AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer’s disease
| Autor: | Niva Natan, Lili Wu, Victoria Nahum, Abraham Fisher, Eitan Gershonov, Nira Bar-Ner, Hanoch Elkon, Rodrigo Medeiros, Frank M. LaFerla, Ilya Bezprozvanny, Daniel A. Ryskamp, Rachel Brandeis |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male drug effects physiology [Avoidance Learning] Drug Evaluation Preclinical Morris water navigation task chemistry pharmacology [Thiazolidines] Pharmacology Hippocampus PC12 Cells Rats Sprague-Dawley 0302 clinical medicine Muscarinic acetylcholine receptor Medicine and Health Sciences Receptor Nootropic Agents Cerebral Cortex Chemistry Muscarinic acetylcholine receptor M1 agonists metabolism [Receptors sigma] drug therapy metabolism pathology [Alzheimer Disease] pathology [Cerebral Cortex] 3. Good health Neurology Thiazolidines Female Alzheimer's disease pharmacology [Nootropic Agents] medicine.drug Agonist medicine.medical_specialty Carbachol medicine.drug_class pharmacology [Spiro Compounds] Allosteric regulation Mice Transgenic Article 03 medical and health sciences Allosteric Regulation Alzheimer Disease Internal medicine physiology [Maze Learning] metabolism [Receptor Muscarinic M1] medicine Avoidance Learning Animals Humans Receptors sigma Spiro Compounds pathology [Synapses] Rats Wistar Maze Learning pathology [Hippocampus] Receptor Muscarinic M1 medicine.disease Rats Disease Models Animal 030104 developmental biology Endocrinology Synapses Neurology (clinical) 030217 neurology & neurosurgery |
| Zdroj: | Fisher, Abraham; Bezprozvanny, Ilya; Wu, Lili; Ryskamp, Daniel A; Bar-Ner, Nira; Natan, Niva; et al.(2016). AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer’s Disease.. Neuro-degenerative diseases, 16(1-2), 95-110. UC Irvine: Institute for Clinical and Translational Science. Retrieved from: http://www.escholarship.org/uc/item/0rm238hc |
| Popis: | We previously developed orthosteric M1 muscarinic agonists (e.g. AF102B, AF267B and AF292), which act as cognitive enhancers and potential disease modifiers. We now report on a novel compound, AF710B, a highly potent and selective allosteric M1 muscarinic and σ1 receptor agonist. AF710B exhibits an allosteric agonistic profile on the M1 muscarinic receptor; very low concentrations of AF710B significantly potentiated the binding and efficacy of carbachol on M1 receptors and their downstream effects (p-ERK1/2, p-CREB). AF710B (1-30 µg/kg, p.o.) was a potent and safe cognitive enhancer in rats treated with the M1 antagonist trihexyphenidyl (passive avoidance impairment). These effects of AF710B involve σ1 receptor activation. In agreement with its antiamnesic properties, AF710B (at 30 nM), via activation of M1 and a possible involvement of σ1 receptors, rescued mushroom synapse loss in PS1-KI and APP-KI neuronal cultures, while AF267B (1 µM) was less potent in PS1-KI and ineffective in APP-KI models, respectively. In female 3xTg-AD mice, AF710B (10 µg/kg, i.p./daily/2 months) (i) mitigated cognitive impairments in the Morris water maze; (ii) decreased BACE1, GSK3β activity, p25/CDK5, neuroinflammation, soluble and insoluble Aβ40, Aβ42, plaques and tau pathologies. AF710B differs from conventional σ1 and M1 muscarinic (orthosteric, allosteric or bitopic) agonists. These results highlight AF710B as a potential treatment for Alzheimer's disease (e.g. improving cognitive deficits, synaptic loss, amyloid and tau pathologies, and neuroinflammation) with a superior profile over a plethora of other therapeutic strategies. |
| Databáze: | OpenAIRE |
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