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

Brain Res. 1996 May 6;719(1-2):36-44. doi: 10.1016/0006-8993(96)00063-7.


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.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects*
  • Glutamic Acid / toxicity
  • Humans
  • Isoxazoles / pharmacology*
  • Neuroprotective Agents / pharmacology*
  • Nicotinic Agonists / pharmacology*
  • Nicotinic Antagonists / pharmacology
  • Pyrrolidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley


  • Isoxazoles
  • Neuroprotective Agents
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Pyrrolidines
  • 3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole
  • Glutamic Acid