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P4‐305: Allosteric potentiation of the M1 muscarinic receptor provides unprecedented selectivity and a novel therapeutic strategy for the treatment of Alzheimer's disease
Author(s) -
Ray William J.,
Seager Matthew,
Ma Lei,
Wittmann Marion,
Getty Krista,
Marlatt Michael,
Crouthamel Ming-Chih,
Wu Guoxin,
Sankaranarayananan Sethu,
Simon Adam,
Burno Maryann,
Jones Keith,
Graufields Valerie Kuzmick,
Bickel Denise,
Posavec Diane,
Cook Jacquelynn,
Veng Lone,
Kuduk Scott,
Sur Cyrille,
Shipe William,
Lindsley Craig,
Kinney Gene,
Pascarella Danette,
Jacobson Marlene,
Seabrook Guy
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.2375
Subject(s) - muscarinic acetylcholine receptor m4 , muscarinic acetylcholine receptor m1 , muscarinic acetylcholine receptor , neuroscience , muscarinic acetylcholine receptor m2 , pharmacology , long term potentiation , allosteric regulation , cholinergic , agonist , muscarinic acetylcholine receptor m3 , muscarinic acetylcholine receptor m5 , allosteric modulator , chemistry , receptor , biology , biochemistry
practice since 5000 years. Objective: The main goal of the studies reported here is to investigate the cerebro-protective and memory improving potentials of PHYLLSARONE-2H. Methods: -amyloid, scopolamine, ibotenic acid, CO2 and aging induced amnesia, KCN and Carotid artery ligationinduced hypoxia were the experimental models. Basal forebrain lesion induced decrease in cerebral Ach and ChAT activity were assessed, Concentrations of Norepinerphrine, Epinephrine, Dopamine, 5-HT in cerebral cortex, cerebellum, hypothalamus, hippocampus, pons and corpus striatum were measured by HPLC analysis. Neuromorphology, contents of MDA, NO, activities of SOA and CAT were also Measured. Exteroceptive models such as Water maze, Hebb william’s maze, Radial arm maze were used to assess acquistion and retention. Results: Neuromorphology, contents of MDA, NO, activities of SOA and CAT were Measured which indicated that PHYLLSARONE-2H significantly protected the experimental animals from hypoxia, stress, amnesia and neurodegeneration. They inhibited KCN and Carotid artery ligation induced hypoxia, reversed amnesia and neurodegeneration induced by -amyloid, scopolamine, ibotenic acid, CO2 and brain aging, produced normalizing action on discrete regions of brain and controlled alterations in neurotransmitter levels due to neurodegeneration. They also decreased ChAT activity in the parietal cortex and inhibited decrease in Ach levels in both parietal and frontal cortex in amnesic rats.Neurohistochemistry revealed that both PHYLLSARONE-2H profoundly reduced the neurodegeneration in the experimental animals. It also improved acquistion and retention capacities of the animals. Conclusions: PHYLLSARONE-2H, profoundly reduced the neurodegeneration, improved learning and memory in the experimental animals. Hence PHYLLSARONE-2H can be of beneficial in the treatment of dementia of Alzheimer’s type and other neurodegenerative disorders.