In vitro neuroprotective properties of the novel cholinergic channel activator (ChCA), ABT-418

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. LMR 32. The neuroprotection elicited by ABT-418 and(-)-nicotine is both time and concentration dependent with an optimal concentration of 10 mu M 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 tvas 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.