Distinct effects of carvone analogues on the isolated nerve of rats.

Carvone (p-mentha-6,8-dien-2-one) is a monoterpene ketone found as the main active component of various essential oils. It is obtained by distillation and occurs naturally as the enantiomers (+)- and (-)-carvone. Our group have shown that the in vivo antinociceptive activity of (-)-carvone is impaired with decreased nerve excitability. To better characterize the neuropharmacology of such a monoterpene, we investigated the profile of several carvone analogues to establish a structure-function relationship related to the compound action potential (CAP) inhibitory effect. We performed ex vivo assays to evaluate the effects of (+)- and (-)-carvone, carvacrol, (-)-carveol, and limonene on CAP characteristics using a modified single sucrose-gap method. Our results demonstrated that (-)-carvone was less potent (IC(50)=10.7+/-0.07 mM) in reducing nerve excitability than its enantiomer, (+)-carvone (IC(50)=8.7+/-0.1mM), although they shared a similar mode of action, since their effects were partially extinguished by nerve washing and also by reduction of depolarization velocity, probably as a result of voltage-gated sodium channel blockades. In a structure-activity relationship study, we demonstrated that hydroxyl groups in the (-)-carveol and carvacrol molecules enhanced the CAP blocking-effect, while the absence of oxygen moiety in (+)-limonene resulted in the effect being almost abolished. Therefore, inhibition of CAP conduction in peripheral nerves by monoterpenes could expand our understanding concerning the pharmacology of such natural bioactive compounds. Moreover, activation or inhibition of nerve excitability with these tested monoterpenes can be achieved by altering their chemical structures, and this can lead to further implications for target-directed drug design.

Evaluation of the sesquiterpene (-)-alpha-bisabolol as a novel peripheral nervous blocker.

Essential oils are natural, complex and multi-component systems composed mainly of terpenes in addition to some other non-terpenes compounds that are widely used to prevent and treat human diseases. (-)-alpha-Bisabolol is an unsaturated monocyclic sesquiterpene alcohol found as the major constituent of many essential oils, like the German chamomile (Chamomilla recutita (L.) Rauschert), a plant reported to reduce the perception of acute pain and used for centuries for their medicinal properties. Recently, our group demonstrated the antinociceptive-like effect promoted by other terpenes could be associated with the decreased peripheral nerve excitability. Therefore, this study investigated the pharmacological activities of (-)-alpha-bisabolol on mice peripheral nervous system observing the changes on the compound action potential (CAP) characteristics. Using modified single sucrose-gap method in mice sciatic nerves, we acquired CAP recordings in the absence and presence of (-)-alpha-bisabolol (0.5, 1, 5 and 10mM). We observed that this sesquiterpene was able to reduce the neuronal excitability in a concentration-dependent manner, although, such effects were not reversed when the nerve was submitted to wash out. Assessing CAP parameters of depolarization and repolarization, we noticed similarities between (-)-alpha-bisabolol and lidocaine but not with 4-aminopyridine that are considered good blockers for sodium and potassium voltage-gated channels, respectively. Additionally, we also characterized the non-use-dependent profile of (-)-alpha-bisabolol action, in contrast to lidocaine. Thus, we suggested that decreased nervous excitability elicited by (-)-alpha-bisabolol might be caused by an irreversible blockade of voltage-dependent sodium channels.