Bonito, Maria Carmela (2009) PHARMACOLOGICAL CHARACTERIZATION OF TERPENIC SECONDARY METABOLITES ISOLATED FROM SALVIA SPECIES. [Tesi di dottorato] (Unpublished)

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Recently most interest has been focused on active compounds extracted from natural sources. This is due to the fact that many of these natural products in plants of medicinal value can offer new sources of drugs. The genus Salvia from the Lamiaceae family has numerous different species - about 900 species- which are extensively distributed in various regions of the world. Many Salvia species are well-studied and widely used in traditional medicine. Plants belonging to the genus Salvia are of particular interest, due to the wide variety of secondary metabolites produced in these plants, such as flavonoids, tannins and terpenoids.The terpenoid class, extracted from Salvia, includes a wide range of mono-, di-, tri-, sesqui- and tetraterpenoids. Many diterpenoids and triterpenoids, isolated from plants of several species of the genus Salvia, have been investigated for their pharmacological activities: analgesic; anti-inflammatory; hemostatic; antioxidant; antimicrobial and as an antitumoral remedy. It has been widely shown that many terpenoid compounds have significant anti-inflammatory effects. For this reason, they are potential molecules for the development of new drugs especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. Some di- and triterpens from Salvia ssp are able to influence the central nervous system (CNS). In this thesis, the pharmacological effects of bioactive diterpenoids and triterpenoids from the Salvia species are investigate. In a screening programme on Salvia medicinal plants, like S. divinorum, S. cinnabarine and S. jamensis, we have find interesting biological effects. Following anecdotal reports that extracts of Salvia divinorum may possess antidiarrhoeal activity and because !-opioid receptors may modulate intestinal peristalsis we investigated the effect of Salvia divinorum, and its main active ingredient, salvinorin A, on myenteric cholinergic transmission. For this purpose we evaluated the effect of a standardized extract from Salvia divinorum leaves (SDE) and of isolated salvinorin A on the contractions elicited either by electrical stimulation or by exogenous acetylcholine in the guinea-pig ileum. These observations strongly support the hypothesis that SDE inhibits the twitch response by acting prejunctionally rather than through a direct action on intestinal smooth muscle. The hallucinogenic herb Salvia divinorum exerted inhibitory effects on enteric cholinergic transmission in 6 the guinea-pig ileum through activation of prejunctional !-opioid receptors. Salvinorin A may be the chemical constituent responsible for this activity. These results could provide the pharmacological basis underlying its traditional antidiarrhoeal use. During this PhD project the author has studied the effects in vivo of a new diterpenoid compound 3,4-secoisopimar-4(18),7,15-triene-3-oic acid (CMP 1) from Salvia cinnabarina. The possibility that CMP 1, like other isolated diterpenoids, may affect the CNS, was the main aim of these investigations. A putative anxiolytic and antidepressive activity of CMP 1 were studied in the elevated plus-maze test and in the forced swimming test. Furthermore, CMP 1 was administered after a pre-treatment with pentobarbital and its effects on sedative activity was monitored. The CMP 1 was also tested for its effects on spontaneous motor activity (total motility and locomotion) and several models of nociception have been used to examine the potential analgesic effects. These studies demonstrate for the first time that CMP 1 has pronounced CNS depressant properties, manifested as antinociception, sedation and axiolitic effects. In another study we evaluated the effect of CMP1 on arterial blood pressure in anaesthetized rats. On different groups of them treated with the ganglion-blocking agent chlorisondamine, the effect of CMP1 was evaluated before and following an infusion of the nitric oxide synthase inhibitor L-NAME. Intravenous administration of CMP1 led to a fall in mean arterial blood pressure that was not modified by treatment of the rat with chlorisondamine nor with L-NAME. The results demonstrate , for the first time, a hypotensive effect of CMP1 due to a peripheral mechanism but independent of endothelial nitric oxide release. The chemical constituents of Salvia x jamensis J. Compton and their platelet antiaggregating activity in vitro were also investigated. The surface exudate of Salvia x jamensis J. Compton, obtained by rinsing the plant material with methylene chloride and terpenic compounds 1-7 isolated have been tested on ADP-induced platelet aggregation. Among all the tested compounds, isopimaric acid 2 showed a significant concentration-dependent antiaggregating activity when ADP (3 "M) was used as agonist on rat platelets. Conversely, a new clerodane derivate 1 increased ADP– induced platelet aggregation.

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