Salvinorin A alleviating cerebral vasospasm after subarachnoid hemorrhage through phosphatidylinositol 3-kinase/protein kinase B/endothelial nitric oxide synthase pathway / 解剖学报

Objective To investigate the effect of salvinorin A (SA) on alleviating cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH). Methods The SAH models were established by endovascular perforation method. Adult male SD rats (n = 91) were randomly divided into the sham group (sham), SAH model group (SAH), control group (SAH+DMSO) and drug administration group (SAH + SA). SA and DMSO were diluted with saline, and injected intraperitoneally at hour 24, hour 48 and hour 72 after SAH. At hour 72 after SAH, the neurological score was evaluated. The diameter and wall thickness of the internal carotid artery were observed through HE staining. Endothelin 1 (ET-1) ELISA kit and nitric oxide (NO) kit were used to observe the ET-1 concentration and NO content on the blood vessels of Willis circle. The expression of phosphorglated PI3K (p-PI3K), PI3K, phosphorylated Akt (p-Akt), Akt and endothelial nitric oxide synthase (eNOS) proteins were detected by Western blotting and the location of eNOS protein was observed by immunofluorescent staining. Results At hour 72 after SAH, SA could increase the neurological score, increase the vessel diameter and reduce the wall thickness of internal carotid artery. SA could reduce the ET-1 concentration and increase NO content in the blood vessels of Willis circle at hour 72 after SAH. SA could increase the ratio of p-PI3K/PI3K, p-Akt/Akt and the expression of eNOS proteins, which could be inhibited by PI3K inhibitor wortmannin and eNOS inhibitor L-NAME. eNOS expressed in vascular endothelial cells was detected by the immunofluorescence staining. Conclusion SA can alleviate CVS after SAH through PI3K/Akt/eNOS pathway.

Salvinorin A preserves cerebral pial artery autoregulation after forebrain ischemia via the PI3K/AKT/cGMP pathway

This study aimed to investigate the protective effect of salvinorin A on the cerebral pial artery after forebrain ischemia and explore related mechanisms. Thirty Sprague-Dawley rats received forebrain ischemia for 10 min. The dilation responses of the cerebral pial artery to hypercapnia and hypotension were assessed in rats before and 1 h after ischemia. The ischemia reperfusion (IR) control group received DMSO (1 µL/kg) immediately after ischemia. Two different doses of salvinorin A (10 and 20 µg/kg) were administered following the onset of reperfusion. The 5th, 6th, and 7th groups received salvinorin A (20 µg/kg) and LY294002 (10 µM), L-NAME (10 μM), or norbinaltorphimine (norBIN, 1 μM) after ischemia. The levels of cGMP in the cerebrospinal fluid (CSF) were also measured. The phosphorylation of AKT (p-AKT) was measured in the cerebral cortex by western blot at 24 h post-ischemia. Cell necrosis and apoptosis were examined by hematoxylin-eosin staining (HE) and TUNEL staining, respectively. The motor function of the rats was evaluated at 1, 2, and 5 days post-ischemia. The dilation responses of the cerebral pial artery were significantly impaired after ischemia and were preserved by salvinorin A treatment. In addition, salvinorin A significantly increased the levels of cGMP and p-AKT, suppressed cell necrosis and apoptosis of the cerebral cortex and improved the motor function of the rats. These effects were abolished by LY294002, L-NAME, and norBIN. Salvinorin A preserved cerebral pial artery autoregulation in response to hypercapnia and hypotension via the PI3K/AKT/cGMP pathway.

Salvia divinorum: enigma psicofarmacológico y resquicio mente-cuerpo / Salvia divinorum: psychopharmacologicai enigma and the mind-body interstice

En el presente trabajo se considera la investigación multidisciplinaria sobre Salvia divinorum y sus principios químicos activos con el objeto de valorar si la etnobotánica, la fitoquímica, la psicofarmacología y la neurofarmacología de esta planta psicoactiva y su principal producto químico, la salvinorina A, clarifican sus efectos mentales y sus usos adivinatorios. Esta labor científica ha trascurrido desde el registro inicial de ceremonias y creencias, ha continuado con la identificación botánica, el aislamiento de los principios químicos, la caracterización de los efectos mentales y cerebrales, las posibles aplicaciones terapéuticas y ha llegado a incurrir en el problema mente-cuerpo. Dado que el punto de partida de esta investigación es la transdisciplina de la etnofarmacología, se retoman aquí las creencias tradicionales, los usos rituales y los efectos mentales de esta menta sagrada de los indios mazatecos tal y como fueron registrados durante un proyecto de campo y laboratorio llevado a cabo entre 1973 y 1983. Un brebaje acuoso de hojas maceradas produjo un breve periodo de ligereza cefálica, disforia, sensaciones táctiles y propioceptivas exacerbadas, un sentido de despersonalización, percepción amplificada de sonidos y un aumento de la imaginación visual y auditiva, pero no verdaderas alucinaciones. Posteriormente otros autores describieron efectos similares usando cuestionarios y eventualmente fueron imputados al diterpeno salvinorina-A, pero no es posible explicar los efectos mentales sólo por la potente actividad agonista del receptor kappa a los opioides encontrada para la salvinorina; de allí el enigma psicofarmacológico. Se proponen algunos requerimientos para una clasificación de drogas que alteran cualitativamente el estado de conciencia e incluyen la activación de redes neuronales que necesariamente comprenden diversos sistemas neuroquímicos y módulos nerviosos. Para caracterizar estas redes será necesario emprender un tipo de investigación top-down, es decir el análisis de imágenes cerebrales obtenidas durante la experiencia psicoactiva analizada mediante un método narrativo, lo cual eventualmente podría permitir la exploración de efectos étnicos diferenciales. Como sucede con otras preparaciones que alteran la conciencia, una investigación rigurosa de la psicofarmacología de esta planta y su principio psicoactivo será relevante a empresas académicas tan diversas como el problema mente-cuerpo, la mejor comprensión del éxtasis chamánico y la posible generación de fármacos analgésicos, antidepresivos y moderadores de la drogadicción.

In the present paper, the multidisciplinary research on Salvia divinorum and its chemical principles is analyzed regarding whether the ethnobotany, phytochemistry, psychopharmacology, and neuropharmacology of this sacred psychoactive plant and main principle clarify its experienced effects and divinatory uses. The scientific endeavor traverses from the recorded traditional ceremonies and beliefs, continues with the botanical identification, the isolation of active molecules, the characterization of mental and neural effects, the possible therapeutic applications, and impinges upon the mind-body problem. The departure point of this search is ethnopharmacology, and therefore the traditional beliefs, ritual uses, and mental effects of this Mazatec sacred mint recorded during a 1973-1983 field research project are described. A water potion of crushed leaves produced short-lasting light-headedness, dysphoria, tactile and proprioceptive sensations, a sense of depersonalization, amplified sound perception, and increased visual and auditory imagery, but no actual hallucinations. Similar effects were described using questionnaires and are attributable to the diteprene salvinorin A, but cannot be explained solely by its specific and potent brain kappa-opioid receptor agonist activity. Some requirements for a feasible classification and mechanism of action of consciousness-altering products are proposed and include the activation of neural networks comprising several neurochemical systems. Top-down analyses should be undertaken in order to characterize such neural networks and eventually allowing to explore the differential ethnic effects. As is the case for other consciousness-altering preparations, a careful and encompassing research on this plant and principle can be consequential to academic undertakings ranging from the mind-body problem and a better understanding of shamanic ecstasy, to the potential generation of analgesic, antidepressant, and drug-abuse attenuating products.

Salvia divinorum Epling & Játiva (Maria Pastora) e Salvinorina A: crescente uso recreacional e potencial de abuso / Salvia divinorum Epling & Játiva (ska María Pastora) and Salvinorin A: increasing recreational use and abuse potential

A planta Salvia divinorum Epling & Játiva (SDI), da família Lamiaceae, tem sido usada por séculos pela cultura mazateca e vem ganhando popularidade como droga recreacional nos últimos anos. Seu princípio ativo - Salvinorina A (SA) - é agonista dos receptores opióides kappa, com potencial psicotrópico. A utilização da planta vem crescendo na Europa e na América do Norte, apesar de ainda não existirem provas concretas sobre abuso. A presente revisão da literatura contemporânea aborda as evidências sobre o potencial de abuso de SDI, bem como o crescente uso recreacional, ainda que seja alucinógeno permitido legalmente e de fácil compra em muitos países.

The plant Salvia divinorum Epling & Játiva (SDI), of the Lamiaceae family, has been used for centuries by the Mazateca culture and has gained popularity as a recreational drug in the last years. Its active principle, Salvinorin A (SA), is a potentially psychotropic agonist of the kappa opioid receptors. The use of SDI has increased in Europe and North America, although there are no concrete proofs about abuse. The present review discusses current evidence on potential SDI abuse, as well as its increasing recreational use, although it is considered a legalized hallucinogen easily acquired in many countries.