Electrophysiological Insights Into Natural Phenylpropanoids: Effects of Trans-Cinnamaldehyde and Eugenol on Nicotinic Acetylcholine Receptors

Abstract

Natural extracts and essential oils, abundant in bioactive compounds, have long been used in traditional medicine and are increasingly recognized as a source of new drug candidates. Recent research has renewed interest in compounds from sources like Cinnamomum verum oil, particularly trans-cinnamaldehyde (TCA) and eugenol (EGN), due to their potential therapeutic effects. As multitarget compounds, natural compounds are especially intriguing for their interactions with neurotransmitter receptors, including nicotinic acetylcholine receptors (nAChRs), which are part of the Cys-loop receptor family. nAChRs are ion channels activated by acetylcholine, present in both the central and peripheral nervous systems, and are key players in muscle contraction, memory, and attention. This study aimed to examine the molecular effects of TCA and EGN on two types of mammalians nAChRs, both implicated in various pathological conditions. Using single- channel electrophysiological recordings, we observed that TCA exerts a negative modulatory effect on both α7 and muscular nAChRs. Specifically, TCA significantly reduces α7 receptor activity by lowering the frequency of activation episodes, without altering amplitude or open duration. In muscle-type nAChRs, both TCA and EGN lead to a concentration-dependent reduction in open channel duration in the micromolar range, accompanied by a shift to shorter durations in the main closed state. The modulatory effects observed underscore the pharmacological importance of nAChRs as therapeutic targets and highlight the potential therapeutic as well as adverse effects of TCA and EGN. Our findings contribute valuable insights into how these natural compounds affect Cys-loop receptors, an area that remains underexplored but could play a critical role in therapeutic strategies.