title: In vitro neuroprotective properties of the novel cholinergic channel activator (ChCA), ABT-418.
abstract: Recent literature has shown that compounds interacting with neuronal nicotinic acetylcholine receptors (nAChRs) have the potential to be neuroprotective both in vitro and in vivo. ABT-418 is a novel ChCA that selectively stimulates discrete subtypes of the nAChRs and exhibits cognitive enhancing activity. In the present study, the neuroprotective effects of ABT-418 and (-)-nicotine, as measured by the release of lactate dehydrogenase (LDH) into the media, were investigated in a glutamate (Glu)-induced cytotoxicity assay using either primary rat cortical neurons or a human differentiated cell line, IMR 32. The neuroprotection elicited by ABT-418 and (-)-nicotine is both time and concentration dependent with an optimal concentration of 10 microM and an optimal pretreatment time of 2 h. ABT-418 remained neuroprotective and not cytotoxic to rat cortical cells following subacute exposure for 7 days. Protection appears to be mediated via an interaction with nAChRs, possibly the alpha 7 subtype, since the neuroprotection was prevented by alpha-bungaratoxin (alpha-Bgt) and methyllycaconitine (MLA), both selective alpha 7 antagonists. Removal of extracellular Ca2+ prevented the neuroprotective effects of ABT-418 and (-)-nicotine, consistent with the known ability of alpha 7 nAChRs to modulate calcium dynamics. These data support the idea that ABT-418 not only enhances cognition, but may possibly slow the progression of the neurodegenerative process.
authors.affiliation: Abbott Laboratories, Neuroscience Discovery, Abbott Park, IL 60064-3500, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Donnelly-Roberts
authors.forename: I C
authors.initials: IC
authors.lastname: Xue
authors.forename: S P
authors.initials: SP
authors.lastname: Arneric
authors.forename: J P
authors.initials: JP
authors.lastname: Sullivan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007555:Isoxazoles; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011759:Pyrrolidines; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D018698:Glutamic Acid