Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways.
The alpha7 nicotinic acetylcholine receptor (nAChR) plays an important role in cognitive processes and may represent a drug target for treating cognitive deficits in neurodegenerative and psychiatric disorders. In the present study, we used a novel alpha7 nAChR-selective agonist, 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) to interrogate cognitive efficacy, as well as examine potential cellular mechanisms of cognition. Exhibiting high affinity to native rat (Ki = 10.8 nM) and human (Ki = 16.7 nM) alpha7 nAChRs, A-582941 enhanced cognitive performance in behavioral assays including the monkey delayed matching-to-sample, rat social recognition, and mouse inhibitory avoidance models that capture domains of working memory, short-term recognition memory, and long-term memory consolidation, respectively. In addition, A-582941 normalized sensory gating deficits induced by the alpha7 nAChR antagonist methyllycaconitine in rats, and in DBA/2 mice that exhibit a natural sensory gating deficit. Examination of signaling pathways known to be involved in cognitive function revealed that alpha7 nAChR agonism increased extracellular-signal regulated kinase 1/2 (ERK1/2) phosphorylation in PC12 cells. Furthermore, increases in ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation were observed in mouse cingulate cortex and/or hippocampus after acute A-582941 administration producing plasma concentrations in the range of alpha7 binding affinities and behavioral efficacious doses. The MEK inhibitor SL327 completely blocked alpha7 agonist-evoked ERK1/2 phosphorylation. Our results demonstrate that alpha7 nAChR agonism can lead to broad-spectrum efficacy in animal models at doses that enhance ERK1/2 and CREB phosphorylation/activation and may represent a mechanism that offers potential to improve cognitive deficits associated with neurodegenerative and psychiatric diseases, such as Alzheimer's disease and schizophrenia.
Bitner
Robert S
RS
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. robert.s.bitner@abbott.com
Bunnelle
William H
WH
Anderson
David J
DJ
Briggs
Clark A
CA
Buccafusco
Jerry
J
Curzon
Peter
P
Decker
Michael W
MW
Frost
Jennifer M
JM
Gronlien
Jens Halvard
JH
Gubbins
Earl
E
Li
Jinhe
J
Malysz
John
J
Markosyan
Stella
S
Marsh
Kennan
K
Meyer
Michael D
MD
Nikkel
Arthur L
AL
Radek
Richard J
RJ
Robb
Holly M
HM
Timmermann
Daniel
D
Sullivan
James P
JP
Gopalakrishnan
Murali
M
D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007858:Learning / Q000187:drug effects / Q000502:physiology; D008253:Macaca mulatta; D008297:Male; D008606:Mental Processes / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011724:Pyridazines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic; D015398:Signal Transduction; D016896:Treatment Outcome; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor
C524029:A-582941; D002491:Central Nervous System Agents; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D011724:Pyridazines; D011758:Pyrroles; D011978:Receptors, Nicotinic; C424127:SL 327; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000607:Aminoacetonitrile; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3