Relative levels of cytoprotection produced by analogs of choline and the role of α7-nicotinic acetylcholine receptors

Several analogs of the acetylcholine precursor molecule choline have been widely studied as potential false cholinergic neurotransmitters with the therapeutic goal of using them to limit cholinergic neurotransmission. More recently, choline itself has been shown to act as a full, if low potency, agonist at the α7 subtype of the nicotinic acetylcholine receptor. This pharmacological property has been associated with the ability of nicotine and other related α7 receptor agonists to offer neuroprotection in a variety of experimental models. We confirm here that choline offers a significant degree of protection against the cytotoxicity induced by growth factor deprivation in differentiated PC-12 cells. Choline-induced cytoprotection (∼1 mM) was about 3 orders of magnitude less potent than that for nicotine (EC₅₀ = 0.7 μM). Choline also exhibited only about 40% of the full cytoprotective effect of nicotine. Ethyl substitution for choline's N-methyl groups did not result in a significant improvement over choline as a cytoprotective agent. In contrast, pyrrolidinecholine exhibited much greater potency (EC₅₀ = 20 μM) and increased efficacy (about 55% of nicotine's effect) than choline. Like choline and nicotine, pyrrolidinecholine fully displaced [¹²⁵I]α-bungarotoxin binding (K_i = 33 μM) and chronic exposure to the analog increased cell surface binding sites. The cytoprotective effects of the analog were completely inhibited by coincubation with methyllycaconitine (MLA), a selective α7-nicotinic receptor antagonist. These findings are consistent with the possibility that the choline structure may serve as a template for the development of novel agents with both α7-nicotinic agonist activity and potential neuroprotective ability, as many of these compounds, including pyrrolidinecholine, are transported along with choline into the central nervous system.