Antagonism of nicotinic acetycholinergic receptors by CN‐105, an apoE‐mimetic peptide reduces stroke‐induced excitotoxicity

Abstract

This letter describes our work identifying the neuronal targets of a clinical-stage stroke therapeutics CN-105, and proposing a novel neuroprotective strategy involving nAChR antagonism. Stroke is a devastating disease with high morbidity and mortality. CN-105 was originally designed to mimic the anti-inflammatory activities of endogenous apolipoprotein E (apoE). Despite its proven efficacy in various animal models of brain injury and wellestablished safety profile in clinical trials, 1,2 our understanding of CN-105's mechanism of action remains incomplete. Early reports suggested that apoE-derived peptides and a number of oligoarginine species may interact directly with various neuronal targets including the nicotinic acetylcholine receptors (nAChR). 3,4 The long-held view regarding nAChR was that its activation was neuroprotective, best exemplified by the cognitive-enhancing effects of nAChR agonists or positive allosteric modulators. 5 One common role of nAChR, which received limited attention in stroke, is its potentiation of glutamate release at the presynaptic terminal. 6 Glutamatergic neurotransmission is arguably the primary reason for the propagation of excitotoxicity in stroke. 7,8 Although postsynaptic nAChR activated by ACh or nicotine could desensitize proximal NMDA receptors, 9 we hypothesized that acute action of nAChR antagonist on presynaptic neurons may serve to downregulate the detrimental cascade associated with glutamate excitotoxicity.After given supratherapeutic dosing of CN-105 several orders of magnitude higher than clinical practice, Cynologous monkey exhibited symptoms of mydriasis and ptosis. A gradual recovery to normal activity took about two serum clearance half-lives of CN-105 (4 h, Table S1; Figure S1). In C57BL6 mice, CN-105 had an LD 80 of 25 mg/kg (Figure 1A) with symptoms of spasm and respiratory suppression. Following intubation and mechanical ventilation, dosing of 50 mg/kg was not associated with mortalityThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.