Pittel Z


Full name : Pittel Zipora

First name : Zipora

Mail : Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

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Country : Israel

Email : pitel@iibr.gov.il

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References (21)

Title : Function-specific blockage of M(1) and M(3) muscarinic acetylcholine receptors by VX and echothiophate - Pittel_2006_Brain.Res_1085_102
Author(s) : Pittel Z , Barak D , Segall Y
Ref : Brain Research , 1085 :102 , 2006
Abstract : Certain organophosphate (OP) cholinesterase inhibitors (ChEIs) are also known to bind to the muscarinic acetylcholine receptor (mAChR). The functional consequences of such binding were investigated here using the following OP compounds: VX, echothiophate, sarin, and soman. VX (charged at physiological pH) and echothiophate (formally charged) inhibited a specific signal transduction pathway in CHO cells expressing either the M(1) or M(3) mAChR. Hence, they blocked carbamylcholine (CCh)-induced cyclic adenosine monophosphate (cAMP) synthesis (muM) and had almost no effect on CCh-induced phosphoinositide (PI) hydrolysis. These substances were inactive on forskolin-induced cAMP inhibition signaling in CHO cells expressing M(2) mAChR. In binding studies, using [(3)H]-N-methyl scopolamine ([(3)H]NMS) as the competitor ligand, the ChEIs, VX and echothiophate exhibited binding to rat cortical mAChR with K(i) values in the muM range. The non-charged compounds, sarin and soman, were inert in modulating both cAMP metabolism and PI hydrolysis in CHO cells expressing M(1), M(2), and M(3) mAChRs, and no binding was observed in presence of [(3)H]NMS. These data suggest that VX and echothiophate act as function-specific blockers via a non-classical path of antagonistic activity, implying the involvement of allosteric/ectopic-binding site in M(1) and M(3) mAChRs. The functionally selective antagonistic behavior of echothiophate and VX makes them potential tools for dissecting the interactions of the mAChR with different G proteins.
ESTHER : Pittel_2006_Brain.Res_1085_102
PubMedSearch : Pittel_2006_Brain.Res_1085_102
PubMedID: 16580648

Title : Poster (46) Major hallmarks in alzheimer's disease (ad) can beneficially be modulated by M1 muscarinic agonists - an added value vs. cholinesterase inhibitors -
Author(s) : Fisher A , Brandeis R , Pittel Z , Haring R , Sparks L , Beach TG , Bons N , Maestre-Frances N , Bar-Ner N , Kliger-Spatz M , Natan N , Marcovitch I , Hartmann T
Ref : In: Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects , (Inestrosa NC, Campos EO) P. Universidad Catolica de Chile-FONDAP Biomedicina :345 , 2004

Title : Beta-amyloids, tau hyperphosphorylation and cognition are beneficially affected by M1 muscarinic agonists. -
Author(s) : Pittel Z , Haring R , Bons N , Bar-Ner N , Sonego H , Natan N , Marcovitch I , Brandeis R
Ref : Cholinergic Mechanisms, CRC Press :345 , 2004

Title : M1 muscarinic agonists can modulate some of the hallmarks in Alzheimer's disease: implications in future therapy - Fisher_2003_J.Mol.Neurosci_20_349
Author(s) : Fisher A , Pittel Z , Haring R , Bar-Ner N , Kliger-Spatz M , Natan N , Egozi I , Sonego H , Marcovitch I , Brandeis R
Ref : Journal of Molecular Neuroscience , 20 :349 , 2003
Abstract : M1 muscarinic receptors (M1 mAChRs) play a role in an apparent linkage of three major hallmarks of Alzheimer's disease (AD): beta-amyloid (Abeta) peptide; tau hyperphosphorylation and paired helical filaments (PHFs); and loss of cholinergic function conducive to cognitive impairments. We evaluated the M1 muscarinic agonists AF102B (Cevimeline, EVOXAC trade mark : prescribed for Sjogren's syndrome), AF150(S), and AF267B on some of these hallmarks of AD. Activation of M1 mAChRs with these agonists leads, inter alia, to enhanced secretion of amyloid precursor protein (alpha-APP), (via alpha-secretase activation), to decreased Abeta (via gamma-secretase inhibition), and to inhibition of Abeta- and/or oxidative stress-induced cell death. In several animal models mimicking different aspects of AD, these drugs restored cognitive impairments, and in select cases induced a decrease in brain Abeta elevation, with a high safety margin, following po administration. Notably, in mice with small hippocampi, unlike rivastigmine and nicotine, AF150(S) and AF267B restored cognitive impairments also on escape latency in a Morris water maze paradigm, in reversal learning. Studies from other labs showed that AF102B and talsaclidine (another M1 agonist) decreased cerbrospinal fluid (CSF) Abeta in AD patients following chronic treatment, being the first reported drugs with such a profile. The clinical significance of these studies remains to be elucidated, yet based on in vivo (rabbits) and in vitro studies (cell cultures), our M1 agonists can decrease brain Abeta, owing to a novel and dual complementary effect (e.g., inhibition of gamma-secretase and activation of alpha-secretase). Remarkably, although M1 agonists can decrease CSF Abeta in AD patients, an increased AD-type pathology in Parkinson's disease was recently been associated with chronic antimuscarinic treatment. In another aspect, these agonists decreased tau hyperphosphorylation in vitro and in vivo. Notably, nicotinic agonists or cholinesterase inhibitors increased tau hyperphosphorylation. In summary, the M1 agonists tested are effective on cognition and behavior and show unique disease-modifying properties owing to beneficial effects on major hallmarks of AD. This may place such drugs in the first line of modern AD therapies (e.g., beta- or gamma-secretase inhibitors, vaccines against Abeta, statins, and inhibitors of tau hyperphosphorylation).
ESTHER : Fisher_2003_J.Mol.Neurosci_20_349
PubMedSearch : Fisher_2003_J.Mol.Neurosci_20_349
PubMedID: 14501019

Title : M1 muscarinic agonists as potential disease-modifying agents in Alzheimer's disease. Rationale and perspectives - Fisher_2000_Ann.N.Y.Acad.Sci_920_315
Author(s) : Fisher A , Michaelson DM , Brandeis R , Haring R , Chapman S , Pittel Z
Ref : Annals of the New York Academy of Sciences , 920 :315 , 2000
Abstract : A cholinergic hypofunction in Alzheimer's disease (AD) may lead to formation of beta-amyloids that might impair the coupling of M1 muscarinic ACh receptors (mAChRs) with G proteins. This disruption in coupling can lead to decreased signal transduction, to a reduction in levels of trophic amyloid precursor proteins (APPs), and to generation of more beta-amyloids that can also suppress ACh synthesis and release, aggravating further the cholinergic deficiency. These "vicious cycles," a presynaptic and a postsynaptic one, may be inhibited, in principle, by M1 selective agonists. Such properties can be detected in the functionally selective M1 agonists from the AF series [e.g., project drugs, AF102B, AF150(S)]. These M1 agonists promote the nonamyloidogenic APP processing pathways and decrease tau protein phosphorylation. The effects on tau proteins suggest a link between M1 mAChR-mediated signal transduction system(s) and the neuronal cytoskeleton via regulation of phosphorylation of tau microtubule-associated protein. This may indicate a dual role for M1 agonists: as inhibitors of two "vicious cycles," one induced by beta-amyloids, and the other due to overactivation of certain kinases (e.g., glycogen synthase kinase-3, GSK-3) or downregulation of phosphatases, respectively. Prolonged administration of AF150(S) in apolipoprotein E-knockout mice restored cognitive impairments, cholinergic hypofunction, and tau hyperphosphorylation, and unveiled a high-affinity binding site to M1 mAChRs. Except M1 agonists, there are no reports of compounds having such combined effects, for example, amelioration of cognition dysfunction and beneficial modulation of APPs together with tau phosphorylation. This unique property of M1 agonists to alter different aspects of AD pathogenesis could represent the most remarkable, yet unexplored, clinical value of such compounds.
ESTHER : Fisher_2000_Ann.N.Y.Acad.Sci_920_315
PubMedSearch : Fisher_2000_Ann.N.Y.Acad.Sci_920_315
PubMedID: 11193170

Title : Poster: Effect of muscarinic stimulation on beta-amyloid precursor protein processing in rat brain and primary cultures -
Author(s) : Pittel Z , Fisher A , Eshhar N , Haring R , Heldman E
Ref : Life Sciences , 64 :572 , 1999

Title : Novel m1 muscarinic agonists in treatment and delaying the progression of Alzheimer's disease: An unifying hypothesis - Fisher_1998_J.Physiol.Paris_92_337
Author(s) : Fisher A , Brandeis R , Haring R , Eshhar N , Heldman E , Karton Y , Eisenberg O , Meshulam H , Marciano D , Bar-Ner N , Pittel Z
Ref : Journal de Physiologie (Paris) , 92 :337 , 1998
Abstract : M1 selective agonists from the AF series (e.g. AF102B, AF150(S)), via m1 muscarinic receptors, activate distinct signal transductions, enhance amyloid precursors proteins secretion from transfected cells and primary cell cultures, show neurotrophic effects and are beneficial in a variety of animal models for Alzheimer's disease. Such m1 agonists may be effective in the treatment and therapy of Alzheimer's disease.
ESTHER : Fisher_1998_J.Physiol.Paris_92_337
PubMedSearch : Fisher_1998_J.Physiol.Paris_92_337
PubMedID: 9789833

Title : M1 muscarinic agonist treatment reverses cognitive and cholinergic impairments of apolipoprotein E-deficient mice - Fisher_1998_J.Neurochem_70_1991
Author(s) : Fisher A , Brandeis R , Chapman S , Pittel Z , Michaelson DM
Ref : Journal of Neurochemistry , 70 :1991 , 1998
Abstract : Recent studies suggest that apolipoprotein E (apoE) plays a specific role in brain cholinergic function and that the E4 allele of apoE (apoE4), a major risk factor for Alzheimer's disease (AD), may predict the extent of cholinergic dysfunction and the efficacy of cholinergic therapy in this disease. Animal model studies relevant to this hypothesis revealed that apoE-deficient (knockout) mice have working memory impairments that are associated with distinct dysfunction of basal forebrain cholinergic neurons. Cholinergic replacement therapy utilizing M1-selective muscarinic agonists has been proposed as effective treatment for AD patients. In the present study, we examined whether the memory deficits and brain cholinergic deficiency of apoE-deficient mice can be ameliorated by the M1-selective agonist 1-methylpiperidine-4-spiro-(2'-methylthiazoline), [AF150(S)]. Treatment of apoE-deficient mice with AF150(S) for 3 weeks completely abolished their working memory impairments. Furthermore, this reversal of cognitive deficit was associated with a parallel increase of histochemically determined brain choline acetyltransferase and acetylcholinesterase levels and with the recovery of these cholinergic markers back to control levels. These findings show that apoE deficiency-related cognitive and cholinergic deficits can be ameliorated by M1-selective muscarinic treatment. They also provide a novel model system for development and evaluation of therapeutic strategies directed specifically at the AD patients whose condition is attributed to the apoE genotype.
ESTHER : Fisher_1998_J.Neurochem_70_1991
PubMedSearch : Fisher_1998_J.Neurochem_70_1991
PubMedID: 9572284

Title : Large-scale purification and long-term stability of human butyrylcholinesterase: a potential bioscavenger drug - Grunwald_1997_J.Biochem.Biophys.Methods_34_123
Author(s) : Grunwald J , Marcus D , Papier Y , Raveh L , Pittel Z , Ashani Y
Ref : Journal of Biochemical & Biophysical Methods , 34 :123 , 1997
Abstract : Butyrylcholinesterase from human plasma (HuBChE) is a potential drug candidate for detoxification of certain harmful chemicals that contain carboxylic or phosphoric acid ester bonds. Large quantities of purified HuBChE, displaying a high stability upon long-term storage, are required for the evaluation of its therapeutic capacity and its pharmaceutical properties. Several modifications of a previously reported procedure enabled us to purify the enzyme > 15,000-fold from pools of up to 100 1 of human plasma. The three-step procedure is based on precipitation of plasma proteins by ammonium sulfate (step I) and batch adsorption of HuBChE on procainamide-Sepharose 4B gel (step II). Ammonium sulfate was also employed in the third stage to fractionate the final product from procainamide-containing HuBChE solution. The overall yield (63%) of electrophoretically pure enzyme was significantly higher than that previously reported (34%) for the purification of HuBChE from 12.5 1 of plasma or from 5 kg of Cohn fraction IV-4. Purified HuBChE was stored at 5 degrees C in 10 mM phosphate buffer (pH 7.4) containing 1 mM EDTA and 0.02% NaN3. The specific activity, protein migration on gel electrophoresis, thermostability at 54 degrees C and the mean residence time in the circulation of mice remained essentially constant for at least 46 months. The modifications introduced can provide large quantities of purified enzyme that maintains its activity and bioavailability properties for several years.
ESTHER : Grunwald_1997_J.Biochem.Biophys.Methods_34_123
PubMedSearch : Grunwald_1997_J.Biochem.Biophys.Methods_34_123
PubMedID: 9178088

Title : Dehydroepiandrosterone (DHEA) increases production and release of Alzheimer's amyloid precursor protein - Danenberg_1996_Life.Sci_59_1651
Author(s) : Danenberg HD , Haring R , Fisher A , Pittel Z , Gurwitz D , Heldman E
Ref : Life Sciences , 59 :1651 , 1996
Abstract : Dehydroepiandrosterone (DHEA), the major secretory product of the human adrenal cortex, significantly declines with advanced age. We have previously demonstrated that DHEA prevents the reduction in non-amyloidogenic APP processing, following prolonged stimulation of the muscarinic receptor, in PC12 cells that express the ml acetylcholine-receptor. The present study examined whether this effect may be mediated via modulation of APP metabolism. It was found that DHEA treatment increases the content of membrane-associated APP holoprotein by 24%, and the accumulation of secreted APP in the medium by 63%. No increase in viable cell number nor in nonspecific protein production was observed in DHEA-treated cells. Thus, DHEA seems to increase specifically both APP synthesis and secretion. We propose that the age-associated decline in DHEA levels may be related to the pathological APP metabolism observed in Alzheimer's disease.
ESTHER : Danenberg_1996_Life.Sci_59_1651
PubMedSearch : Danenberg_1996_Life.Sci_59_1651
PubMedID: 8913330

Title : M1 agonists for the treatment of Alzheimer's disease. Novel properties and clinical update - Fisher_1996_Ann.N.Y.Acad.Sci_777_189
Author(s) : Fisher A , Heldman E , Gurwitz D , Haring R , Karton Y , Meshulam H , Pittel Z , Marciano D , Brandeis R , Sadot E , Barg Y , Pinkas-Kramarski R , Vogel Z , Ginzburg I , Treves TA , Verchovsky R , Klimowsky S , Korczyn AD
Ref : Annals of the New York Academy of Sciences , 777 :189 , 1996
Abstract : The AF series compounds, AF102B and congeners of AF150(S), are functionally selective agonists for m1 muscarinic receptors (m1AChRs). This is shown in stable transfected CHO and PC12 cells (PC12M1) with m1m5AChRs and m1AChRs, respectively. AF102B and AF150(S) are partial agonists, but AF150, AF151, and AF151 (S) are full agonists in stimulating phosphoinositides hydrolysis or arachidonic acid release in these cells. Yet, all these compounds behave as antagonists when compared with carbachol in elevating cAMP levels. In PC12M1 cells, unlike carbachol, the AF series compounds induce only minimal to moderate neurite outgrowth. Yet, these agonists synergize strongly with NGF, which by itself mediates only a mild response. Stimulation of m1AChRs by AF102B, AF150(S) and AF151(S) in PC12M1 cells enhances secretion of beta/A4 amyloid precursor protein derivatives (APPs). The enhanced APPs secretion induced by AF102B is potentiated by NGF. AF102B also stimulates APPs secretion from rat cortical slices. Stimulation of m1AChR in PC12M1 cells with carbachol or AF102B decreases tau phosphorylation as indicated by specific tau-1 mAb and alkaline phosphatase treatment. Due to the above mentioned properties m1 agonists may be of unique value in delaying the progression of Alzheimer's disease (AD). The AF series compounds show a wide safety margin and improve memory and learning deficits in animal models for AD. There is a dearth of clinical reports on m1 agonists. These include studies on AF102B and xanomeline, another m1 selective agonist. We tested AF102B in escalating doses of 20, 40, 60 mg, tid, po, (each dose for 2 weeks) for a total of 10 weeks. This was a single-blind placebo-controlled, parallel-group study in patients with probable AD. AF102B was significantly effective at 40 and 60 mg, tid in the ADAS, ADAS-cognitive and ADAS-word recognition scales.
ESTHER : Fisher_1996_Ann.N.Y.Acad.Sci_777_189
PubMedSearch : Fisher_1996_Ann.N.Y.Acad.Sci_777_189
PubMedID: 8624083

Title : Muscarinic control of amyloid precursor protein secretion in rat cerebral cortex and cerebellum - Pittel_1996_Brain.Res_742_299
Author(s) : Pittel Z , Heldman E , Barg J , Haring R , Fisher A
Ref : Brain Research , 742 :299 , 1996
Abstract : It was previously shown by us and by others that activation of muscarinic acetylcholine receptors evoke amyloid precursor protein (APP) secretion in various cell lines. Here we examined if such muscarinic control of APP secretion occurs also in normal brain tissues. We found that the secretion of APP from rat cerebrocortical slices (rich in M1 receptors) was significantly increased by K+ depolarization, the non-selective agonist, carbachol (CCh), and the M1-selective agonist, AF102B. CCh also increased APP secretion from cerebellar slices (rich in M2 receptors) while AF102B had no significant effect in this brain region. Despite of its stimulatory effect on APP release in the cerebellum, CCh had no effect on phosphoinositide (PI) metabolism in this brain region. In the cerebral cortex PI metabolism was significantly increased by CCh but only partially increased by AF102B. These results suggest that APP secretion in the brain is mediated via muscarinic receptors. In the cerebral cortex APP secretion seems to be regulated via M1 receptors. Our results also suggest that PI metabolism is not a pronounced step in mediating APP processing.
ESTHER : Pittel_1996_Brain.Res_742_299
PubMedSearch : Pittel_1996_Brain.Res_742_299
PubMedID: 9117408

Title : Dehydroepiandrosterone augments M1-muscarinic receptor-stimulated amyloid precursor protein secretion in desensitized PC12M1 cells - Danenberg_1995_Ann.N.Y.Acad.Sci_774_300
Author(s) : Danenberg HD , Haring R , Heldman E , Gurwitz D , Ben-Nathan D , Pittel Z , Zuckerman A , Fisher A
Ref : Annals of the New York Academy of Sciences , 774 :300 , 1995
Abstract : Epidemiologic studies suggest that the age-related decline in dehydroepiandrosterone (DHEA) levels may be associated with Alzheimer's disease (AD). Cholinergic markers also decline with age, and are associated with AD pathology. Activation of m1AChR-transfected PC12 cells (PC12M1) with cholinergic agonists results in secretion of Alzheimer's beta-amyloid precursor protein (APP) which in turn reduces beta-amyloid production. This study examined whether DHEA affects APP processing in m1AChR-transfected PC12 cells. DHEA treatment did not significantly alter basal or m1AChR-stimulated APP secretion. However, DHEA (0.1 microM) significantly diminished the desensitization of APP secretion in cells exposed to carbachol for 24 h. The effect of DHEA on APP processing is probably not related to up-regulation of m1AChR or increased m1AChR-activated phosphoinositide hydrolysis since these parameters did not change following DHEA treatment. These findings imply a possible involvement of DHEA in APP processing. Thus, the age-associated decline in DHEA levels may contribute to decreased APP secretion and a consecutive increase in beta-amyloid deposition, which in turn may play a role in the development of AD.
ESTHER : Danenberg_1995_Ann.N.Y.Acad.Sci_774_300
PubMedSearch : Danenberg_1995_Ann.N.Y.Acad.Sci_774_300
PubMedID: 8597471

Title : Poster: Transmembrane signaling of M1 muscarinic receptors in the rat brain and cell cultures -
Author(s) : Pittel Z , Fisher A , Vogel Z , Heldman E
Ref : Life Sciences , 52(5-6) :565 , 1993

Title : Selective signaling via unique M1 muscarinic agonists - Fisher_1993_Ann.N.Y.Acad.Sci_695_300
Author(s) : Fisher A , Heldman E , Gurwitz D , Haring R , Barak D , Meshulam H , Marciano D , Brandeis R , Pittel Z , Segal M , et al.
Ref : Annals of the New York Academy of Sciences , 695 :300 , 1993
Abstract : Rigid analogs of acetylcholine (ACh) were designed for selective actions at muscarinic receptor (mAChR) subtypes and distinct second messenger systems. AF102B, AF150, and AF151 are such rigid analogs of ACh. AF102B, AF150 and AF151 are centrally active M1 agonists. AF102B has a unique agonistic profile showing, inter alia: only part of the M1 electrophysiology of ACh and unusual binding parameters to mAChRs. AF150 and AF151 are more efficacious agonists than AF102B for M1 AChRS in rat cortex and in CHO cells stably transfected with the m1 AChR subtype. Notably, the selectivity of the new m1 agonists is reflected also by activation of select second messenger systems via distinct G-proteins. These compounds reflect a new pharmacological concept, tentatively defined as ligand-selective signaling. Thus, agonist/m1AChR complexes may activate different combinations of signaling pathways, depending on the ligand used. Rigid agonists may activate a limited repertoire of signaling systems. In various animal models for Alzheimer's disease (AD) the agonists AF102B, AF150 and AF151, exhibited positive effects on mnemomic processes and a wide safety margin. Such agonists, and especially AF102B, can be considered as a rational treatment strategy for AD.
ESTHER : Fisher_1993_Ann.N.Y.Acad.Sci_695_300
PubMedSearch : Fisher_1993_Ann.N.Y.Acad.Sci_695_300
PubMedID: 8239299

Title : Progress in medicinal chemistry of novel selective muscarinic agonists - Fisher_1993_Drug.Des.Discov_9_221
Author(s) : Fisher A , Karton Y , Heldman E , Gurwitz D , Haring R , Meshulam H , Brandeis R , Pittel Z , Segall Y , Marciano D , et al.
Ref : Drug Des Discov , 9 :221 , 1993
Abstract : Rigid analogs of acetylcholine (ACh) were designed for selective actions at muscarinic receptor subtypes. AF102B, AF125, AF150 and AF151 are such rigid analogs of ACh. Whilst AF125 is an M2 > M1 agonist, AF102B, AF150 and AF151 are centrally active M1 agonists. AF102B has a unique agonistic profile showing, inter alia, only part of the M1 electrophysiology of ACh and unusual binding parameters to mAChRs. AF150 and AF151 are more efficacious agonists than AF102B for M1 AChRs in rat cortex and in CHO cells stably transfected with the m1 AChR subtype. In various animal models for Alzheimer's disease (AD) all three agonists (AF102B, AF150 and AF151), and in particular AF102B, exhibited positive effects on mnemonic processes and a wide safety margin. Such agonists, and especially AF102B, can be considered as a rational treatment strategy in AD. Here we review some current features of these compounds, which may be relevant to a rational treatment strategy in AD. Comparison is made, whenever possible, with some new and old muscarinic agonists.
ESTHER : Fisher_1993_Drug.Des.Discov_9_221
PubMedSearch : Fisher_1993_Drug.Des.Discov_9_221
PubMedID: 8400004

Title : Differential long-term effect of AF64A on [3H]ACh synthesis and release in rat hippocampal synaptosomes - Pittel_1992_Brain.Res_586_148
Author(s) : Pittel Z , Cohen S , Fisher A , Heldman E
Ref : Brain Research , 586 :148 , 1992
Abstract : The activities of various presynaptic cholinergic parameters were determined in hippocampal synaptosomes of rats 29 weeks after intracerebroventricular injection of ethylcholine aziridinium (AF64A) (3 nmol/2 microliters/side) or vehicle (saline). Synaptosomes were preloaded with [3H]choline ([3H]Ch), treated with diisopropyl fluorophosphate to inhibit cholinesterase activity and then were assayed for their content of [3H]Ch and [3H]acetylcholine ([3H]ACh) and for their ability to synthesize and release [3H]ACh. In synaptosomes from AF64A-treated rats compared with synaptosomes from vehicle-treated rats we observed that: (i) specific uptake of [3H]Ch was reduced to 60% of control; (ii) residing [3H]ACh levels were 43% of control while residing [3H]Ch levels were 72% of control; (iii) basal and K(+)-induced [3H]ACh release were 77% and 73% of control, respectively; (iv) high K(+)-induced synthesis of [3H]ACh was only 9% of control; (v) but, choline acetyltransferase activity remained relatively high, being 80% of control. These results suggest that AF64A-induced cholinergic hypofunction is expressed by both loss of some cholinergic neurons and impairment in the functioning of the spared neurons.
ESTHER : Pittel_1992_Brain.Res_586_148
PubMedSearch : Pittel_1992_Brain.Res_586_148
PubMedID: 1511344

Title : Inhibition of choline efflux results in enhanced acetylcholine synthesis and release in the guinea-pig corticocerebral synaptosomes - Pittel_1992_Neurochem.Int_20_219
Author(s) : Pittel Z , Heldman E , Rubinstein R , Cohen S
Ref : Neurochem Int , 20 :219 , 1992
Abstract : Synthesis and release of [3H]acetylcholine ([3H]ACh) were measured in synaptosomes from the guinea pig cerebral cortex after preloading with [3H]choline ([3H]Ch). We demonstrate here that inhibition of choline (Ch) efflux results in an increase in acetylcholine (ACh) synthesis and release. Our findings are as follows: (1) inhibition of [3H]Ch efflux by hemicholinium-3 (HC-3) (100 microM), increased the levels of both the released (116% of control) and the residing (115% of control) [3H]ACh. (2) The muscarinic agonist, McN-A-343 (100 microM), which was previously shown to inhibit Ch efflux, also increased the released (121% of control) and the residing (109% of control) [3H]ACh. (3) Omission of Na+ ions (which are required for Ch transport) from the incubation medium had similar effects to those observed with McN-A-343 and HC-3. These results suggest inverse relationships between Ch efflux on one hand, and ACh synthesis and release on the other hand. (4) Depolarization with 50 mM K+, or with the K+ channel blocker, 4-aminopyridine (100 microM), also increased the total level of [3H]ACh (113 and 107% of nondepolarized synaptosomes, respectively). However, whereas conditions that inhibit Ch transport such as HC-3, McN-A-343 and "no sodium" increased both the residing and the released [3H]ACh depolarization with high K+ or 4-aminopyridine reduced the residing (79 and 87% of control, respectively) and increased only the released [3H]ACh (182 and 148% of control, respectively).
ESTHER : Pittel_1992_Neurochem.Int_20_219
PubMedSearch : Pittel_1992_Neurochem.Int_20_219
PubMedID: 1284802

Title : (+-)-cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine, an M1 selective cholinergic agonist, attenuates cognitive dysfunctions in an animal model of Alzheimer's disease - Fisher_1991_J.Pharmacol.Exp.Ther_257_392
Author(s) : Fisher A , Brandeis R , Karton I , Pittel Z , Gurwitz D , Haring R , Sapir M , Levy A , Heldman E
Ref : Journal of Pharmacology & Experimental Therapeutics , 257 :392 , 1991
Abstract : AF102B [(+-)-cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine], a structurally rigid analog of acetylcholine, was investigated in a number of neurochemical, pharmacological and behavioral tests related to cholinergic functions. AF102B induced atropine-sensitive contractions of isolated guinea pig ilea and trachea preparations with EC50 values of 3.5 and 3 microM being 87- and 1.3-fold less potent than acetylcholine, respectively. Binding studies using the radioligands pirenzepine, cis-dioxolane and quinuclidinyl benzilate in rat cerebral cortex and quinuclidinyl benzilate in cerebellar homogenates indicated that AF102B was a potent and highly selective M1-type muscarinic probe, being more selective for M1 receptors than oxotremorine, carbachol and AF102A (the trans-isomer of AF102B). AF102B had a 3-fold higher apparent affinity for M1 receptors than the prototype M1 agonist, McN-A-343, cis- and trans-AF30 (other rigid analogs of acetylcholine). Treatment of rat cortical homogenates with Cu++ ions did not modify the affinity observed for the muscarinic antagonists atropine, scopolamine and pirenzepine, whereas increasing the proportion of high affinity sites for the agonists oxotremorine-M, carbachol and McN-A-343. The apparent affinity of AF102B also increased by Cu++ treatment suggesting that this compound interacts with rat cerebral cortex muscarinic receptors as an agonist. AF102B did not affect high affinity choline transport, choline acetyltransferase and acetylcholinesterase activities in rat brain preparations. In rats treated with AF64A (the cholinotoxin ethylcholine aziridinium ion; 3 nmol/2 microliters/side i.c.v.), AF102B (1 mg/kg p.o. or i.p.), AF102A (1 mg/kg i.p.), cis-AF30 (1 mg/kg, i.p.) and physostigmine (0.06 mg/kg i.p.), each reversed cognitive impairments in a step-through passive avoidance task. Both AF102B and AF102A (1 mg/kg i.p.), but not physostigmine (0.1 mg/kg i.p.), were effective also in reversing reference memory impairments in a Morris water maze test. Repetitive administrations of AF102B (0.2 mg/kg/day i.p.) improved AF64A-induced working memory deficits in the Morris water maze test, but did not affect open field behavior. The data show that the selective M1 agonist AF102B can restore AF64A-induced cognitive impairments, without producing adverse central and peripheral side effects at the effective doses and this can indicate its potential use for the treatment of Alzheimer's disease.
ESTHER : Fisher_1991_J.Pharmacol.Exp.Ther_257_392
PubMedSearch : Fisher_1991_J.Pharmacol.Exp.Ther_257_392
PubMedID: 2019998

Title : Distinct muscarinic receptor subtypes differentially modulate acetylcholine release from corticocerebral synaptosomes - Pittel_1990_J.Neurochem_55_665
Author(s) : Pittel Z , Heldman E , Rubinstein R , Cohen S
Ref : Journal of Neurochemistry , 55 :665 , 1990
Abstract : The effect of McN-A-343 and oxotremorine on acetylcholine (ACh) release and choline (Ch) transport was studied in corticocerebral synaptosomes of the guinea pig. The synaptosomes were preloaded with [3H]Ch after treatment with the irreversible cholinesterase inhibitor, diisopropyl fluorophosphate, and then tested for their ability to release isotope-labeled ACh and Ch in the presence and absence of these agents. The kinetics of release were determined at the resting state (basal release) and in the presence of 50 mM K+. Under either condition, McN-A-343 enhanced the release of isotope-labeled ACh, whereas oxotremorine inhibited the K(+)-evoked release but had no effect on the basal release. The enhancing effect of McN-A-343 on basal ACh release was fully blocked by the selective M1 muscarinic antagonist, pirenzepine (100 nM). In contrast to its enhancing effect on ACh release, McN-A-343 potently inhibited Ch efflux as well as Ch influx. These effects were not blocked by atropine, a nonselective muscarinic antagonist. Oxotremorine had no effect on Ch transport. Binding studies showed that McN-A-343 was 3.6-fold more potent in displacing radiolabeled quinuclidinyl benzilate from cerebral cortex muscarinic receptors (mostly M1 subtype) than from cerebellar receptors (mostly M2 subtype), whereas oxotremorine was 2.6-fold more potent in the cerebellum. The displacements of radio-labeled pirenzepine and cis-dioxolane confirmed the M1 subtype preference of McN-A-343 and the M2 subtype preference of oxotremorine.
ESTHER : Pittel_1990_J.Neurochem_55_665
PubMedSearch : Pittel_1990_J.Neurochem_55_665
PubMedID: 1695243

Title : Poster: Synaptosomal acetycholine release is modulated by M1 and M2 mACh receptors -
Author(s) : Pittel Z , Heldman E , Rubinstein R , Cohen S
Ref : Trends in Pharmacological Sciences , Suppl :105 , 1989