No abstract

(؊)-Carvone is a monoterpene ketone that is the main active component of Mentha plant species like Mentha spicata. This study aimed to investigate the antinociceptive activity of (؊)-carvone using different experimental models of pain and to investigate whether such effects might be involved in the nervous excitability elicited by others monoterpenes. In the acetic acid-induced writhing test, we observed that (؊)-carvone-treated mice exhibited a significant decrease in the number of writhes when 100 and 200 mg/kg was administered. It was also demonstrated that (؊)-carvone inhibited the licking response of the injected paw when 100 and 200 mg/kg was administered (i.p.) to mice in the first and second phases of the formalin test. Since naloxone (5 mg/kg, s.c.), an opioid antagonist, showed no influence on the antinociceptive action of (؊)-carvone (100 mg/kg), this suggested nonparticipation of the opioid system in the modulation of pain induced by (؊)-carvone. Such results were unlikely to be provoked by motor abnormality, since (؊)-carvone-treated mice did not exhibit any performance alteration on the Rota-rod apparatus. Because the antinociceptive effects could be associated with neuronal excitability inhibition, we performed the single sucrose gap technique and observed that (؊)-carvone (10 mM) was able to reduce the excitability of the isolated sciatic nerve through a diminution of the compound action potential amplitude by about 50% from control recordings. We conclude that (؊)-carvone has antinociceptive activity associated with decreased peripheral nerve excitability.

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.

Leishmaniasis is a complex of parasitic protozoan diseases caused by more than 20 different species of parasites from Leishmania genus. Conventional treatments are high costly, and promote a sort of side effects. Besides, protozoan resistance to treatments has been reported. Natural products have been investigated as a source of new therapeutic alternatives, not only acting directly against the parasite but also being able to synergistically act on the host immune system in order to control parasitemia. Gallic acid (GA) and ellagic acid (EA) are plant-derived phenolic compounds which are able to induce antiinflammatory, gastroprotective, and anticarcinogenic activities. Therefore, the antileishmania, cytotoxic, and immunomodulatory activities of GA and EA were evaluated in this study. Both GA and EA were able to inhibit the growth of Leishmania major promastigotes (effective concentration (EC) values 16.4 and 9.8 μg/mL, respectively). The cytotoxicity against BALB/c murine macrophages for GA and EA was also assessed (CC values 126.6 and 23.8 μg/mL, respectively). Interestingly, GA and EA also significantly reduced the infection and infectivity of macrophages infected by L. major (EC values 5.0 and 0.9 μg/mL, respectively), with selectivity index higher than 20. Furthermore, both GA and EA induced high immunomodulatory activity evidenced by the increase of phagocytic capability, lysosomal volume, nitrite release, and intracellular calcium [Ca] in macrophages. Further investigations are reinforced in order to evaluate the therapeutic effects of GA and EA in in vivo experimental infection model of leishmaniasis.

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.