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Pharmacological profile of PMS777, a new AChE inhibitor with PAF antagonistic activity

The key pathophysiological mechanisms in Alzheimers disease involve the selective loss of cholinergic neurons and pro-inflammatory mediator-related chronic inflammatory responses in the brain, therefore interventions of these processes are crucial to the treatment of this disease. In the present stu... Full description

Journal Title: The International Journal of Neuropsychopharmacology 2007, Vol.10(1), pp.21-29
Main Author: Li, Juan
Other Authors: Huang, Hong, Miezan Ezoulin, Jean-marc, Gao, Xiao-ling, Massicot, France, Dong, Chang-zhi, Heymans, Franoise, Chen, Hong-zhuan
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 1461-1457 ; E-ISSN: 1469-5111 ; DOI: 10.1017/S1461145705006425
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title: Pharmacological profile of PMS777, a new AChE inhibitor with PAF antagonistic activity
format: Article
creator:
  • Li, Juan
  • Huang, Hong
  • Miezan Ezoulin, Jean-marc
  • Gao, Xiao-ling
  • Massicot, France
  • Dong, Chang-zhi
  • Heymans, Franoise
  • Chen, Hong-zhuan
subjects:
  • Pharmacy, Therapeutics, & Pharmacology
ispartof: The International Journal of Neuropsychopharmacology, 2007, Vol.10(1), pp.21-29
description: The key pathophysiological mechanisms in Alzheimers disease involve the selective loss of cholinergic neurons and pro-inflammatory mediator-related chronic inflammatory responses in the brain, therefore interventions of these processes are crucial to the treatment of this disease. In the present study, the pharmacological profile of PMS777, a new acetylcholinesterase (AChE) inhibitor with platelet-activating factor (PAF) antagonistic activity, has been evaluated in vitro and in vivo. PMS777 (1100 ) dose-dependently inhibited PAF-induced rabbit platelet aggregation by competing with HPAF for its receptor on platelets, and protected a human neuroblastoma cell line SH-SY5Y against PAF-induced neurotoxicity. Moreover, it markedly inhibited brain AChE activity in mice and showed a modest selectivity for AChE (AChE: IC=2.480.12 ; butyrylcholinesterase: IC=4.470.15 ). Ex vivo, PMS777 (5, 10, 20 or 40 mgkg i.p.) reduced brain AChE activity in a dose-dependent manner. In-vivo studies revealed that PMS777 (0.25, 0.5, 1, 2.5 or 5 mgkg i.p.) could reverse scopolamine-induced memory retrieval deficits in mice, and displayed a typical bell-shaped doseresponse relationship. Taken together, these results demonstrate that PMS777 possesses dual activities for PAF receptor antagonism and AChE inhibition, suggesting that this compound may be a promising lead compound for further investigation related to the treatment for Alzheimers disease.
language: eng
source:
identifier: ISSN: 1461-1457 ; E-ISSN: 1469-5111 ; DOI: 10.1017/S1461145705006425
fulltext: fulltext
issn:
  • 14611457
  • 1461-1457
  • 14695111
  • 1469-5111
url: Link


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titlePharmacological profile of PMS777, a new AChE inhibitor with PAF antagonistic activity
creatorLi, Juan; Huang, Hong; Miezan Ezoulin, Jean-marc; Gao, Xiao-ling; Massicot, France; Dong, Chang-zhi; Heymans, Franoise; Chen, Hong-zhuan
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descriptionThe key pathophysiological mechanisms in Alzheimers disease involve the selective loss of cholinergic neurons and pro-inflammatory mediator-related chronic inflammatory responses in the brain, therefore interventions of these processes are crucial to the treatment of this disease. In the present study, the pharmacological profile of PMS777, a new acetylcholinesterase (AChE) inhibitor with platelet-activating factor (PAF) antagonistic activity, has been evaluated in vitro and in vivo. PMS777 (1100 ) dose-dependently inhibited PAF-induced rabbit platelet aggregation by competing with HPAF for its receptor on platelets, and protected a human neuroblastoma cell line SH-SY5Y against PAF-induced neurotoxicity. Moreover, it markedly inhibited brain AChE activity in mice and showed a modest selectivity for AChE (AChE: IC=2.480.12 ; butyrylcholinesterase: IC=4.470.15 ). Ex vivo, PMS777 (5, 10, 20 or 40 mgkg i.p.) reduced brain AChE activity in a dose-dependent manner. In-vivo studies revealed that PMS777 (0.25, 0.5, 1, 2.5 or 5 mgkg i.p.) could reverse scopolamine-induced memory retrieval deficits in mice, and displayed a typical bell-shaped doseresponse relationship. Taken together, these results demonstrate that PMS777 possesses dual activities for PAF receptor antagonism and AChE inhibition, suggesting that this compound may be a promising lead compound for further investigation related to the treatment for Alzheimers disease.
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titlePharmacological profile of PMS777, a new AChE inhibitor with PAF antagonistic activity
descriptionThe key pathophysiological mechanisms in Alzheimers disease involve the selective loss of cholinergic neurons and pro-inflammatory mediator-related chronic inflammatory responses in the brain, therefore interventions of these processes are crucial to the treatment of this disease. In the present study, the pharmacological profile of PMS777, a new acetylcholinesterase (AChE) inhibitor with platelet-activating factor (PAF) antagonistic activity, has been evaluated in vitro and in vivo. PMS777 (1100 ) dose-dependently inhibited PAF-induced rabbit platelet aggregation by competing with HPAF for its receptor on platelets, and protected a human neuroblastoma cell line SH-SY5Y against PAF-induced neurotoxicity. Moreover, it markedly inhibited brain AChE activity in mice and showed a modest selectivity for AChE (AChE: IC=2.480.12 ; butyrylcholinesterase: IC=4.470.15 ). Ex vivo, PMS777 (5, 10, 20 or 40 mgkg i.p.) reduced brain AChE activity in a dose-dependent manner. In-vivo studies revealed that PMS777 (0.25, 0.5, 1, 2.5 or 5 mgkg i.p.) could reverse scopolamine-induced memory retrieval deficits in mice, and displayed a typical bell-shaped doseresponse relationship. Taken together, these results demonstrate that PMS777 possesses dual activities for PAF receptor antagonism and AChE inhibition, suggesting that this compound may be a promising lead compound for further investigation related to the treatment for Alzheimers disease.
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abstractThe key pathophysiological mechanisms in Alzheimers disease involve the selective loss of cholinergic neurons and pro-inflammatory mediator-related chronic inflammatory responses in the brain, therefore interventions of these processes are crucial to the treatment of this disease. In the present study, the pharmacological profile of PMS777, a new acetylcholinesterase (AChE) inhibitor with platelet-activating factor (PAF) antagonistic activity, has been evaluated in vitro and in vivo. PMS777 (1100 ) dose-dependently inhibited PAF-induced rabbit platelet aggregation by competing with HPAF for its receptor on platelets, and protected a human neuroblastoma cell line SH-SY5Y against PAF-induced neurotoxicity. Moreover, it markedly inhibited brain AChE activity in mice and showed a modest selectivity for AChE (AChE: IC=2.480.12 ; butyrylcholinesterase: IC=4.470.15 ). Ex vivo, PMS777 (5, 10, 20 or 40 mgkg i.p.) reduced brain AChE activity in a dose-dependent manner. In-vivo studies revealed that PMS777 (0.25, 0.5, 1, 2.5 or 5 mgkg i.p.) could reverse scopolamine-induced memory retrieval deficits in mice, and displayed a typical bell-shaped doseresponse relationship. Taken together, these results demonstrate that PMS777 possesses dual activities for PAF receptor antagonism and AChE inhibition, suggesting that this compound may be a promising lead compound for further investigation related to the treatment for Alzheimers disease.
doi10.1017/S1461145705006425
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