ABSTRACT
Title
Salviae neoclerodane derivatives differently affect catecholamine release in mammals brains: comparison with Salvinorin A.
Authors
G. Olivero1, S. Di Prisco1, M. Summa1, E. Giacomelli2, M. Grilli1,3, A. Bisio2, G. Romussi2, M. Marchi1,3, A. Pittaluga1,3
1 Department of Experimental Medicine, Pharmacology and Toxicology Section, University of Genoa, viale Cembrano4, 16148 Genova
2Department of Chemistry and Pharmaceutical and Food Technology, University of Genoa, via Brigata Salerno, 16148, Genova
3Center of Excellence for Biomedical Research, University of Genoa, via Leon Battista Alberti, 16100 Genova
1 Department of Experimental Medicine, Pharmacology and Toxicology Section, University of Genoa, viale Cembrano4, 16148 Genova
2Department of Chemistry and Pharmaceutical and Food Technology, University of Genoa, via Brigata Salerno, 16148, Genova
3Center of Excellence for Biomedical Research, University of Genoa, via Leon Battista Alberti, 16100 Genova
Abstract
Salvinorin A, the main active compound found in Salvia divinorium, has gained considerable interest among the scientific community. Firstly isolated from this plant in 1982, it remains one of the most potent naturally occurring hallucinogen known to mankind. Salvinorin A is a unique furanolactone, belonging to the neoclerodane class of diterpenes that acts as an highly selective and potent opioid receptor agonist. It is chemically and structurally unique from other hallucinogens, being the first known psychoactive diterpene and the first non-nitrogenous hallucinogen. Because of these chemical features, the compound could represent the prototype of a new class of compounds acting at opioid receptors, useful to therapeutic approach aimed at the cure of ansia and depression, pain and drug seeking.
In a recent work, we investigated the effects of salvinorin A on the basal and the 12 mM K+-evoked release of preloaded [3H]noradenaline ([3H]NA) from mouse hippocampal nerve terminals (synaptosomes) and of preloaded [3H]dopamine ([3H]DA) from mouse striatal synaptosomes. Our results demonstrated that salvinorin A can increase the depolarization-evoked release of [3H]NA from hippocampal terminals, while it inhibited the [3H]DA exocytosis from striatal nerve endings. The opposite effects were found to rely on the binding of the diterpene to distinct receptor repertoires. Indeed, our results led us to conclude that dand kheterodimers presynaptically located on mouse hippocampal noradrenergic terminals may account for the salvinorin A-induced facilitation of NA release, while binding of the diterpenoid to khomodimers was at the basis of the inhibitory effect salvinorin A exerted on dopamine exocytosis from striatal dopaminergic terminals. Considering the main role the two cathecolamines play in central disorders, we extended our investigation to new clerodane diterpenes isolated from Salvia jamensis (i.e the compund SJ217) andSalvia wagneriana(the compounds SW8 and SW22) were analyzed fro their ability to modify the KCl-evoked release of both [3H]DA and [3H]NA exocytosis from mouse striatal and hippocampal terminals . In particular, the ability of these compounds in mimicking or preventing salvinorinA-mediated modification to cathecolamine exocytosis was investigated. Our results unveiled a complex scenario where the abovementioned compounds differently affected cathecolamine exocytosis. In particular, SW8 mimicked Salvinorin A in inhibiting dopamine exocytosis, while SW22 and SJ217 were ineffective. On the contrary, both SW8 and SJ217 facilitated , although to a different extent, noradrenaline exocytosis, while SW22 inhibited it. Furthermore, SW22 and SW8, not SJ217, prevented the positive effects Salvinorin A exerts on [3H]NA exocytosis, while SJ217 was almost inactive. The heterogeneous profile of the compounds under study allow us to predict that these compounds may recognize different binding site on dand kopioid receptor subunits.
Supported by Italian Ministero Università Ricerca to, by European project ALCOTRA (Cooperazione territoriale europea Italia-Francia (Alpi) “AROMA”, by the European project PYRGI ( progetto Italia-Francia “Marittimo” 2007-2013) and by Compagnia di San Paolo.
In a recent work, we investigated the effects of salvinorin A on the basal and the 12 mM K+-evoked release of preloaded [3H]noradenaline ([3H]NA) from mouse hippocampal nerve terminals (synaptosomes) and of preloaded [3H]dopamine ([3H]DA) from mouse striatal synaptosomes. Our results demonstrated that salvinorin A can increase the depolarization-evoked release of [3H]NA from hippocampal terminals, while it inhibited the [3H]DA exocytosis from striatal nerve endings. The opposite effects were found to rely on the binding of the diterpene to distinct receptor repertoires. Indeed, our results led us to conclude that dand kheterodimers presynaptically located on mouse hippocampal noradrenergic terminals may account for the salvinorin A-induced facilitation of NA release, while binding of the diterpenoid to khomodimers was at the basis of the inhibitory effect salvinorin A exerted on dopamine exocytosis from striatal dopaminergic terminals. Considering the main role the two cathecolamines play in central disorders, we extended our investigation to new clerodane diterpenes isolated from Salvia jamensis (i.e the compund SJ217) andSalvia wagneriana(the compounds SW8 and SW22) were analyzed fro their ability to modify the KCl-evoked release of both [3H]DA and [3H]NA exocytosis from mouse striatal and hippocampal terminals . In particular, the ability of these compounds in mimicking or preventing salvinorinA-mediated modification to cathecolamine exocytosis was investigated. Our results unveiled a complex scenario where the abovementioned compounds differently affected cathecolamine exocytosis. In particular, SW8 mimicked Salvinorin A in inhibiting dopamine exocytosis, while SW22 and SJ217 were ineffective. On the contrary, both SW8 and SJ217 facilitated , although to a different extent, noradrenaline exocytosis, while SW22 inhibited it. Furthermore, SW22 and SW8, not SJ217, prevented the positive effects Salvinorin A exerts on [3H]NA exocytosis, while SJ217 was almost inactive. The heterogeneous profile of the compounds under study allow us to predict that these compounds may recognize different binding site on dand kopioid receptor subunits.
Supported by Italian Ministero Università Ricerca to, by European project ALCOTRA (Cooperazione territoriale europea Italia-Francia (Alpi) “AROMA”, by the European project PYRGI ( progetto Italia-Francia “Marittimo” 2007-2013) and by Compagnia di San Paolo.