Monoterpenoid Terpinen-4-ol Exhibits Anticonvulsant Activity in Behavioural and Electrophysiological Studies

Abstract

Terpinen-4-ol (4TRP) is a monoterpenoid alcoholic component of essential oils obtained from several aromatic plants. We investigated the psychopharmacological and electrophysiological activities of 4TRP in male Swiss mice and Wistar rats. 4TRP was administered intraperitoneally (i.p.) at doses of 25 to 200 mg/kg and intracerebroventricularly (i.c.v.) at concentrations of 10, 20, and 40 ng/2 μL. For in vitro experiments, 4TRP concentrations were 0.1 mM and 1.0 mM. 4TRP (i.p.) inhibited pentylenetetrazol- (PTZ-) induced seizures, indicating anticonvulsant effects. Electroencephalographic recordings showed that 4TRP (i.c.v.) protected against PTZ-induced seizures, corroborating the behavioural results. To determine whether 4TRP exerts anticonvulsant effects via regulation of GABAergic neurotransmission, we measured convulsions induced by 3-mercapto-propionic acid (3-MP). The obtained results showed involvement of the GABAergic system in the anticonvulsant action exerted by 4TRP, but flumazenil, a selective antagonist of the benzodiazepine site of the GABAA receptor, did not reverse the anticonvulsant effect, demonstrating that 4TRP does not bind to the benzodiazepine-binding site. Furthermore, 4TRP decreased the sodium current through voltage-dependent sodium channels, and thus its anticonvulsant effect may be related to changes in neuronal excitability because of modulation of these channels.

Anticonvulsant Essential Oils and Their Relationship with Oxidative Stress in Epilepsy

“…When examining electroencephalogram changes caused by intra-cerebroventricular administration of 4TRP (100 and 200 ng/2µL) after PTZ injection, and compared to the control group there was an increase in latency for both myoclonic and tonic-clonic seizures. Surprisingly, 4TRP reduced Na + and K + currents in a concentration-dependent manner in dorsal root ganglion neurons, probably the main inhibition mechanisms for neuronal excitability and convulsive processes [256,257].…”

“…Another important mechanism of EOs compounds is the reduction of seizure-induced inflammation and/or oxidative stress as observed in α-asarone, (-)-verbenone, β-caryophyllene, borneol, carvacryl acetate, eugenol and nerolidol [117,136,158,181,208,235,282]. Some constituents of EOs such as eugenol, terpinen-4-ol and thymol are able to reduce seizures via the modulation of ion channels [206,256,272]. It is worth noting that the constituents of EOs differ in chemical structure and in the position of their functional groups.…”

“…4TRP presents several documented pharmacological effects that include antibacterial activity [250], anticancer [251], antifungal [252], antihypertensive [253], and anti-inflammatory activity [254], and is also widely used in the food, sanitary, and cosmetic industries [255]. Thus, Nóbrega et al [256] performed studies demonstrating that although 4TRP modulates the GABAergic system, its activity is not reversed by pre-treatment with flumazenil, suggesting that the substance does not bind to the benzodiazepine site at the GABA A receptor. When examining electroencephalogram changes caused by intra-cerebroventricular administration of 4TRP (100 and 200 ng/2µL) after PTZ injection, and compared to the control group there was an increase in latency for both myoclonic and tonic-clonic seizures.…”

Kazakh Ziziphora Species as Sources of Bioactive Substances

“…Analgesic activity reviewed [199] Review on metabolism and toxicity [200] Borneol (67) Z. clinopodioides (0.9%-1.2%) [184] Inhibition of nicotinic acetylcholine receptor [323] DNA-protective effects against H2O2 in primary rat hepatocytes and testicular cells [324] Anti-inflammatory in an ALI model in mice through inhibition of the NF-κB and MAPKs signalling pathways [325]; suppression of expression of IL-1β and IL-6 in TNBS-induced colitis in mice [326] Penetration enhancer [327]; increasing of the brain bioavailability of different drugs [328] Antibacterial (multi-drug resistant E. coli) [329] Antiviral (HSV-1) [282] OH endo-Borneol (68) Z. tenuior (0.14%) [202] Vasorelaxant effect on rat thoracic aorta artery rings [330] Positive modulation of the activation of GABAA receptors [331] Potentiation of SeC-induced apoptosis in human hepatocellular carcinoma cells [332] Prolonging anaesthesia time of propofol by inhibiting its glucuronidation [333] O H Bornyl acetate (69) Z. clinopodioides (3.3%) [184] Antifungal (against Pyrenophora avenae) [334] Insecticidal (against Callosobruchus chinensis and Sitophilus oryzae) [228] Anti-inflammatory in an ALI model in mice [335] and in human chondrocytes [336] Antiabortive in pregnant mice [337] Cytotoxic ((Eca-109, HepG2, HT29, MDA-MB-231, PC-3, SGC7901, SW1990 and U2-OS) and a normal cell line (HL-7702) [338] O O Terpinen-4-ol (70) Z. clinopodioides (0.36%-18.2%) [15,184] Sedative and anaesthetic (on silver catfish juveniles) [339]; depressant effect on the CNS and significant anticonvulsant activity probably due to interaction with GABA receptors [340,341] Low inhibition of acetylcholinesterase and butyrylcholinesterase [224] Relaxant effect on vascular smooth muscle …”

“…rigida (0.4%) [21] Sedative and anaesthetic (on silver catfish juveniles) [339]; depressant effect on the CNS and significant anticonvulsant activity probably due to interaction with GABA receptors [340,341] Low inhibition of acetylcholinesterase and butyrylcholinesterase [224] Relaxant effect on vascular smooth muscle [342] Review on some effects on cardiovascular system [221] Anticancer (melanoma) [343]; antiproliferative activity in two murine cancer cell lines through induction of necrosis and cell cycle arrest [344]; induction of apoptosis in human non-small cell lung cancer [345]; anti-tumoral activity in human melanoma cells by induction of caspase-dependent form of apoptosis [346] Antiviral activity against influenza A⁄PR⁄8 virus subtype H1N1 [231] Anti-inflammatory (inhibition of NO production in LPS-stimulated RAW-264.7 macrophages) [223]; anti-inflammatory [216]; anti-inflammatory activity in a murine model of oral candidiasis [347]; suppression of the production of TNFα, IL-1β, IL-8, IL-10 and PGE2 by LPS-activated monocytes [348] Antibacterial against MRSA and CoNS [349] Low antinematocidal activity [281] Antimycotic (C. albicans) [307,350] Insecticidal (against L. serricorne) [351] Trypanocidal activity against Trypanosoma evansi [222] OH Z. clinopodioides subsp. rigida (0.4%) [21] Z. clinopodioides subsp.…”