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ISSN 0344-8622

26(2003)3

26(2003)3

Zeitschrift für Ethnomedizin und transkulturelle Psychiatrie Journal of Medical Anthropology and Transcultural Psychiatry hrsg von/edited by: Arbeitsgemeinschaft Ethnomedizin e.V. – AGEM

Neue Trends in der Ethnobotanik und Ethnopharmakologie / New Trends in Ethnobotany and Ethnopharmakology

Berichte Buchbesprechungen Dokumentation Zeitschrift Etnoiatria

VWB – Verlag für Wissenschaft und Bildung ISBN 3-86135-686-4

Zum Titelbild und zur Rückseite: In zwei Varianten der wiederholten Neuauflagen diente dieses Frontinspiz aus Moses Charas „Pharmacopoea regia galenica“, Du Four, Genf 1684, als Emblem für die XI. Internationale Fachkonferenz Ethnomedizin/bzw. das 2. Europäische Kolloquium Ethnopharmakologie: „Heilmittel und Nahrungsmittel aus ethnopharmakologischer Sicht“ vom 24.-27.3.1993 in Heidelberg und als Titelbild dieser Zeitschirift (vgl. curare 3/92, 1/93 und 2/93). Für das 6. Europäische Kolloquium Ethnopharmakologie, das ebenfalls als Joint-Meeting mit der 20. Fachkonferenz Ethnomedizin vom 10.-12. Mai 2007 in Leipzig geplant ist, soll dieses Frontispiz wieder als Emblem dienen. Siehe zum Tielbild auch Seite 197.

Arbeitsgemeinschaft Ethnomedizin – AGEM , Herausgeber der curare, Zeitschrift für Ethnomedizin und transkulturelle Psychiatrie, gegründet 1978 Die Arbeitsgemeinschaft Ethnomedizin (AGEM) hat als rechtsfähiger Verein ihren Sitz in Hamburg und ist eine Vereinigung von Wissenschaftlern und die Wissenschaft fördernden Personen und Einrichtungen, die ausschließlich und unmittelbar gemeinnützige Zwecke verfolgt. Sie bezweckt die Förderung der interdisziplinären Zusammenarbeit zwischen der Medizin einschließlich der Medizinhistorie, der Humanbiologie, Pharmakologie und Botanik und angrenzender Naturwissenschaften einerseits und den Kultur- und Gesellschaftswissenschaften andererseits, insbesondere der Ethnologie, Kulturanthropologie, Soziologie, Psychologie und Volkskunde mit dem Ziel, das Studium der Volksmedizin, aber auch der Humanökologie und Medizin-Soziologie zu intensivieren. Insbesondere soll sie als Herausgeber einer ethnomedizinischen Zeitschrift dieses Ziel fördern, sowie durch regelmäßige Fachtagungen und durch die Sammlung themenbezogenen Schrifttums die wissenschaftliche Diskussionseben verbreitern. (Auszug der Satzung von 1970)

Zeitschrift für Ethnomedizin und transkulturelle Psychiatrie / Journal of Medical Anthropology and Transcultural Psychiatry Impressum Vol. 26(2003)3 Herausgegeben im Auftrag der / Edited on the behalf of: Arbeitsgemeinschaft Ethnomedizin e. V. – AGEM von Ekkehard Schröder, auch verantwortlich im Sinne des Presserechtes V.i.S.d.P. Geschäftsadresse/office AGEM: AGEM-curare c/o E. Schröder, Spindelstr. 3, 14482 Potsdam, Germany e-mail: , Fax: 0331-704 46 82 Redaktionsadressen 2003 - 2004: Dr. Anita Zahlten-Hingurange, Almstr. 7, 69151 Neckargemünd, // Martine Verwey, Zürich // Prof. Dr.Armin Prinz, c/o ven, Wien // Prof. Dr. Michael Heinrich, London Begründet von / Founding Editors: Beatrix Pfleiderer (Hamburg) – Gerhard Rudnitzki (Heidelberg) – Wulf Schiefenhövel (Andechs) – Ekkehard Schröder (Potsdam) Ehrenbeirat / Honorary Editors: Hans-Jochen Diesfeld (Starnberg) – Host Figge (Freiburg) – Dieter H. Frießem (Stuttgart) – Wolfgang Jilek (Vancouver) – Guy Mazars (Strasbourg)

Verlag und Vertrieb / Publishing House VWB – Verlag für Wissenschaft und Bildung, Amand Aglaster Postfach 11 03 68 • D-10833 Berlin Tel.: 030-251 04 15 • Fax: 030-251 11 36 e-mail: [email protected] http://www.vwb-verlag.com Bezug/Supply: Der Bezug der curare ist in der Mitgliedschaft bei der Arbeitsgemeinschaft Ethnomedizin (AGEM) enthalten. Einzelne Hefte können beim VWB-Verlag bezogen werden / curare is included in a regular membership of AGEM. Single copies can be ordered at VWB-Verlag Abonnementspreis/Subscription Rates: Die jeweils gültigen Abonnementspreise finden Sie im Internet unter / Valid subscription rates you can find at the internet under: www.vwb-verlag.com/reihen/Periodika/curare.html Copyright: © VWB – Verlag für Wissenschaft und Bildung, Berlin 2005 ISSN 0344-8622

ISBN 3-86135-686-4

Inhalt

193

Zeitschrift für Ethnomedizin und transkulturelle Psychiatrie/ Journal of Medical Anthropology and Transcultural Psychiatry Hrsg. von/Ed. by Arbeitsgemeinschaft Ethnomedizin (AGEM)

Inhalt Vol. 26 (2003) 3 Neue Trends in der Ethnobotanik und Ethnopharmakologie / New Trends in Ethnobotany and Ethnopharmacology zusammengestellt von / compiled by Michael HEINRICH, Guy MAZARS & Ekkehard SCHRÖDER

Inhalt Michael HEINRICH: Editorial: Ethnobotanik – Versuch einer Standortbestimmung . . . . . . . . . . . . . .

195

Reprint: Zum Titelbild/Frontispiece/Frontispice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

197

Die Autoren dieses Heftes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

198

Message from the Editor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

199

Artikel Jacques FLEURENTIN: Ethics, Regulations and Development: New Perspectives in Ethnopharmacology for the Next Decade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

201

Carla Pilar AGUIRRE MARCO: Nationalism and Science: the “new” American plants in 19th century North American materia medica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

213

Andrea PIERONI & Michael HEINRICH: Liakra – nicht-kultivierte Nahrungspflanzen der Albaner Süditaliens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

221

Elaine ELISABETSKY & L. F. SILVA BRUM: Linalool as active component of traditional remedies: Anticonvulsant proprties and mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

237

Pierre CABALION: Kava in Modern Therapeutic Uses: to a Better Evaluation of the Benefit/Risk Relation. Researches in New Caledonia and in Futuna . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

245

Reprint: Bo HOLMSTEDT & Jan G. BRUHN: Ethnopharmacology – a challenge. (Is there a place for ethnopharmacology in our time?) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

263

Dokument: Die Zeitschrift Etnoiatria. Varese/Italien (1967/68), herausgegeben von Antonio SCARPA

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Inhalt

Buchbesprechungen / Book Reviesw . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

276

Mitteilungen der Arbeitsgemeinschaft Ethnomedizin 25/2003 . . . . . . . . . . . . . . . . . . . . . . . . . . . .

277

Jean Benoist Ehrenmitglied der AGEM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

277

1994 – 2003. 10 Jahre Ethnomedizin im „Neuen Wiener Medizincurriculum“ . . . . . . . . . . . . . . . . . .

277

Qualitätszirkel Ethnomedizin in Hannover gegründet. Ärztekammer Niedersachsen gibt Fortbildungspunkte für Ethnomedizin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

277

30 Jahre Fachkonferenzen AGEM 1973 - 2003 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

278

Bericht zum 5. Kongress „Anthropologie der Geschlechter“, Potsdam 2003 . . . . . . . . . . . . . . . . . . . .

279

15 Jahre internationale Konferenzen zur Ethnopharmakologie . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

280

Jean-Marie Pelt zum 70. Geburtstag . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

280

Publication of the Proceedings of the 5th European Colloquium on Ethnopharmacology/ International congress 2003 – Valencia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

281

Message des éditeurs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

285

Résumés des articles curare 2(2003)3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

286

Impressum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hinweise für Autoren / Instructions to the Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

U2 U3

Redaktion: Ekkehard Schröder Redaktionschluss dieses Heftes: Juli 2005

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Linalool as Active Component of Traditional Remedies: Anticonvulsant Properties and Mechanisms of Action* E. ELISABETSKY & L. F. SILVA BRUM

Abstract: Linalool is a monoterpene compound, commonly found as a major component of essential oils in aromatic species. Several linalool-producing species are used in traditional systems of medicines, including Aeollanthus suaveolens Spreng. (Labiatae) used in home made anticonvulsant remedies throughout the Brazilian Amazon. Anticonvulsant activity of linalool was initially detected in a maximal electroshock test (MES), pentylenetetrazole (PTZ)-induced convulsions in mouse and later confirmed in various other in vivo and in vitro models. Linalool mechanism of action is multifactorial, modulating several relevant elements of the glutamatergic transmission, likely to include antagonism of glutamate and NMDA cortical receptors, as well as impairment of K+-stimulated glutamate release. Linalol als biochemisch aktive Komponente in traditionellen Heilmitteln: antikonvulsive Eigenschaften und Wirkmechanismus Zusammenfassung: Linalol ist ein Monoterpen und wird regelmässig als wesentliche Komponente in den essentiellen Ölen aromatischer Pflanzen gefunden. Etliche Linalol-produzierende Pflanzenarten kommen in traditionellen Medizinsystemen regelmässig zur Anwendung. Dazu gehört auch der Lippenblütler Aeollanthus suaveolens Spreng., der in selbst hergestellten antikonvulsiven Heilmitteln des gesamten brasilianischen Amazonasbecken verwendet wird. Die antikonvulsive Aktivität des Linalols wurde anfänglich bei maximalen Elektroschocktests (MES) entdeckt, und zwar bei Pentylentetrazol-(PTZ)-induzierten Krämpfen bei Mäusen und wurde später in verschiedensten anderen in vitro und in vivo Modellen bestätigt. Der Wirksmechanismus von Linalol muss als multifaktoriell angesehen werden, da die Verbindung der verschiedenste wichtige Teile der glutamatergen Transmission moduliert. Ebenso schliesst er den Antagonismus von Glutamat und den kortikalen NMDA-Rezeptoren ein wie auch die K+stimulierte Freizetzung von Glutamat. Keywords (Schlagwörter): Brasil (Brasilien) – traditional anticonvulsant remedies (traditionelle Antiepileptika) – Linalool (Linalol) – Aeollanthus suaveolens Mart. ex Spreng. – Ethnopharmacology – Glutamate and cortical receptors (Glutamat und zerebraler Stoffwechsel)

Introduction Traditional medicines are organized as cultural systems (FOSTER 1976), including medical practices that may be addressed to non physiological aspects of diseases (UMOREN 1990). Nevertheless, most systems share the practice of processing raw plant material into therapeutic drugs, and often traditional plant-based remedies correlate with relevant pharmacological properties of plant-derived substances. Because epilepsy is an universal and ancient disease, it is reasonable to regard traditional treatments of epilepsy as potential sources of potential anticonvulsant agents. In fact, dozens of species are reported to be used as antiepileptic home remedies, many *

of which have shown activity in preliminary evaluation (CHAUHAN et al. 1988). In the search for anticonvulsant plant derived compounds, ethnopharmacological surveys were conducted within Amazonian traditional communities. A widespread recipe that includes Cissus sicyoides (Vitaceae), Aeollanthus suaveolens (Lamiaceae), Ruta graveolens (Rutaceae) and Sesamun indicum (Pedaliaceae) was identified, prompting to laboratory scrutiny. Following the ethnopharmacological methodology, pharmacologically monitored chemical investigation lead to the identification of linalool as a major active ingredient. This paper provides an overview of the psychopharmacological properties and mechanisms of action of linalool,

This paper is in part based on a keynote lecture presented at the joint international conference of the International Society for Ethnopharmacology and the South African Association of Botanists, Pretoria, January 2003.

curare 26(2003)3: 237-244

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likely to participate in many traditionally used recipes for treating epilepsy. Ethnopharmacology Ethnopharmacology, rather than a contemporary version of Pharmacognosy, is a discipline with its own rational and methodology. In studying traditional medicines by the ethnopharmacological approach, plants are regarded as just one component of a traditional treatment. The fact that traditional medical systems are organized as cultural systems (JANZEN 1978; KLEINMAN 1978; SACHS & THOMSON 1992) allows for profound differences in meanings of health, disease, and disease etiologies (BASTIEN 1985; WING 1998; WHYTE 1982). Accordingly, such differences result in a variety of therapeutic practices not easily accommodated in the bio-mechanical paradigm of modern medicine. An ethnopharmacological study takes into account the disease concepts, the treatment(s) used within this context, the plants (if any) included in the treatment, the mode of preparation of a given remedy, the posology associated with each traditional remedy and finally the contextualized evaluation of efficacy. A commonly used application of ethnopharmacology is the pharmacological evaluation of medicinal plants included in traditional remedies, as starting point for discovering new medicinal compounds. In the search for psychoactive compounds, ethnopharmacological surveys accomplished among caboclos (Amazonian non-Indian rural population), in the State of Pará (Brazilian Amazon), a remedy repeatedly reported for treating convulsions was identified. It was first noticed that epilepsy has several popular names among caboclos of the State of Pará, some not having any obvious association with convulsions or epilepsy itself. Eliciting descriptions of symptoms and the natural course of the disease as reported by healers and users permitted the creation of a list of emic diseases that could be related to the nosological category known as Epilepsy in biomedicine. The remedy consists of a mixture from the saps (extracted by mechanical pressure) of a few leaves of fresh Ruta graveolens L. (Rutaceae), Cissus sicyoides L. (Vitaceae), Aeollanthus suaveolens Mart. ex Spreng. (Lamiaceae) and a tea spoon of seeds of Sesamun indicum L. (Pedaliaceae). This traditional formulation was proven to delay convul-

Figure 1. Chemical structures of essential oil of Aeollanthus suaveolens.

sions (given i.p. to mice), induced by pentylenetetrazol (PTZ) (ELISABETSKY et al. 1984) and studies proceeded with the evaluation of individual species. It is beyond the scope of this paper to fully discuss all data. In brief, anticonvulsant properties of R. graveolens have been previously reported, the essential oil tested for depressant activity in gold fish (WESLEY-HADZIJA & BOHING 1956). C. sicyoides contains significant amounts of α-tocopherol (Vitamin E) (BARBOSA 1994), a compound proved to be an useful adjunct to anticonvulsant drugs in clinical studies, although devoid of anticonvulsant effects in standard animal models. We concluded that the role of S. indicum seeds in the recipe was to act as a carrier for extracting lipophilic active components present in the leaves of the other species. A. suaveolens is one of the best known medicinal plants in the Amazon, recognized as medicinal by 93% of the women interviewed in extractive reserves in the State of Acre (KAINER et al. 1992). Because A. suaveolens is heavily aromatic, its essential oil was obtained, evaluated and proved active (ELISABETSKY et al. 1995). The main components identified in the essential oil were E-β-farnesen (37.75%), δ-decen-2-lactone (20.6-44.3%), linalyl acetate (11.32%), linalool (10.49%) and δ-decanolactone (0.37-3.02%) (Figure 1). These findings prompt us to evaluate these compounds as anticonvulsant agents. Although the study of E-β-farnesen is limited, we found that linalyl acetate (ELISABETSKY et al. 1995), δ-decen-2-lactone and δ-decanolactone (COELHO DE SOUZA et al. 1997) were devoid of activity; linalool and γ-decanolactone (structurally related to δ-decanolactone) proved to be active in sev-

VWB – Verlag für Wissenschaft und Bildung

Linalool as Active Component of Traditional Remedies

eral animal models (ELISABETZKY et al. 1995; COSOUZA et al. 1997).

ELHO DE

Behavior experiments Animals: Male adult albino mice, strain CF-1, from Instituto de Pesquisas Biológicas (Porto Alegre, Brazil) were used throughout the study. The animals were kept on a 12 h light/dark cycle, at 22 ± 1 ∞ C, with free access to food (Nuvilab CR1) and water. All procedures were carried out according to institutional policies on experimental animals handling. Methodological considerations discussed by SWINYARD & KUPFERBERG 1985 and GLADDING et al. 1985 were taken into account. Behaviors were observed with animals placed individually in plexiglas chambers after convulsive stimuli. Pentylenetetrazol-induced convulsions: The method has been detailed elsewhere (ELISABETSKY et al. 1995). Briefly, thirty minutes after i.p. treatment with saline, linalool, vehicle or standard anticonvulsants, animals received s.c. PTZ 88 mg/kg. The presence of clonic convulsions lasting more than 3 seconds was observed (60 min). Data was analyzed by Fisher’s Exact test. Transcorneal electroshock-induced convulsions: The method has been detailed elsewhere (ELISABETSKY et al. 1995). Thirty minutes after i..p. treatment with saline, linalool, vehicle or standard anticonvulsants, animals received transcorneal electroshock (ECC, 68 mA, 0.2 sec). The presence of tonic convulsions (full extension of hind limbs) was observed (30min). Results were analyzed by means of Fisher's exact test. Interaction of linalool with standard anticonvulsants in PTZ and ECC-induced convulsions: ED50 for standard anticonvulsants and linalool were determined in PTZ and ECC-induced convulsions as described above. The interaction of linalool with standard anticonvulsants (diazepam, ethosuximide, phenobarbital and sodium valproate) was investigated in PTZ and ECC-induced convulsions by administering linalool ED50 and the ED50 of standard anticonvulsants (60 min interval). Convulsants (PTZ or ECC) were applied 30 minutes after the last drug administration. Fisher Exact test was used. PTZ-induced kindling in mice: Behavior: The method has been detailed elsewhere (SILVA et al. 1998). Mice (8 weeks old at the start of the expericurare 26(2003)3

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ment) were divided in three groups. Each treatment consisted of two drug administrations, repeated once every third day, in a total of 6 treatments. The first drug administration was an oral administration of tween (linalool vehicle), 2200 and 2500g/kg linalool. Thirty minutes after the oral treatment groups received s.c. 60 mg/kg of PTZ; controls were treated equally to experimental groups, except that both injections consisted of saline solution. Following PTZ injection animals were observed (30 minutes) for clonic convulsions lasting more than 3 seconds. Twenty-four hours after the last injection (PTZ or saline), mice were decapitated, brains were rapidly removed and binding assays performed. Differences in seizuring animals in different groups were evaluated by Fisher’s Exact test. Binding values were compared by means of one way ANOVA followed by Duncan test. Neurochemistry analysis Binding of L-[3H]glutamate: Membranes and binding assays were performed according to PEREIRA et al., 1997. Protein was measured according the method of LOWRY et al., 1951. Inhibition curve: Inhibition curve studies were carried out by incubating 100 mg membrane protein with 1000 nM L[3H]glutamate at 30∞ C for 15 min in 50 mM Tris/ HCl buffer, pH 7.4, in the presence of linalool (0.1; 0.3; 1 ; 3 or 5 mM). Saturation and competition curve: Saturation and competition curves were produced by incubating L-[3H]glutamate at increasing concentrations (40 - 3000 nM) with 100 µg membrane protein at 30∞ C for 15 min in 50 mM Tris/ HCl buffer, pH 7.4, in the absence (control curve) or presence of linalool (0.3 and 1 mM). [3H] MK801 binding: Membrane Preparation: Membranes were prepared as described by EMANUELLI et al. 1998. The binding assay was based on the method of PIGOTT et al. 1992. Inhibition curve: Inhibition curve studies were carried out by incubating 200 mg membrane protein with 2 nM [3H]MK801 at 25∞ C for 1h in 5 mM Tris/HCl buffer (pH 7.4) containing glutamate (50 µM) and glycine (30 µM) in the presence of linalool (0.1; 0.3; 1 ; 3 or 5 mM). Saturation and competition curve: Saturation and competition curves were produced by incubating [3H]MK801 at increasing concentrations (1 - 15 nM) with 200 µg membrane protein at

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Figure 2. Effects of linalool interaction with classical anticonvulsants on PTZ induced convulsions. TWE = tween, LIN = linalool, ETH = ethosuximide, PHE = phenobarbital, DZP = diazepam and VPA = sodium valproate. ** p < 0.01, Ficher Exact test.

25∞ C for 1h in 5 mM Tris/HCl buffer ( pH 7.4), containing glutamate (50 µM) and glycine (30 µM) in the absence (control curve) or presence of linalool (1 and 3 mM). [3H]muscimol binding Membrane Preparation: Membranes were prepared as described by ZUKIN et al., 1974. Binding of [3H]muscimol: The binding assay was based on the method of DEMASI et al., 1996. Inhibition curve: Inhibition curve studies were carried out by incubating 300 µg membrane protein 3 with 12 nM [ H]muscimol at 4∞ C for 30 min in 50 mM Tris/Citrate buffer (pH 7.1) in presence of linalool (0.3; 1 ; or 3 mM). [3H]Glutamate release: Cortical synaptosomes were prepared on a discontinuous Percoll gradient according to NAGY and DELGADO-ESCUETA 1984. Protein concentration was measured according to the method of LOWRY et al. 1951. Glutamate release was evaluated as previously described by MIGUES et al. 1999. [3H]Glutamate uptake: Cortical synaptosomes were prepared on a discontinuous Percoll gradient according to NAGY & DELGADO-ESCUETA 1984.

Protein concentration was measured according to the method of LOWRY et al. 1951. Results and Discussion Linalool (Figure 1) seems to be an important active component of traditionally used plant-based sedatives. Psychopharmacological in vivo evaluation of linalool revealed that this compound possesses dose-dependent marked central sedative effects, including protection against PTZ and ECC, quinolinic acid and picrotoxin induced convulsions, delayed onset of NMDA induced convulsions, hypnotic, and hypothermic properties (BARROS & ELISABETSKY 1996; ELISABETSKY et al. 1995; ELISABETSKY et al. 1999). Regarding protection against PTZ, apparently no significant interaction is seen with phenobarbital or ethosuximide, whereas significant interaction was obtained with sodium valproate and diazepam (Figure 2). In respect to protection against ECC, no interaction was seen with phenobarbital or carbamazepine, whereas significant interaction was VWB – Verlag für Wissenschaft und Bildung

Linalool as Active Component of Traditional Remedies

241

Figure 3. Effects of linalool interaction with classical anticonvulsants on ECC induced convulsions. TWE = tween, LIN = linalool, PHE = phenobarbital, VPA = sodium valproate, CBZ = carbamazepine and PHE = phenytoin. ** p < 0.01, Ficher Exact test.

obtained with sodium valproate and phenytoin (Figure 3). Considering the central role of glutamate in epileptic phenomena, the effects of linalool in glutamate associated transmission was examined. Specifically linalool was investigated in regard to: (i) its inhibition of L-[3H]glutamate and [3H]MK801 (NMDA Antagonist) binding at cortical membranes; (ii) its effects on [3H]glutamate release (basal and potassium-stimulated) and [3H]glutamate uptake in mice cortical synaptosomes; and (iii) its effects on the behavioral and neurochemical correlates of PTZ-kindling. Relevant to its mechanism of action, linalool behaves as a competitive antagonist of [3H]glutamate binding (increased Kd with unchanged Bmax in the presence of increasing linalool concentrations) (Figure 4), and as a noncompetitive antagonist of [3H]dizocilpine (NMDA antagonist) binding (decreased Bmax with no significant alteration in Kd in the presence of increasing linalool concentrations) (Figure 5) in brain cortical membranes. Linalool (1.0 and 3.0 mM) had no effect on the basal [3H]glutamate release, but significurare 26(2003)3

Figure 4. Inhibition curves and Scatchard plot (inset) of L-[3H]glutamate binding to rat cortex membranes in the presence of linalool. Membranes were incubated with increasing concentrations of L-[3H]glutamate (40-3000 nM) in the absence (♦) or presence of linalool 0.3 mM (∆) or 1.0 mM (❍). B=Bound; B/F=Bound/Free. Each point represents the mean ± SEM of four separate experiments determined in triplicate. * = p < 0.05, ** = p < 0.01, ANOVA.

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Figure 5. Inhibition curves and Scatchard plot (inset) of [3H]MK801 binding to mouse cortical membranes in the presence of linalool. Membranes were incubated with increasing concentrations of [3H]MK 801 (1-15 nM) in the absence (◆) or presence of linalool 1 mM (∆) or 3 mM (❍). B=Bound; B/F=Bound/Free. Each point represents the mean ± SEM of three separate experiments determined in triplicate. * = p < 0.05 and ** = p < 0.01, ANOVA.

cantly inhibited (28% and 31% respectively) the potassium-stimulated [3H]glutamate release (Figure 6). Linalool (0.1 - 3.0 mM) significantly decreased the [3H]glutamate uptake by mice cortical synaptosomes in a dose-dependent manner (Figure 7, IC50=1.50 ± 0.08 mM). Such modulation of glutamatergic transmission is in accordance with its ability in delaying sc NMDA-induced convulsions and blocking icv quinolinic acid-induced convulsions. The protection afforded by linalool against picrotoxin and PTZ-induced convulsions raised the hypothesis of gabaergic involvement in its mode(s) of action. However, results obtained through the binding assay used in this study do not support direct interaction with GABAA receptors (data not shown); changes in GABA-mediated neuronal inhibition or effects on GABA release and uptake cannot be ruled out. Linalool partially inhibited and significantly delayed the behavioral expression of PTZ-kindling, but did not modify the PTZ-kindling induced increase in L-[3H]glutamate binding (Figure 8).

E. Elisabetsky & L. F. Silva Brum

Figure 6. Effects of linalool on the release of [3H]glutamate from mice cortical synaptosomes. Glutamate released is expressed as a percentage of synaptosomal total radioactivity content. Data are expressed as mean ± sem from 4 independent experiments performed in triplicate. * = p
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