in the absence of bovine serum albumin (BSA) and presence of the dispersant, Pluronic F-127. Excess indicator was removed by two centrifugation washes at 100g for 10 min, a procedure that did not impair sperm motility. Upon resuspension in medium containing 20 mg/ml BSA to promote capacitation, the sperm cells exhibited readily detectable fluorescence uniformly distributed in the cytoplasm. Cell fluorescence was stable over the time of the experiments and was responsive to changes in intracellular calcium concentration, [Ca2+]i. Initial [Ca2+]i was 231 +/- 58 nM (+/- SE, n = 43). Addition of heat-solubilized mouse zonae pellucidae to capacitated sperm increased [Ca2+]i by 106 +/- 19 nM (+/- SE, n = 18), the higher steady-state concentration being reached after 30 min. Subsequent addition of the non-fluorescent calcium ionophore Br-A23187 resulted in a further increase of 114 +/- 18 nM (+/- SE, n = 18), the higher steady-state concentration being reached after 6 min. The increase in [Ca2+]i induced by solubilized zonae pellucidae was largely blocked by 3-Quinuclidinyl Benzilate (QNB), an antagonist of muscarinic receptors that was earlier shown to block the zona pellucida induced acrosome reaction in mouse sperm (Florman and Storey, 1982: Dev Biol 91:121-130). This [Ca2+]i increase was completely blocked by the tyrosine kinase inhibitor, tyrphostin A48, and by the inactivator of G1 proteins, pertussis toxin. At the concentrations at which they blocked the zona pellucida-induced increase in [Ca2+]i, all three inhibitors also blocked the zona pellucida-induced acrosome reaction. These results indicate that [Ca2+]i increase in is an early, if not the initial, reaction in the sequence leading to zona pellucida induced acrosomal exocytosis in mouse sperm. The observation that the three inhibitors, each having a different mode of action, all block the zona pellucida induced [Ca2+]i suggests that the sperm plasma membrane receptors mediating the zona pellucida induced acrosome reaction may function as a complex, whose formation is activated by zona pellucida ligand binding.

  • Solubilization and partial purification from mouse sperm membranes of the specific binding activity for 3-Quinuclidinyl Benzilate, a potent inhibitor of the zona pellucida-induced acrosome reaction.
    Molecular reproduction and development, 1994
    Co-Authors: Cynthia R. Ward, Gregory S. Kopf, Bayard T Storey

    Abstract:

    3-Quinuclidinyl Benzilate (QNB), a potent antagonist of muscarinic acetylcholine receptors, has been demonstrated to inhibit specifically the zona pellucida (ZP)-inducud acrosome reaction (AR) in mouse sperm (Florman and Storey, 1982; Dev Biol 91:121–130). In this study we describe the solubilization and partial purification of the mouse sperm QNB binding activity which may represent a component of the putative receptor complex for ZP on the sperm plasma membrane. Sperm membranes were isolated from cell homogenates of washed, capacitated, epididymal mouse sperm. Scatchard plots of QNB binding to these membranes indicated a single class of binding sites with KD = 7.2 nM and Bmax = 8700 sites/cell. These binding characteristics are similar to those seen with QNB binding to whole cells (Florman and Storey, 1982, J Androl 3:157–164). Sperm membranes were solubilized using 1% digitonin/0.2% cholate, and the resultant detergent-soluble fraction possessed QNB binding activity similar to that of intact membranes. The detergent-soluble fraction maintained intact ZP receptor(s)–G protein coupling in that treatment of this fraction with either ZP or mastoparan resulted in a 35% or 65% increase in specific GTPγS binding, respectively. The solubilized membrane preparation was fractionated by gel permeation HPLC. A majority of specific QNB binding activity was confined to one HPLC fraction. Analysis of this fraction by SDS–PAGE revealed a complex of approximately 5 proteins unique to this fraction. The most prominent protein had a Mr of 72 kDa, which is within the Mr range for muscarinic receptors. A protein with Mr = 41 kDa was also present within this fraction. Subsequent pertussis toxin (PTX)-catalyzed ADP-ribosylation of this fraction revealed this protein to be the α subunit of the Gi class of G proteins. Although the QNB binding activity could not be positively identified, we propose that it is contained in one or more of the proteins unique to this fraction and that these proteins, including Gi, may act as part of a sperm receptor complex for the ZP. © 1994 Wiley-Liss, Inc.

  • A transient rise in intracellular Ca2+ is a precursor reaction to the zona pellucida-induced acrosome reaction in mouse sperm and is blocked by the induced acrosome reaction inhibitor 3-Quinuclidinyl Benzilate.
    Molecular reproduction and development, 1992
    Co-Authors: Bayard T Storey, Catherine L. Hourani, J. B. Kim

    Abstract:

    The acrosome reaction induced by the zona pellucida in mouse sperm has been shown to proceed in two stages experimentally distinguishable by the fluorescent probe chlortetracycline. Entry into the first stage of sperm bound to isolated, structurally intact zonae pellucidae is blocked by the compound 3-Quinuclidinyl Benzilate. In this study, we show, utilizing the fluorescent Ca2+ indicator fluo-3, that the first stage of the zona-induced acrosome reaction is characterized by an increase in intracellular Ca2+, followed by a decrease as the acrosome reaction proceeds. This calcium transient is completely suppressed by 3-Quinuclidinyl Benzilate. We conclude that the Ca2+ transient is induced by the zona pellucida and is required for the zona-induced acrosome reaction. Blockage of this sperm intracellular Ca2+ transient provides a mechanism for the inhibitory action of 3-Quinuclidinyl Benzilate on the zona-induced acrosome reaction in mouse sperm. © 1992 Wiley-Liss, Inc.

Jiri Kassa – One of the best experts on this subject based on the ideXlab platform.

  • Effects of novel tacrine-related cholinesterase inhibitors in the reversal of 3-Quinuclidinyl Benzilate-induced cognitive deficit in rats—Is there a potential for Alzheimer’s disease treatment?
    Neuroscience letters, 2015
    Co-Authors: Jan Misik, Jan Korabecny, Eugenie Nepovimova, Alzbeta Kracmarova, Jiri Kassa

    Abstract:

    Inhibitors of cholinesterase are important drugs for therapy of Alzheimer’s disease and the search for new modifications is extensive, including dual inhibitors or multi-target hybrid compounds. The aim of the present study was a preliminary evaluation of pro-cognitive effects of newly-developed 7-MEOTA-donepezil like hybrids (compounds no. 1 and 2) and N-alkylated tacrine derivatives (compounds no. 3 and 4) using an animal model of pharmacologically-induced cognitive deficit. Male Wistar rats were subjected to tests of learning and memory in a water maze and step-through passive avoidance task. Cognitive impairment was induced by 3-Quinuclidinyl Benzilate (QNB, 2mgkg(-1)), administered intraperitoneally 1h before training sessions. Cholinesterase inhibitors were administered as a single therapeutic dose following the QNB at 30min at the following dose rates; 1 (25.6mgkg(-1)), 2 (12.3mgkg(-1)), 3 (5.7mgkg(-1)), 4 (5.2mgkg(-1)). The decrease in total path within the 10-swim session (water maze), the preference for target quadrant (water maze) and the entrance latency (passive avoidance) were taken as indicators of learning ability in rats. The effects of novel compounds were compared to that of standards tacrine (5.2mgkg(-1)) and donepezil (2.65mgkg(-1)). QNB significantly impaired spatial navigation as well as fear learning. Generally, the performance of rats was improved when treated with novel inhibitors and this effect reached efficiency of standard donepezil at selected doses. There was a significant improvement in the groups treated with compounds 2 and 3 in all behavioral tasks. The rest of the novel compounds succeed in the passive avoidance test. In summary, the potential of novel inhibitors (especially compounds 2 and 3) was proved and further detailed evaluation of these compounds as potential drugs for Alzheimer’s disease treatment is proposed.

  • Chapter 12 – Psychotomimetic Agent BZ (3-Quinuclidinyl Benzilate)
    Handbook of Toxicology of Chemical Warfare Agents, 2015
    Co-Authors: Josef Fusek, Jiri Bajgar, Jiri Kassa, Kamil Kuca, Daniel Jun

    Abstract:

    Agent BZ is the code name for 3-Quinuclidinyl Benzilate (BZ), an anticholinergic ester of glycolic acid. BZ is a psychotomimetic chemical warfare agent described as an anticholinergic hallucinogen. BZ is a competitive inhibitor of the effects of acetylcholine (ACh) acting at the postsynaptic muscarinic receptors in the peripheral nervous system (PNS) and central nervous system (CNS). In the PNS, this inhibition is observed in the muscle, autonomic ganglia, and exocrine glands. BZ’s ability to readily cross the blood–brain barrier causes mental status changes and delirium. BZ is one of the most potent anticholinergic psychotomimetics known with only small doses necessary to produce incapacitation. BZ at single doses of less than 1 mg produces delirium lasting several days. BZ is usually disseminated as an aerosol, and the primary route of absorption is through the respiratory system. Absorption also can occur through the skin or by gastrointestinal tract absorption. The pharmacologic activity of BZ is similar to atropine or scopolamine but with a much longer duration of action. Physicochemical properties and biological effects of BZ are described. The effect is characterized by vegetative symptoms progressing to hallucinations. Distribution of BZ in the body is preferably in the peripheral, followed by the CNS. Its mechanism of effect (toxicodynamics) is based on its interaction with cholinergic receptors in the CNS and PNS, and the resulting lack of a neuromediator—ACh. The antidotal effect against BZ intoxication is based on an increase of ACh levels caused by reversible cholinesterase inhibitors. From this group of compounds, physostigmine was used as the first antidote against BZ. However, physostigmine has a very thin margin between its therapeutic and toxic doses. Therefore, new inhibitors were developed, and acridine derivatives were found to be the most promising. From these compounds, 7-methoxytacrine (7-MEOTA) was the most effective. It is less toxic than physostigmine and tacrine and its central effect is pronounced. It was introduced in the Czech army as an antidote against BZ poisoning.

  • chapter 12 psychotomimetic agent bz 3 quinuclidinyl Benzilate
    Handbook of Toxicology of Chemical Warfare Agents (Second Edition), 2015
    Co-Authors: Josef Fusek, Jiri Bajgar, Jiri Kassa, Kamil Kuca, Daniel Jun

    Abstract:

    Agent BZ is the code name for 3-Quinuclidinyl Benzilate (BZ), an anticholinergic ester of glycolic acid. BZ is a psychotomimetic chemical warfare agent described as an anticholinergic hallucinogen. BZ is a competitive inhibitor of the effects of acetylcholine (ACh) acting at the postsynaptic muscarinic receptors in the peripheral nervous system (PNS) and central nervous system (CNS). In the PNS, this inhibition is observed in the muscle, autonomic ganglia, and exocrine glands. BZ’s ability to readily cross the blood–brain barrier causes mental status changes and delirium. BZ is one of the most potent anticholinergic psychotomimetics known with only small doses necessary to produce incapacitation. BZ at single doses of less than 1 mg produces delirium lasting several days. BZ is usually disseminated as an aerosol, and the primary route of absorption is through the respiratory system. Absorption also can occur through the skin or by gastrointestinal tract absorption. The pharmacologic activity of BZ is similar to atropine or scopolamine but with a much longer duration of action. Physicochemical properties and biological effects of BZ are described. The effect is characterized by vegetative symptoms progressing to hallucinations. Distribution of BZ in the body is preferably in the peripheral, followed by the CNS. Its mechanism of effect (toxicodynamics) is based on its interaction with cholinergic receptors in the CNS and PNS, and the resulting lack of a neuromediator—ACh. The antidotal effect against BZ intoxication is based on an increase of ACh levels caused by reversible cholinesterase inhibitors. From this group of compounds, physostigmine was used as the first antidote against BZ. However, physostigmine has a very thin margin between its therapeutic and toxic doses. Therefore, new inhibitors were developed, and acridine derivatives were found to be the most promising. From these compounds, 7-methoxytacrine (7-MEOTA) was the most effective. It is less toxic than physostigmine and tacrine and its central effect is pronounced. It was introduced in the Czech army as an antidote against BZ poisoning.

J. B. Kim – One of the best experts on this subject based on the ideXlab platform.

  • A transient rise in intracellular Ca2+ is a precursor reaction to the zona pellucida-induced acrosome reaction in mouse sperm and is blocked by the induced acrosome reaction inhibitor 3-Quinuclidinyl Benzilate.
    Molecular reproduction and development, 1992
    Co-Authors: Bayard T Storey, Catherine L. Hourani, J. B. Kim

    Abstract:

    The acrosome reaction induced by the zona pellucida in mouse sperm has been shown to proceed in two stages experimentally distinguishable by the fluorescent probe chlortetracycline. Entry into the first stage of sperm bound to isolated, structurally intact zonae pellucidae is blocked by the compound 3-Quinuclidinyl Benzilate. In this study, we show, utilizing the fluorescent Ca2+ indicator fluo-3, that the first stage of the zona-induced acrosome reaction is characterized by an increase in intracellular Ca2+, followed by a decrease as the acrosome reaction proceeds. This calcium transient is completely suppressed by 3-Quinuclidinyl Benzilate. We conclude that the Ca2+ transient is induced by the zona pellucida and is required for the zona-induced acrosome reaction. Blockage of this sperm intracellular Ca2+ transient provides a mechanism for the inhibitory action of 3-Quinuclidinyl Benzilate on the zona-induced acrosome reaction in mouse sperm. © 1992 Wiley-Liss, Inc.