Scali C

References (32)

Title : N-[5-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl]-4-piperidin-1-ylbutyramide (SEN78702, WYE-308775): a medicinal chemistry effort toward an alpha7 nicotinic acetylcholine receptor agonist preclinical candidate - Zanaletti_2012_J.Med.Chem_55_10277
Author(s) : Zanaletti R , Bettinetti L , Castaldo C , Ceccarelli I , Cocconcelli G , Comery TA , Dunlop J , Genesio E , Ghiron C , Haydar SN , Jow F , Maccari L , Micco I , Nencini A , Pratelli C , Scali C , Turlizzi E , Valacchi M
Ref : Journal of Medicinal Chemistry , 55 :10277 , 2012
Abstract : alpha7 Nicotinic acetylcholine receptors (alpha7 nAChR) represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort around previously reported compound 1 (SEN15924, WAY-361789) led to the identification of 12 (SEN78702, WYE-308775) a potent and selective full agonist of the alpha7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models.
ESTHER : Zanaletti_2012_J.Med.Chem_55_10277
PubMedSearch : Zanaletti_2012_J.Med.Chem_55_10277
PubMedID: 23083093

Title : Discovery of a novel alpha-7 nicotinic acetylcholine receptor agonist series and characterization of the potent, selective, and orally efficacious agonist 5-(4-acetyl[1,4]diazepan-1-yl)pentanoic acid [5-(4-methoxyphenyl)-1H-pyrazol-3-yl] amide (SEN15924, WAY-361789) - Zanaletti_2012_J.Med.Chem_55_4806
Author(s) : Zanaletti R , Bettinetti L , Castaldo C , Cocconcelli G , Comery T , Dunlop J , Gaviraghi G , Ghiron C , Haydar SN , Jow F , Maccari L , Micco I , Nencini A , Scali C , Turlizzi E , Valacchi M
Ref : Journal of Medicinal Chemistry , 55 :4806 , 2012
Abstract : Alpha-7 nicotinic acetylcholine receptors (alpha7 nAChR) are implicated in the modulation of many cognitive functions such as attention, working memory, and episodic memory. For this reason, alpha7 nAChR agonists represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort, around our previously reported chemical series, permitted the discovery of a novel class of alpha7 nAChR agonists with improved selectivity, in particular against the alpha3 receptor subtype and better ADME profile. The exploration of this series led to the identification of 5-(4-acetyl[1,4]diazepan-1-yl)pentanoic acid [5-(4-methoxyphenyl)-1H-pyrazol-3-yl] amide (25, SEN15924, WAY-361789), a novel, full agonist of the alpha7 nAChR that was evaluated in vitro and in vivo. Compound 25 proved to be potent and selective, and it demonstrated a fair pharmacokinetic profile accompanied by efficacy in rodent behavioral cognition models (novel object recognition and auditory sensory gating).
ESTHER : Zanaletti_2012_J.Med.Chem_55_4806
PubMedSearch : Zanaletti_2012_J.Med.Chem_55_4806
PubMedID: 22468936

Title : Preclinical assessment of an adjunctive treatment approach for cognitive impairment associated with schizophrenia using the alpha7 nicotinic acetylcholine receptor agonist WYE-103914\/SEN34625 - Marquis_2011_Psychopharmacology.(Berl)_218_635
Author(s) : Marquis KL , Comery TA , Jow F , Navarra RL , Grauer SM , Pulicicchio C , Kelley C , Brennan JA , Roncarati R , Scali C , Haydar S , Ghiron C , Terstappen GC , Dunlop J
Ref : Psychopharmacology (Berl) , 218 :635 , 2011
Abstract : RATIONALE: alpha7 nicotinic acetylcholine receptor (nAChR) agonists are proposed as candidate agents for the adjunctive treatment of cognitive deficits associated with schizophrenia. Despite the pursuit of such an approach clinically, it is surprising that the preclinical profile of pro-cognitive agents in conjunction with antipsychotic drugs is currently unexplored. OBJECTIVES: We determined if the memory-enhancing effects of the selective alpha7 nAChR agonist WYE-103914 were preserved in the presence of the atypical antipsychotic drug risperidone, and if the antipsychotic-like profile of risperidone was preserved in the presence of WYE-103914.
METHODS: Using the rat novel object recognition (NOR) paradigm, the maintenance of memory-enhancing activity of the alpha7 nAChR agonist WYE-103914 in the presence of risperidone was examined. Similarly, in the standard tests of antipsychotic-like activity, apomorphine-induced climbing (AIC) in mice and conditioned avoidance responding (CAR) in rats, the preservation of antipsychotic-like activity of risperidone was evaluated in the presence of WYE-103914.
RESULTS: WYE-103914 exhibited memory-enhancing activity in rat NOR, and this effect of WYE-103914 was retained in the presence of risperidone. In AIC, the atypical antipsychotic profile of risperidone was not significantly altered by WYE-103914. In contrast, WYE-103914 moderately potentiated the efficacy profile of risperidone in CAR, an effect that did not appear to be convincingly linked to a pharmacokinetic interaction.
CONCLUSIONS: These data underscore the value of a preclinical evaluation of the adjunctive profile of a memory-enhancing agent in combination with antipsychotics and provide further support to augmentation with alpha7 nAChR agonists to address the cognitive deficits associated with schizophrenia.
ESTHER : Marquis_2011_Psychopharmacology.(Berl)_218_635
PubMedSearch : Marquis_2011_Psychopharmacology.(Berl)_218_635
PubMedID: 21643676

Title : Novel alpha-7 nicotinic acetylcholine receptor agonists containing a urea moiety: identification and characterization of the potent, selective, and orally efficacious agonist 1-[6-(4-fluorophenyl)pyridin-3-yl]-3-(4-piperidin-1-ylbutyl) urea (SEN34625\/WYE-103914) - Ghiron_2010_J.Med.Chem_53_4379
Author(s) : Ghiron C , Haydar SN , Aschmies S , Bothmann H , Castaldo C , Cocconcelli G , Comery TA , Di L , Dunlop J , Lock T , Kramer A , Kowal D , Jow F , Grauer S , Harrison B , La Rosa S , Maccari L , Marquis KL , Micco I , Nencini A , Quinn J , Robichaud AJ , Roncarati R , Scali C , Terstappen GC , Turlizzi E , Valacchi M , Varrone M , Zanaletti R , Zanelli U
Ref : Journal of Medicinal Chemistry , 53 :4379 , 2010
Abstract : Alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4-18) of the alpha7 nAChR deriving from our continuing efforts in the areas of Alzheimer's disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the alpha7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.
ESTHER : Ghiron_2010_J.Med.Chem_53_4379
PubMedSearch : Ghiron_2010_J.Med.Chem_53_4379
PubMedID: 20465311

Title : Procognitive and neuroprotective activity of a novel alpha7 nicotinic acetylcholine receptor agonist for treatment of neurodegenerative and cognitive disorders - Roncarati_2009_J.Pharmacol.Exp.Ther_329_459
Author(s) : Roncarati R , Scali C , Comery TA , Grauer SM , Aschmi S , Bothmann H , Jow B , Kowal D , Gianfriddo M , Kelley C , Zanelli U , Ghiron C , Haydar S , Dunlop J , Terstappen GC
Ref : Journal of Pharmacology & Experimental Therapeutics , 329 :459 , 2009
Abstract : The alpha7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of alpha7 nAChR. SEN12333 shows high affinity for the rat alpha7 receptor expressed in GH4C1 cells (K(i) = 260 nM) and acts as full agonist in functional Ca(2+) flux studies (EC(50) = 1.6 microM). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC(50) = 12 microM). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at alpha3-containing receptors. SEN12333 treatment (3 mg/kg i.p.) improved episodic memory in a novel object recognition task in rats in conditions of spontaneous forgetting as well as cognitive disruptions induced via glutamatergic [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MK-801] or cholinergic (scopolamine) mechanisms. This improvement was blocked by the alpha7-selective antagonist methyllycaconitine, indicating that it is mediated by alpha7 activation. SEN12333 also prevented a scopolamine-induced deficit in a passive avoidance task. In models targeting other cognitive domains, including attention and perceptual processing, SEN12333 normalized the apomorphine-induced deficit of prepulse inhibition. Neuroprotection of SEN12333 was demonstrated in quisqualate-lesioned animals in which treatment with SEN12333 (3 mg/kg/day i.p.) resulted in a significant protection of choline acetyltransferase-positive neurons in the lesioned hemisphere. Cumulatively, our results demonstrate that the novel alpha7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of alpha7 agonists for treatment of neurodegenerative and cognitive disorders.
ESTHER : Roncarati_2009_J.Pharmacol.Exp.Ther_329_459
PubMedSearch : Roncarati_2009_J.Pharmacol.Exp.Ther_329_459
PubMedID: 19223665

Title : Poster: Characterization of the alpha-7 nicotinic receptor agonist WYE-103914 in models relevant to schizophrenia and interaction with antipsychotics -
Author(s) : Marquis KL , Comery TA , Navarra RL , Leiser S , Grauer SM , Pulicicchio C , Kelley C , Roncarati R , Scali C , Haydar S , Ghiron C , Harrison B , Robichaud A , Terstappen GC , Dunlop J
Ref : Biochemical Pharmacology , 78 :911 , 2009
PubMedID:

Title : SAR and biological evaluation of SEN12333\/WAY-317538: Novel alpha 7 nicotinic acetylcholine receptor agonist - Haydar_2009_Bioorg.Med.Chem_17_5247
Author(s) : Haydar SN , Ghiron C , Bettinetti L , Bothmann H , Comery TA , Dunlop J , La Rosa S , Micco I , Pollastrini M , Quinn J , Roncarati R , Scali C , Valacchi M , Varrone M , Zanaletti R
Ref : Bioorganic & Medicinal Chemistry , 17 :5247 , 2009
Abstract : Alpha 7 nicotinic acetylcholine receptor (alpha(7) nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment associated with a variety of disorders including Alzheimer's disease and schizophrenia. Alpha 7 nAChRs are expressed in brain regions associated with cognitive function, regulate cholinergic neurotransmission and have been shown to be down regulated in both schizophrenia and Alzheimer's disease. Herein we report a novel, potent small molecule agonist of the alpha 7 nAChR, SEN12333/WAY-317538. This compound is a selective agonist of the alpha(7) nAChR with excellent in vitro and in vivo profiles, excellent brain penetration and oral bioavailability, and demonstrates in vivo efficacy in multiple behavioural cognition models. The SAR and biological evaluation of this series of compounds are discussed.
ESTHER : Haydar_2009_Bioorg.Med.Chem_17_5247
PubMedSearch : Haydar_2009_Bioorg.Med.Chem_17_5247
PubMedID: 19515567

Title : Poster: In vitro pharmacological characterization and pro-cognitive effects of the selective alpha-7 nicotinic agonist WYE-103914 -
Author(s) : Dunlop J , Comery TA , Lock T , Kramer A , Kowal D , Yeola S , Jow F , Aschmies S , Lin Q , Beyer CE , Brennan J , Kelley C , Roncarati R , Scali C , Haydar S , Ghiron C , Marquis KL , Harrison B , Robichaud A , Terstappen GC
Ref : Biochemical Pharmacology , 78 :911 , 2009
PubMedID:

Title : Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice - Bellucci_2006_Neurobiol.Dis_23_260
Author(s) : Bellucci A , Luccarini I , Scali C , Prosperi C , Giovannini MG , Pepeu G , Casamenti F
Ref : Neurobiol Dis , 23 :260 , 2006
Abstract : In 7-month-old TgCRND8 mice, the extracellular cortical acetylcholine levels in vivo, the number and morphology of cholinergic neurons in the nucleus basalis magnocellularis and the ability to acquire an inhibitory avoidance response in the step-down test were studied. The TgCRND8 mouse brain is characterized by many beta-amyloid plaques, reduced neuronal and axonal staining, white matter demyelination, glia reaction and inducible nitric oxide synthase immunoreactivity. Choline acetyltransferase immunoreactivity in the nucleus basalis magnocellularis was significantly decreased. Basal and potassium-stimulated extracellular acetylcholine levels, investigated by microdialysis, and m2 muscarinic receptor immunoreactivity were reduced in the cortex of TgCRND8 mice, and scopolamine administration increased cortical extracellular acetylcholine levels in control but not in TgCRND8 mice. A cognitive impairment was demonstrated in the step-down test. These findings demonstrate that neuronal damage and cholinergic dysfunction in vivo underlie the impairment in learning and memory functions in this mouse model of Alzheimer's disease.
ESTHER : Bellucci_2006_Neurobiol.Dis_23_260
PubMedSearch : Bellucci_2006_Neurobiol.Dis_23_260
PubMedID: 16766197

Title : Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent - Greig_2005_Proc.Natl.Acad.Sci.U.S.A_102_17213
Author(s) : Greig NH , Utsuki T , Ingram DK , Wang Y , Pepeu G , Scali C , Yu QS , Mamczarz J , Holloway HW , Giordano T , Chen D , Furukawa K , Sambamurti K , Brossi A , Lahiri DK
Ref : Proc Natl Acad Sci U S A , 102 :17213 , 2005
Abstract : Like acetylcholinesterase, butyrylcholinesterase (BChE) inactivates the neurotransmitter acetylcholine (ACh) and is hence a viable therapeutic target in Alzheimer's disease, which is characterized by a cholinergic deficit. Potent, reversible, and brain-targeted BChE inhibitors (cymserine analogs) were developed based on binding domain structures to help elucidate the role of this enzyme in the central nervous system. In rats, cymserine analogs caused long-term inhibition of brain BChE and elevated extracellular ACh levels, without inhibitory effects on acetylcholinesterase. In rat brain slices, selective BChE inhibition augmented long-term potentiation. These compounds also improved the cognitive performance (maze navigation) of aged rats. In cultured human SK-N-SH neuroblastoma cells, intra- and extracellular beta-amyloid precursor protein, and secreted beta-amyloid peptide levels were reduced without affecting cell viability. Treatment of transgenic mice that overexpressed human mutant amyloid precursor protein also resulted in lower beta-amyloid peptide brain levels than controls. Selective, reversible inhibition of brain BChE may represent a treatment for Alzheimer's disease, improving cognition and modulating neuropathological markers of the disease.
ESTHER : Greig_2005_Proc.Natl.Acad.Sci.U.S.A_102_17213
PubMedSearch : Greig_2005_Proc.Natl.Acad.Sci.U.S.A_102_17213
PubMedID: 16275899

Title : The selective cyclooxygenase-2 inhibitor rofecoxib suppresses brain inflammation and protects cholinergic neurons from excitotoxic degeneration in vivo - Scali_2003_Neurosci_117_909
Author(s) : Scali C , Giovannini MG , Prosperi C , Bellucci A , Pepeu G , Casamenti F
Ref : Neuroscience , 117 :909 , 2003
Abstract : Brain inflammatory processes underlie the pathogenesis of Alzheimer's disease, and non-steroidal anti-inflammatory drugs have a protective effect in the disease. The aim of this work was to study in vivo whether attenuation of brain inflammatory response to excitotoxic insult by the selective cyclooxygenase-2 inhibitor, rofecoxib, may prevent neurodegeneration, as a contribution to a better understanding of the role inflammation plays in the pathology of Alzheimer's disease. We investigated, by immunohistochemical methods, glia reaction, the activation of p38 mitogen-activated protein kinase (p38MAPK) pathway with an antibody selective for the phosphorylated form of the enzyme and the number of choline acetyltransferase-positive neurons and, by in vivo microdialysis, cortical extracellular levels of acetylcholine following the injection of quisqualic acid into the right nucleus basalis of adult rats. Seven days after injection, a marked reduction in the number of choline acetyltransferase-positive neurons was found, along with an intense glia reaction, selective activation of p38MAPK at the injection site and a significant decrease in the extracellular levels of acetylcholine in the cortex ipsilateral to the injection site. The loss of cholinergic neurons persisted for at least up to 28 days. Rofecoxib (3 mg/kg/day, starting 1 h prior to injection of quisqualic acid) treatment for 7 days significantly attenuated glia activation and prevented the loss of choline acetyltransferase-positive cells and a decrease in cortical acetylcholine release. The prevention of cholinergic cell loss by rofecoxib occurred concomitantly with the inhibition of p38MAPK phosphorylation. Our findings suggest an important role of brain inflammatory reaction in cholinergic degeneration and demonstrate a neuroprotective effect of rofecoxib, presumably mediated through the inhibition of p38MAPK phosphorylation.
ESTHER : Scali_2003_Neurosci_117_909
PubMedSearch : Scali_2003_Neurosci_117_909
PubMedID: 12654342

Title : Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway - Giovannini_2002_Neurobiol.Dis_11_257
Author(s) : Giovannini MG , Scali C , Prosperi C , Bellucci A , Vannucchi MG , Rosi S , Pepeu G , Casamenti F
Ref : Neurobiol Dis , 11 :257 , 2002
Abstract : Injection into the nucleus basalis of the rat of preaggregated Abeta(1-42) produced a congophylic deposit and microglial and astrocyte activation and infiltration and caused a strong inflammatory reaction characterized by IL-1beta production, increased inducible cyclooxygenase (COX-2), and inducible nitric oxide synthase (iNOS) expression. Many phospho-p38MAPK-positive cells were observed around the deposit at 7 days after Abeta injection. Phospho-p38MAPK colocalized with activated microglial cells, but not astrocytes. The inflammatory reaction was accompanied by cholinergic hypofunction. We investigated the protective effect of the selective COX-2 inhibitor rofecoxib in attenuating the inflammatory response and neurodegeneration evoked by Abeta(1-42). Rofecoxib (3 mg/kg/day, 7 days) reduced microglia and astrocyte activation, iNOS induction, and p38MAPK activation to control levels. Cholinergic hypofunction was also significantly attenuated by treatment with rofecoxib. We show here for the first time in vivo the pivotal role played by the p38MAPK microglial signal transduction pathway in the inflammatory response to the Abeta(1-42) deposit.
ESTHER : Giovannini_2002_Neurobiol.Dis_11_257
PubMedSearch : Giovannini_2002_Neurobiol.Dis_11_257
PubMedID: 12505419

Title : Rivastigmine antagonizes deficits in prepulse inhibition induced by selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis - Ballmaier_2002_Neurosci_114_91
Author(s) : Ballmaier M , Casamenti F , Scali C , Mazzoncini R , Zoli M , Pepeu G , Spano PF
Ref : Neuroscience , 114 :91 , 2002
Abstract : Impairments of cortical cholinergic inputs from the nucleus basalis magnocellularis fundamentally alter information processing and attentional function, thereby advancing the severity of psychopathology in major neuropsychiatric disorders. It was previously shown in adult rats that bilateral 192 IgG saporin-induced selective immunolesioning of the cholinergic neurons in the nucleus basalis produces pronounced and long-lasting deficits in sensorimotor gating measured by prepulse inhibition of the startle reflex. This behavioral paradigm is considered a valid model of sensorimotor gating deficits in the psychotic spectrum and efforts to analyze the significance of the cholinergic basal forebrain in this context are of great interest. In the present study the predictive value of the selective cholinergic immunolesioning model was tested by examining the ability of the cholinesterase inhibitor rivastigmine to restore prepulse inhibition in immunolesioned rats. We report here a pronounced restoring effect of acute (0.75 or 1.5 mg/kg s.c.) as well as repeated (0.75 mg/kg s.c. b.i.d., for 10 days) treatment with rivastigmine in this model of disrupted prepulse inhibition. Intra-nucleus basalis magnocellularis infusions of 192 IgG saporin resulted in extensive loss of basal-cortical cholinergic neurons as shown by the marked decrease in basal telencephalic choline acetyltransferase immunopositive neurons and cortical choline acetyltransferase activity. In this condition, rivastigmine was found to significantly increase cortical acetylcholine extracellular levels in lesioned animals measured by in vivo microdialysis. Taken together, our results strengthen the proposal that the nucleus basalis represents a critical station of the startle gating circuitry. In addition, our findings strongly indicate that even after dramatic decrease of cholinergic neurons, inhibition of acetylcholinesterase restores the cholinergic synaptic function to a point approaching normalization of experimentally induced psychopathology.
ESTHER : Ballmaier_2002_Neurosci_114_91
PubMedSearch : Ballmaier_2002_Neurosci_114_91
PubMedID: 12207957

Title : Effect of subchronic administration of metrifonate, rivastigmine and donepezil on brain acetylcholine in aged F344 rats - Scali_2002_J.Neural.Transm_109_1067
Author(s) : Scali C , Casamenti F , Bellucci A , Costagli C , Schmidt B , Pepeu G
Ref : J Neural Transm , 109 :1067 , 2002
Abstract : The changes in extracellular acetylcholine levels were investigated by microdialysis in the cortex and hippocampus of aging rats after administration of metrifonate (80 mg/kg), rivastigmine (0.75 mg/kg), donepezil (1.5 mg/kg) or vehicle for 21 days (twice daily p.o.). Eighteen h after the last administration, cholinesterase inhibition was 85, 52 and 39% after metrifonate, rivastigmine and donepezil, respectively, and was accompanied by 988, 590 and 75% increase in cortical acetylcholine level. In the hippocampus, metrifonate and rivastigmine brought about a 169 and 108% increase in acetylcholine levels. A challenge dose of metrifonate, rivastigmine and donepezil was followed by a further increase in cortical and hippocampal acetylcholine levels. The retrograde perfusion of the M(2)-M(4) receptor antagonist AFDX-384 (10 microM) induced a 500 and 300% increase in cortical and hippocampal acetylcholine release, in control and rivastigmine-treated rats, respectively, no increase in metrifonate-treated rats, and a 210% increase in donepezil-treated rats. In conclusion, chronic treatment of aging rats with metrifonate, rivastigmine and donepezil induces a long-lasting increase in acetylcholine levels, and reveals marked differences between the three drugs.
ESTHER : Scali_2002_J.Neural.Transm_109_1067
PubMedSearch : Scali_2002_J.Neural.Transm_109_1067
PubMedID: 12111444

Title : Brain inflammatory reaction in an animal model of neuronal degeneration and its modulation by an anti-inflammatory drug: implication in Alzheimer's disease - Scali_2000_Eur.J.Neurosci_12_1900
Author(s) : Scali C , Prosperi C , Vannucchi MG , Pepeu G , Casamenti F
Ref : European Journal of Neuroscience , 12 :1900 , 2000
Abstract : Brain inflammatory processes underlie the pathogenesis of Alzheimer's disease, and nonsteroidal anti-inflammatory drugs have a protective effect in the disease. The aim of this study was to characterize in vivo in the rat brain the inflammatory reaction in response to excitotoxic insult and to investigate the efficacy of nimesulide treatment. Quisqualic acid was injected into the right nucleus basalis of rats. The excitotoxin induced cholinergic degeneration, an intense glial reaction and the production of inflammatory mediators. Three hours after injection, a five-fold elevation in the concentration of interleukin-1beta in the injected area was observed. This elevation was reduced by 50% by nimesulide (10 mg/kg, i.m.) pretreatment. Electron microscope examination and immunocytochemical staining revealed an intense activation of microglia and astrocytes at both 24 h and 7 days after injection. Cyclooxygenase-2-immunoreactivity was induced in the blood vessels of the injected hemisphere in perivascular microglial and endothelial cells 24 h after injection. Seven days postinjection, a cyclooxygenase-2-positive signal was induced in the parenchymal microglia and large amounts of prostaglandin-E2 were measured in the injected area. Twenty-four hours and 7 days after injection, many inducible nitric oxide synthase-positive cells and a high level of nitrite were detected at the injection site. Seven days of nimesulide (10 mg/kg/day, i.m.) treatment strongly attenuated the microglial reaction, reduced the number of inducible nitric oxide synthase-positive cells and completely abolished the increase in prostaglandin-E2 formation. These data provide valuable support in vivo for the potential efficacy of cyclooxygenase-2 inhibitors in Alzheimer's disease therapy.
ESTHER : Scali_2000_Eur.J.Neurosci_12_1900
PubMedSearch : Scali_2000_Eur.J.Neurosci_12_1900
PubMedID: 10886331

Title : Interleukin-1beta activates forebrain glial cells and increases nitric oxide production and cortical glutamate and GABA release in vivo: implications for Alzheimer's disease - Casamenti_1999_Neurosci_91_831
Author(s) : Casamenti F , Prosperi C , Scali C , Giovannelli L , Colivicchi MA , Faussone-Pellegrini MS , Pepeu G
Ref : Neuroscience , 91 :831 , 1999
Abstract : Interleukin-1beta (10 U) was injected into the nucleus basalis of adult male Wistar rats. The inflammation-induced changes in glial cell morphology and expression of inducible nitric oxide synthase in the injected area, the release of acetylcholine, GABA and glutamate from the ipsilateral cortex, the production of nitrite levels in the injected area and ipsilateral cortex, and changes in motor activity were investigated. Saline-injected rats were used as control. Interleukin-1beta induced an activation of both microglia and astrocytes which was already evident 24 h after injection. Seven days after injection, many reactive microglial cells and astrocytes were seen in the injected area and in other brain regions of the same hemisphere. Microglia reaction, but not astrocyte activation, disappeared 30 days post-injection. Seven days after interleukin-1beta injection, many cells immunopositive for inducible nitric oxide synthase were found surrounding the injection site. Inducible nitric oxide synthase-positive cells were identified, by double staining immunohistochemistry, in the reactive microglial cells and, by electron microscope examination, in the perineuronal subpopulation of resident activated microglia. Microdialysis investigations revealed a transient increase in reactive nitrogen intermediates (at seven days post-injection), a delayed (at 30 days post-injection) increase in GABA and glutamate release, and no changes in acetylcholine release in the ipsilateral cortex in interleukin-1beta, but not saline, injected rats. Inhibition of inducible nitric oxide synthase expression by N(G)-nitro-L-arginine methyl ester administration prevented the increase in nitrogen intermediates and GABA release, but not in glutamate release. Our findings suggest that an inflammatory reaction of the basal forebrain facilitates GABA release through the production of nitric oxide.
ESTHER : Casamenti_1999_Neurosci_91_831
PubMedSearch : Casamenti_1999_Neurosci_91_831
PubMedID: 10391466

Title : Effects of novelty and pain on behavior and hippocampal extracellular ACh levels in male and female rats - Ceccarelli_1999_Brain.Res_815_169
Author(s) : Ceccarelli I , Casamenti F , Massafra C , Pepeu G , Scali C , Aloisi AM
Ref : Brain Research , 815 :169 , 1999
Abstract : In vivo microdialysis was used to assess the effects of novelty and pain on hippocampal ACh release in male and female rats. Experiments were carried out during the dark phase and consisted of 2 days of tests: on Day 1, after Baseline 1, animals were exposed to a new cage (Novelty) to which, 30 min later, a plastic cylinder (Object) was introduced. On Day 2, after Baseline 2, the Formalin test (50 microl of formalin 10%, s.c. injected in the dorsal hindpaw) was carried out in the animal's home cage. All behaviors were recorded. The extracellular levels of ACh in the dorsal hippocampus were estimated, in 10-min samples, by assay of ACh in the dialysates by HPLC. On Day 1 the raw values of ACh were higher in females than in males, but no sex difference was present when the percentage of change was considered. In both sexes the Novelty and Object tests induced an increase in ACh levels with respect to Baseline. Higher levels of exploration were present in females than males during the first 10 min of Novelty. On Day 2, ACh release increased in both sexes during the Formalin test. No sex difference in either ACh raw values or the percentages of change were found. Females showed higher levels of licking and lower levels of activity than males. The present study shows that novelty and pain induce similar hippocampal cholinergic activation in male and female rats but different behaviors. The results are discussed in light of the several anatomical and functional sex differences present in the hippocampus.
ESTHER : Ceccarelli_1999_Brain.Res_815_169
PubMedSearch : Ceccarelli_1999_Brain.Res_815_169
PubMedID: 9878722

Title : Long-term changes in the aggregation state and toxic effects of beta-amyloid injected into the rat brain - Giovannelli_1998_Neurosci_87_349
Author(s) : Giovannelli L , Scali C , Faussone-Pellegrini MS , Pepeu G , Casamenti F
Ref : Neuroscience , 87 :349 , 1998
Abstract : The long-term effects of beta-amyloid peptide 1-40 injection into the rat forebrain were studied. Ten micrograms of pre-aggregated peptide were injected into the right nucleus basalis of male Wistar rats which were then killed four or six months later. Congo Red staining of histological sections showed that the peptide deposit was aggregated in a fibrillary form four months post-surgery, whereas at six months almost no trace of birefringency was detected at the deposit site, indicating a loss of fibril organization. This result was confirmed by electron microscopic analysis of the peptide deposits. The presence of the peptide at the injection site six months post-surgery was demonstrated by both Haematoxylin staining and beta-amyloid immunoreactivity. The number of choline acetyltransferase-immunoreactive neurons was reduced by 66% in the injected nucleus basalis four months after injection. A decrease in cortical acetylcholine release was also found at this time. Concomitantly with the loss of fibril conformation, a complete recovery of choline acetyltransferase immunoreactivity in the nucleus basalis and of acetylcholine release in the cortex was observed at six months. These data provide in vivo evidence that beta-amyloid neurotoxicity is related to the fibrillary conformation of the peptide aggregates, thus confirming previous in vitro studies.
ESTHER : Giovannelli_1998_Neurosci_87_349
PubMedSearch : Giovannelli_1998_Neurosci_87_349
PubMedID: 9740397

Title : Effect of subchronic treatment with metrifonate and tacrine on brain cholinergic function in aged F344 rats - Giovannini_1998_Eur.J.Pharmacol_354_17
Author(s) : Giovannini MG , Scali C , Bartolini L , Schmidt B , Pepeu G
Ref : European Journal of Pharmacology , 354 :17 , 1998
Abstract : The effects of 21-day treatment with the acetylcholinesterase inhibitors metrifonate (80 mg kg(-1) per os (p.o.)) and tacrine (3 mg kg(-1) p.o.), twice daily, on cortical and hippocampal cholinergic systems were investigated in aged rats (24-26 months). Extracellular acetylcholine levels were measured by transversal microdialysis in vivo; choline acetyltransferase and acetylcholinesterase activities were measured ex vivo by means of radiometric methods. Basal cortical and hippocampal extracellular acetylcholine levels, measured 18 h after the last metrifonate treatment, were about 15 and two folds higher, respectively, than in control and tacrine-treated rats. A challenge with metrifonate further increased cortical and hippocampal acetylcholine levels by about three and four times, respectively. Basal extracellular acetylcholine levels, measured 18 h after the last treatment with tacrine were not statistically different from those of the control rats. A challenge with tacrine increased cortical and hippocampal extracellular acetylcholine levels by about four and two times. A 75% inhibition of cholinesterase activity was found 18 h after the last metrifonate administration, while only a 15% inhibition was detectable 18 h after the last tacrine administration. The challenge with metrifonate or tacrine resulted in 90 and 80% cholinesterase inhibition, respectively. These results demonstrate that in aging rats a subchronic treatment with metrifonate results in a long-lasting, cholinesterase inhibition, and a persistent increase in acetylcholine extracellular levels which compensate for the age-associated cholinergic hypofunction. Metrifonate is therefore a potentially useful agent for the cholinergic deficit accompanying Alzheimer's disease.
ESTHER : Giovannini_1998_Eur.J.Pharmacol_354_17
PubMedSearch : Giovannini_1998_Eur.J.Pharmacol_354_17
PubMedID: 9726626

Title : Tacrine administration enhances extracellular acetylcholine in vivo and restores the cognitive impairment in aged rats - Scali_1997_Pharmacol.Res_36_463
Author(s) : Scali C , Giovannini MG , Prosperi C , Bartolini L , Pepeu G
Ref : Pharmacol Res , 36 :463 , 1997
Abstract : The effect of oral tacrine administration on cortical and hippocampal extracellular acetylcholine (ACh) levels has been investigated by a microdialysis technique, coupled to a HPLC method, in 6- and 22-24-month-old rats. In order to assess whether the increase in extracellular ACh levels was associated with an improvement in the age-related cognitive impairment, the object recognition and step-trough passive avoidance tests were carried out in the treated rats. The extracellular ACh levels measured in the cortex and hippocampus of aged rats without cholinesterase inhibitor in the perfusion Ringer solution were 39 and 54% lower, respectively, than in the young rats. At the dose of 3 mg kg-1, tacrine brought about a three- to four-fold increase in extracellular ACh levels, both in young and aged rats, which peaked 60-80 min after administration and disappeared within the next 60 min. At the same dose, tacrine caused a twofold increase in extracellular ACh levels in the hippocampus of young rats and a sixfold increase in aged rats. The absolute ACh levels at the peak in aged rats were not significantly different from those of young rats. In the object recognition test, aging rats were unable to discriminate between the familiar and novel object. Discrimination was restored by the administration of tacrine at the dose of 1 and 3 mg kg-1, but not 0. 3 mg kg-1 given 30 min before the first trial. Tacrine (3 mg kg-1 p. o.) administered to aging rats before the training trial significantly improved the acquisition of the passive avoidance conditioned response. Our findings demonstrate that tacrine increased both cortical and hippocampal extracellular ACh levels and improved behavioural functions in aged rats.
ESTHER : Scali_1997_Pharmacol.Res_36_463
PubMedSearch : Scali_1997_Pharmacol.Res_36_463
PubMedID: 9446713

Title : Effects of novelty, pain and stress on hippocampal extracellular acetylcholine levels in male rats - Aloisi_1997_Brain.Res_748_219
Author(s) : Aloisi AM , Casamenti F , Scali C , Pepeu G , Carli G
Ref : Brain Research , 748 :219 , 1997
Abstract : In vivo microdialysis was used to assess the effects of Novelty, persistent pain (Formalin test) and stress (Restraint) on hippocampal acetylcholine (ACh) release. Experiments were carried out during the dark phase, i.e. during the active period of the animal, and consisted of four experimental phases: Baseline (30 min), Novelty (30 min), Formalin test (90 min) and Restraint (30 min); each animal was consecutively exposed to all phases. The extracellular levels of ACh in the dorsal hippocampus were estimated by measurement of its concentration in the perfusion fluid by high-performance liquid chromatography with electrochemical detection. The introduction to a new environment (Novelty) induced in all rats higher ACh levels than Baseline. Formalin treatment decreased ACh release only in animals considered 'Inactive' during the Novelty phase while no modification in ACh release was observed in the 'Active' ones. Restraint did not produce any modification of ACh release but increased Corticosterone plasma levels both in sham- and formalin-treated animals. Results indicate that Novelty, but not Formalin or Restraint, increases ACh release in the hippocampus and that the type of behavioral state displayed by the animal at the time of formalin injection determines the response of the septo-hippocampal cholinergic pathway.
ESTHER : Aloisi_1997_Brain.Res_748_219
PubMedSearch : Aloisi_1997_Brain.Res_748_219
PubMedID: 9067465

Title : Selective muscarinic antagonists differentially affect in vivo acetylcholine release and memory performances of young and aged rats - Vannucchi_1997_Neurosci_79_837
Author(s) : Vannucchi MG , Scali C , Kopf SR , Pepeu G , Casamenti F
Ref : Neuroscience , 79 :837 , 1997
Abstract : Brain acetylcholine release and memory performance were investigated in young (three- to six-months) and old (20- to 24-months) rats. Acetylcholine release was measured in vivo in the cortex and hippocampus of freely-moving animals, under basal conditions and in the presence of the following muscarinic antagonists: scopolamine, (+/-)-5,11-dihydro-11-[[(2-[2-[(dipropylamino) methyl]-1-piperidinyl]ethyl) amino] carbonyl]-6H-pyrido(2,3-b)(1,4)-benzodiazepine-6-one (AFDX 384) and pirenzepine. The amount of acetylcholine released from the cortex and hippocampus of old rats was significantly reduced. In the presence of scopolamine and AFDX 384 but not of pirenzepine, the acetylcholine release was significantly higher in the old than the young rats, suggesting that changes in presynaptic M2/M4 muscarinic receptor function occur with ageing in the two brain regions. Cognitive capacities were evaluated using two different behavioural tasks: object recognition and passive avoidance response. Old rats were unable to discriminate between familiar and novel objects and had impaired performance in the passive avoidance test. AFDX 384 restored the performance in both tests. Furthermore, in young rats AFDX 384 reversed the impairment of both object recognition and passive avoidance response induced by scopolamine. The effect of AFDX 384 on acetylcholine release and behaviour in the old rats offers further support to a relationship between the age-related cholinergic hypofunction and cognitive impairment and indicates the blockade of presynaptic muscarinic receptors as a possible selective target for therapeutic strategies aimed at improving age-associated memory deficits.
ESTHER : Vannucchi_1997_Neurosci_79_837
PubMedSearch : Vannucchi_1997_Neurosci_79_837
PubMedID: 9219946

Title : Effect of metrifonate on extracellular brain acetylcholine and object recognition in aged rats - Scali_1997_Eur.J.Pharmacol_325_173
Author(s) : Scali C , Giovannini MG , Bartolini L , Prosperi C , Hinz V , Schmidt B , Pepeu G
Ref : European Journal of Pharmacology , 325 :173 , 1997
Abstract : The effects of metrifonate were investigated in 4-6- and 22-24-month-old rats. Extracellular acetylcholine levels were measured by transversal microdialysis in vivo. Baseline extracellular acetylcholine levels in the cerebral cortex and hippocampus were 42% and 60% lower, respectively, in old than in young rats. Old rats did not discriminate between familiar and novel objects. In old rats, metrifonate (80 mg/kg p.o.) brought about 85% inhibition of cholinesterase activity in the cortex and hippocampus, a 4-fold increase in extracellular acetylcholine levels in the cortex only, and restored object recognition. In young rats, metrifonate caused 75% cholinesterase inhibition in the cerebral cortex and hippocampus, a 2-fold increase in cortical and hippocampal extracellular acetylcholine levels, and no effect on object recognition. The slight cholinesterase inhibition following metrifonate (30 mg/kg) in aged rats had no effect on cortical acetylcholine levels and object recognition. In conclusion, metrifonate may improve the age-associated cholinergic hypofunction and cognitive impairment.
ESTHER : Scali_1997_Eur.J.Pharmacol_325_173
PubMedSearch : Scali_1997_Eur.J.Pharmacol_325_173
PubMedID: 9163564

Title : Amyloid beta-peptides injection into the cholinergic nuclei: morphological, neurochemical and behavioral effects -
Author(s) : Pepeu G , Giovannelli L , Casamenti F , Scali C , Bartolini L
Ref : Prog Brain Res , 109 :273 , 1996
PubMedID: 9009716

Title : Differential effects of amyloid peptides beta-(1-40) and beta-(25-35) injections into the rat nucleus basalis - Giovannelli_1995_Neurosci_66_781
Author(s) : Giovannelli L , Casamenti F , Scali C , Bartolini L , Pepeu G
Ref : Neuroscience , 66 :781 , 1995
Abstract : The nucleus basalis of male Charles River Wistar rats was injected with 10 micrograms of the beta-amyloid peptides beta-(1-40) and beta-(25-35) and changes in the morphology of the lesioned area, the release of acetylcholine from the cortex, and in behavior were investigated. Injections of saline and a scrambled (25-35) peptide were used as controls. One week after lesioning, a Congo Red-positive deposit of aggregated material was found at the beta-peptides injection site, which lasted for about 21 days in the case of the beta-(25-35) peptide and at least two months for beta-(1-40). No deposit was detected after scrambled peptide injection. At one week post injection, an extensive glial reaction surrounded the injection site of all peptides and saline as well. Such a reaction was still present but rather attenuated after two months. A decrease in the number of cholinergic neurons was detected in the nucleus basalis after one week with all treatments except saline. After two months, a reduction in the number of choline acetyltransferase-immunopositive neurons was still detectable in the rats injected with beta-(1-40) but not in the beta-(25-35)-or scrambled-injected. The reduction in choline acetyltransferase immunoreactivity was closely paralleled by a decrease in basal acetylcholine release from the parietal cortex ipsilateral to the lesion. Disruption of object recognition was observed in the first weeks after beta-(25-35) peptide injection, whereas the beta-(1-40) peptide impaired the performance only two months after lesion. Rats with lesions induced by beta-peptides may be a useful animal model of amyloid deposition for investigation of the pathogenetic mechanisms leading to Alzheimer's disease.
ESTHER : Giovannelli_1995_Neurosci_66_781
PubMedSearch : Giovannelli_1995_Neurosci_66_781
PubMedID: 7651609

Title : Peripherally injected scopolamine differentially modulates acetylcholine release in vivo in the young and aged rats - Scali_1995_Neurosci.Lett_197_171
Author(s) : Scali C , Vannucchi MG , Pepeu G , Casamenti F
Ref : Neuroscience Letters , 197 :171 , 1995
Abstract : The effect of intraperitoneal administration of scopolamine (1 mg/kg) on acetylcholine (ACh) release in vivo in 3- and 24-month-old freely behaving rats was investigated in the cerebral cortex, hippocampus and striatum by means of transverse microdialysis. In the parietal cortex, the increase in ACh release after scopolamine administration was significantly greater in the old than in the young rats, reaching a maximum increase of about 600 and 300% in the old and young animals, respectively. In the hippocampus, scopolamine caused a larger increase in ACh release in the young (+900%) than in the old rats (+600%). In the striatum of aged rats, a 40% increase occurred only at 40 min after scopolamine administration while in the striatum of young animals the increase lasted for at least 2 h, reaching a maximum of about 100%. These findings demonstrate that the modulation of ACh release in vivo is affected in a different manner in the cerebral cortex than in the hippocampus and striatum by aging.
ESTHER : Scali_1995_Neurosci.Lett_197_171
PubMedSearch : Scali_1995_Neurosci.Lett_197_171
PubMedID: 8552291

Title : Nerve growth factor increases extracellular acetylcholine levels in the parietal cortex and hippocampus of aged rats and restores object recognition - Scali_1994_Neurosci.Lett_170_117
Author(s) : Scali C , Casamenti F , Pazzagli M , Bartolini L , Pepeu G
Ref : Neuroscience Letters , 170 :117 , 1994
Abstract : Male Wistar rats (3- and 20-month-old) were perfused i.c.v. with 1.5 micrograms of either nerve growth factor (NGF) or cytochrome C daily for 14 days. At the end of the infusion, the object-recognition test was carried out and extracellular acetylcholine levels (ACh) were measured in the cortex and hippocampus by transversal microdialysis technique. In 20-month-old control rats, the cortical and hippocampal ACh levels were 35 and 45% lower, respectively, than in 3-month-old rats and the ability to discriminate between a familiar and new object was impared. In the old rats treated with NGF, the ACh release as well as the behavioral performance showed no difference from those of young rats. These findings indicate that both ACh levels and memory impairment are improved in aged rats by NGF treatment and suggest that there is a relationship between object recognition and the activity of the forebrain cholinergic system.
ESTHER : Scali_1994_Neurosci.Lett_170_117
PubMedSearch : Scali_1994_Neurosci.Lett_170_117
PubMedID: 8041485

Title : Administration of amyloid beta-peptides into the medial septum of rats decreases acetylcholine release from hippocampus in vivo - Abe_1994_Brain.Res_636_162
Author(s) : Abe E , Casamenti F , Giovannelli L , Scali C , Pepeu G
Ref : Brain Research , 636 :162 , 1994
Abstract : The septum of male Wistar rats was injected with synthetic beta-amyloid fragments, beta 12-28, beta 25-35 and beta 1-40, and hippocampal acetylcholine (ACh) release was evaluated by transversal microdialysis. A marked decrease in basal and K(+)-evoked ACh release was found 7 or 21 days after injection of 5 nmol of beta 12-28 and beta 25-35, or 3 nmol of beta 1-40, respectively. These data indicate that septal injection of beta-amyloid peptides causes hypofunction of the septo-hippocampal cholinergic system.
ESTHER : Abe_1994_Brain.Res_636_162
PubMedSearch : Abe_1994_Brain.Res_636_162
PubMedID: 8156403

Title : The brain cholinergic system in ageing mammals - Pepeu_1993_J.Reprod.Fertil.Suppl_46_155
Author(s) : Pepeu G , Casamenti F , Pepeu IM , Scali C
Ref : J Reprod Fertil Suppl , 46 :155 , 1993
Abstract : The complex picture of age-associated brain cholinergic deficiency in humans and animals, and the possibilities of correcting it, are presented in this article. The changes that occur during ageing and senile dementias in cholinergic neurones and receptors and in the release and synthesis of acetylcholine are described and discussed. The drugs that have so far been administered to humans to correct cholinergic deficiency are listed and the effects of cholinesterase inhibitors, nerve growth factor and phosphatidylserine are discussed in some detail.
ESTHER : Pepeu_1993_J.Reprod.Fertil.Suppl_46_155
PubMedSearch : Pepeu_1993_J.Reprod.Fertil.Suppl_46_155
PubMedID: 8315616

Title : Long-term ethanol consumption by rats: effect on acetylcholine release in vivo, choline acetyltransferase activity, and behavior - Casamenti_1993_Neurosci_56_465
Author(s) : Casamenti F , Scali C , Vannucchi MG , Bartolini L , Pepeu G
Ref : Neuroscience , 56 :465 , 1993
Abstract : The extent and duration of cholinergic hypofunction induced by long-term ethanol consumption was investigated in the rat. Ethanol (20% v/v) was administered to male adult Wistar rats as a sole source of fluid for three or six months. Control rats received tap water. The body weight, food and fluid intake in ethanol-treated rats were lower than in control rats throughout the treatment. After three months of ethanol consumption, and one week withdrawal, acetylcholine release in freely moving rats, investigated by microdialysis technique coupled to high-performance liquid chromatography quantification, was significantly decreased by 57 and 32% in the hippocampus and cortex, respectively, while choline acetyltransferase activity was significantly decreased (-30%) only in the hippocampus. A complete recovery of choline acetyltransferase activity and acetylcholine release was found after four ethanol-free weeks. Conversely, after four weeks of withdrawal following six months of ethanol treatment, the recovery in acetylcholine release was not accompanied by that in choline acetyltransferase activity, which remained significantly lower than in control rats in both cortex and hippocampus. The ability of rats to negotiate active and passive avoidance conditioned response tasks, tested after four ethanol-free weeks, was strongly impaired in both three- and six-month ethanol-treated rats. In conclusion, our experiments demonstrate that the development of a long-lasting cholinergic hypofunction requires at least six months of ethanol administration. The hypofunction affects choline acetyltransferase activity and acetylcholine release differently, and undergoes a remarkable recovery.
ESTHER : Casamenti_1993_Neurosci_56_465
PubMedSearch : Casamenti_1993_Neurosci_56_465
PubMedID: 8247273

Title : Aging of brain cholinergic neurons: pharmacological interventions -
Author(s) : Pepeu G , Casamenti F , Scali C , Jeglinski W
Ref : Clinical Neuropharmacology , 15 Suppl 1 Pt A :31A , 1992
PubMedID: 1498852

Title : Phosphatidylserine reverses the age-dependent decrease in cortical acetylcholine release: a microdialysis study - Casamenti_1991_Eur.J.Pharmacol_194_11
Author(s) : Casamenti F , Scali C , Pepeu G
Ref : European Journal of Pharmacology , 194 :11 , 1991
Abstract : In vivo basal acetylcholine (ACh) and choline (Ch) output from the parietal cortex of 3- and 19-month-old freely moving rats was measured by microdialysis. A dialysis tubing was inserted transversally through the parietal cortex 24 h before the experiment. ACh and Ch concentrations were determined in the same perfusate samples by HPLC with electrochemical detection. In 19-month-old rats treated with Tris buffer, ACh and Ch outputs were 39 and 16% lower, respectively, than in 3-month-old rats. Phosphatidylserine (PtdSer) administration (15 mg/kg i.p. daily) for 8 days to 19-month-old rats markedly attenuated the decrease in ACh release. The same treatment did not affect ACh and Ch outputs in 3-month-old rats. ACh and Ch outputs in 19-month-old rats administered either phosphatidylcholine (PtdCho) or o-phospho-dl-serine (P-Ser) (15 mg/kg i.p. daily) for 8 days were as low as in 19-month-old rats receiving Tris buffer only. It is possible that chronic PtdSer treatment improve ACh release in aging rats by increasing the availability of Ch for ACh synthesis.
ESTHER : Casamenti_1991_Eur.J.Pharmacol_194_11
PubMedSearch : Casamenti_1991_Eur.J.Pharmacol_194_11
PubMedID: 2060587