Study On The Analgesic And Sedative Effects Of Aquilaria Sinensi

The peeled roots,stems or twigs of Syringa pinnatifolia Hemsl.(SP)is a representative Mongolian medicine with anti-Heyi,analgesic,anti-asthma,and clearing-heat effects.It has been used for the treatment of heart tingling,heart palpitations,upset,insomnia and other symptoms.We have conducted a preliminary study on the anti-ischemic effect of ethanol extract of SP(T).And for the first time,we revealed its mechanism on PGI2/TXA2 was relevant to regulating the expression of cyclooxygenase(COX).Inspired by Mongolian medical theory and clinical practices,in addition to the application of treating heart tingling,it is also used for analgesia and sedation.This study evaluated the analgesic effect of T using three analgesic models including acetic acid writhing test,formalin test,and hot plate test.The sedative effect of T was evaluated by locomotor activity and synergistic sleeping experiments.The pharmacological mechanism of its sedative effects was explored in the hope of providing scientific basis for its clinic application.Moreover,active substances are also in the scope of present research.We have isolated zerumbone(ZER)by phytochemical study on SP,which composes 64.7%of its essential oil.However,it is the first time to obtain ZER from a nonZingiberaceae plant.ZER had also been reported to produce an analgesic effect,indicating it is the primary effective substance of SP.Therefore this research has studied the sedative effect of ZER to comfirm it is the eactive substance in SP.Review on SPAn updated progress of the chemical constituents and pharmacological effects of SP over the past five years was summarized.Recently,a total of 85 compounds were reported,including 24 lignans,32 sesquiterpenes,and 29 phytochemicals in other categories,of which 49 were new compounds.Lignans and sesquiterpenes are the major chemical constituents and active substances of SP,showing cardiomyocyte protection,tumor cytotoxicity,anti-inflammatory and antibacterial effects.Such as T,macroporous resin-separated part,and SP ultrafine powder,all have anti-myocardial ischemic effects.The potential mechanism is related to antiinflammatory and inhibiting myocardial cell apoptosis.These researches provide scientific evidence for the treatment of Heyi-type cardiopulmonary disease.In addition to the antimyocardial ischemic effects,there are also research reports on the analgesia and sedation of SP ultrafine powder,but not comprehensive enough.The updated progress shows that the bark of SP mainly contains lignans and cycloterpenoids,but no sesquiterpenes and triterpenoids have been reported.However,there are no cyclic allene terpenoids reported in the peeled roots,stems and thick branches of SP.The chemical variety among different parts of SP provides a reference for its ecological research and focuses on the top that if sesquiterpenes are produced by "agarwood production".The research object is mainly ethanol extract or mountain agaric powder,not limited to volatile oil.Analgesic and sedative effect evaluationResults of acetic acid writhing,formalin and hot plate assays have shown that T(60-230 mg/kg)can significantly reduce the writhing frequency and licking time in phase-Ⅱ and extend the thermal threshold in mice,suggesting that T has a significant analgesic effect.Results of the locomotor activity and pentobarbital collaborative experiment have shown that both T(60-230 mg/kg)and ZER(5-20 mg/kg)can reduce the sleep latency of mice,extend their sleep duration and reduce their activity,suggesting that T and ZER have a sedative effect.Mechanistic study on the sedative effect of T and ZERELISA results of T(160 mg/kg)have shown that it can increase the content of γaminobutyric acid/glutamic acid(GABA/Glu)in rat cortex,hippocampus and hypothalamus,especially a 19.2%up-regulation in hypothalamus.Immunohistochemical and Western Blot results have shown that T can up-regulate the protein expression of glutamic acid decarboxylase 67(GAD67)in hypothalamus.qRT-PCR results showed that T increased genetic expression of GABAA Rα1、α2、α3、α5、β1-3、γ1-3,and GABAA Rα2、β2、γ1 were significantly upregulated,hinting it can produce sedative effect through GABAergic nervous system.ELISA results of ZER(14 mg/kg)have shown that it can increase the content of GABA/Glu in rat cortex,hippocampus and hypothalamus,especially a 61%up-regulation in hypothalamus.Molecular docking results have shown that ZER has a strong affinity to GAD67 and gephyrin proteins,mainly through hydrogen bonding and hydrophobic interactions binding to amino acid residues.Immunohistochemical and Western Blot results have shown that ZER can up-regulate GAD67 protein which is the specific marker of GABAergic neurons and Gephyin which is the core skeleton protein of inhibitory postsynaptic protein matrix of the central nervous system.Reversal test results have shown that both flumazenil and bicuculline can reverse the effect of ZER in pentobarbital collaborative experiment,indicating that ZER can produce palliative effect through GABAA receptor.Testing the influence on chloride ion concentration in cerebellar granule cell has shown that ZER can dose-dependently increase the channel permeability of chloride ion,induce its internal flow,produce hyperpolarization by enlarging electric potential of the intracellular membrane,and reduce neuron discharge,thus producing a central nervous system inhibition.In summary,T has significant analgesic and sedative effects,and ZER has a sedative effect.Furthermore,the pharmacological mechanism of their sedative mechanism is probably associated with the GABAergic nervous system.This research therefore provides a scientific basis for the efficacy of SP in suppressing Heyi and relieving pain,hinting that ZER is the active substance of SP.These investigations provided a beneficial reference for the pharmacological researches on Syringa pinnatifolia Hemsl.