Effects of monoterpenes on ion channels of excitable cells

Abstract

Monoterpenes are a structurally diverse group of phytochemicals and a major constituent of plant-derived ‘essential oils’. Monoterpenes such as menthol, carvacrol, and eugenol have been utilized for therapeutical purposes and food additives for centuries and have been reported to have anti-inflammatory, antioxidant and analgesic actions. In recent years there has been increasing interest in understanding the pharmacological actions of these molecules. There is evidence indicating that monoterpenes can modulate the functional properties of several types of voltage and ligand-gated ion channels, suggesting that some of their pharmacological actions may be mediated by modulations of ion channel function. In this report, we review the literature concerning the interaction of monoterpenes with various ion channels.

Introduction

Phytochemicals have been used for centuries for therapeutic purposes, and they still constitute an important part of therapeutics in medicine (Cupp, 2000, Spinella, 2001, Tracy and Kingston, 2007). Recently, there has been an increasing interest in unveiling the biological activities of specific phytochemicals and understanding the mechanisms of their molecular and cellular effects. One of the major groups of biologically active phytochemicals is the terpenes. They are a large and diverse group of naturally occurring compounds that exist as the main constituents of essential oils of several plants with plethora of pharmacological actions (for recent reviews, Miguel, 2010, de Almeida et al., 2011, de Araújo et al., 2011, de Sousa, 2011, Amorati et al., 2013, Bhalla et al., 2013, Kozioł et al., 2014). To date, more than 25,000 terpenes have been identified, constituting the largest category of phytochemicals (Harrewijn et al., 2001, Kozioł et al., 2014). It has been suggested that terpenes provide plants with an evolutionary advantage. With their distinct odor and flavor, while some of the terpenes are pungent enough to repel insects and animal grazers either as an irritating warning to drive away herbivores that would eat the plant, or to attract predators of the herbivore (Gershenzon & Dudareva, 2007), other terpenes prevent fungus, attract bees and other animals that carry the plant's pollen to other plants. Plants synthesize combinations of many terpenes, providing them with their unique smell by activating olfactory receptors (Hallem & Carlson, 2006) or generating flavor by activating taste receptors (Frasnelli et al., 2011, Viana, 2011).

Terpenes are mostly hydrocarbon in nature and their building block is a five-carbon isoprene unit (2-methyl-1,4-butadiene). The structure of most terpenes consist of ‘head-to-tail’ condensation of isoprene units, also known as ‘isoprene rule’(Christmann, 2010) and they are classified according to the number of isoprene units with a molecular formula of (C5 H8) n (n is the number of isoprene units). Consequently, there are monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes with two, three, four, six, and eight isoprene units respectively (Aldred et al., 2009). Considering the large volume of literature on this diverse group of chemicals, this review will focus on the activities of monoterpenes on ion channels.

Most monoterpenes have highly volatile and non-polar (lipophilic) structures conferring high membrane penetration (Fig. 1). They are colorless liquids that are chemically reactive and have characteristic aromatic odors (Clarke, 2008). This group of diverse compounds possesses variable basic skeletons and also exhibit stereoisomerism. Moreover, there are a wide range of oxygenated derivatives (alcohols, aldehydes, ketones and carboxylic acids) that can be derived from native basic skeletons (Silvestre & Gandini, 2008). Those oxygenated forms are also known as terpenoids (Clarke, 2008).

Several ancient civilizations valued the assumed therapeutic and medicinal effects of essential oils and utilized them for health promotion, well-being and mental relaxation for centuries. Essential oils are still used for therapeutic and culinary purposes as flavoring agents or food preservation. Several earlier investigations have focused on studying the biological effects of essential oils as a whole or, more recently, on their major isolated active constituents i.e., monoterpenes. These studies provided evidence that monoterpenes have significant anti-oxidant, anti-viral, anti-microbial, anti-cancer, analgesic, and anti-inflammatory effects (for recent reviews, de Cássia da Silveira e Sá et al., 2013, Guimarães et al., 2013, Guimarães and Serafini, 2014 Kozioł et al., 2014). This review will focus on the effects of monoterpenes on cellular excitability and include the work on excitability related clinical conditions such as pain, seizure, and neurodegenerative disorders.