Anti-inflammatory And Antipruritic Effects Of (+) Borneol And The Molecular Mechanisms

Itch is an unpleasant feeling,which can lead to the desire to scratch,have a negative impact on people's psychological and physiological aspects,and seriously reduce the quality of life of patients.It is a painful symptom,covering the clinical symptoms of various skin diseases,nervous system diseases,systemic diseases and mental diseases.The causes of itch are extremely complex and involve many factors,while itch persists for a long time,often accompanied by depression,insomnia,anxiety and other symptoms.However,the mechanism of itch is still unclear.The main topical antipruritic drugs include corticosteroids and calcineurin inhibitors.Other treatments include topical and oral antibiotics,phototherapy and systemic immunosuppressive agents.But at present,there are many limitations in the treatment of drugs,so it is of great clinical significance to find an antipruritic drug with definite curative effect and less toxic side effects.The molecular mechanism of itch is complex.The causes of itch are various.Its mechanism is mainly divided into cellular mechanism and molecular mechanism.Among the cellular mechanisms involved are: epithelial cells,which are the main components of the epidermis,secrete mediators to nerve endings,activate primary sensory neurons to produce itching;and mast cells,dendritic cells,central granulocytes,macrophages,which release a variety of inflammatory mediators to produce allergic itching,and various inflammatory skin diseases;and adaptive immune system;Interaction with the nervous system also plays a key role in the pathogenesis of itch.Molecular mechanisms are related to itch,including thymic stromal lymphocyte growth factor(TSLP),histamine and histamine receptors,5-hydroxytryptamine(5-HT),Toll-like receptors(TLR),Mas-related G protein-coupled receptors(Mrgprs),and transient receptor potential channel(TRP).Studies have shown that TRP channels are divided into several large families and play a widespread role as receptors in various aspects of the human body,such as skin,respiratory tract,nasal cavity,etc.Physical or chemical stimulation of primary nociceptors can mediate itching and pain.Current studies have found that the formation and transmission of itching sensation are closely related to some ion channels: some channels are activated to cause itching,while others are activated to inhibit itching.Therefore,blocking itch formation from the source of sensation with ion channels as targets may be a new way to treat itching.(+)Borneol,as a commonly used traditional Chinese medicine,has been included in the Chinese Pharmacopoeia,and has a long history in many fields of clinical application of traditional Chinese medicine.Since the twentieth century,(+)Borneol has been widely used in clinic to relieve itching and treat skin diseases such as febrile rash."Removing swelling and pain,clearing away heat and dispersing toxins" is another important role of(+)Borneol.Is described in Chinese medicine as "laborious in taste and cool in nature" and is used for "red eyes,sores,sores,sores,sores,sores,sores,sores,etc.It has also been proved in clinic that(+)Borneol has a good anti-inflammatory effect.However,at present,the research on anti-inflammatory and anti-itching of(+)Borneol is only at the level of clinical application,and there is no single study on the anti-inflammatory and anti-itching mechanism of(+)Borneol.In order to explore the anti-inflammatory and anti-itch mechanism of(+)Borneol and promote the in-depth study of this ancient Chinese medicine,a series of animal and molecular biological experiments were carried out in this study.Firstly,we established Histamine-induced acute itching model,CQ-induced acute itching model of non-histamine pathway induced by chloroquine,and GRP-induced acute itching model directly acting on the central nervous system.In addition,we also used chronic itching models closely related to clinic,such as psoriasis model induced by IMQ,SADBE-induced chronic itching model.Allergic contact dermatitis ACD.According to the statistics of animal behavioral results,it was found that(+)Borneol had significant antipruritic effects in three different models of acute itching,including histamine,chloroquine and GRP,and in the chronic itching models of IMQ and SADBE,which were closely related to clinic.TRPM8 is a menthol receptor expressed on peripheral afferent nerves and can be activated by cold and menthol ion channels.For centuries,cooling or applying a cool liniment to the skin has been considered a routine treatment for itch.Considering that(+)Borneol can induce a sense of cooling and has a similar chemical structure and molecular weight to menthol,we infer that TRPM8 channel is a potential cellular mechanism for inducing itch relief,thus stably expressing mTRPM8 channel gene in HEK293 cells and in vitro.A series of calcium imaging experiments were carried out on cultured DRG neurons of newborn mice to demonstrate the activation of TRPM8 channel by(+)Borneol.Then we further explored the relationship between(+)Borneol's antipruritic effect and TRPM8 channel by using TRPM8 inhibitors.The results showed that there was no difference in the number of itching between TRPM8-blocked mice and wild-type mice born in the same litter,which means TRPM8 was not the direct molecular pathway causing itching.However,the number of itching increased significantly in the(+)Borneol group when the TRPM8 channel was blocked by inhibitors compared with the wild(+)Borneol group,suggesting that the anti-itching effect of(+)Borneol was reversed after the TRPM8 channel was blocked.In other words,the anti-itching effect of(+)Borneol depended on the TRPM8 channel.This discovery fully demonstrates that TRPM8 is a new molecular target of antipruritic drugs,and promotes the study of the antipruritic mechanism of(+)Borneol,an ancient Chinese medicine,and further clarifies the specific molecular mechanism of(+)Borneol's antipruritic effect by using modern scientific theory.(+)Borneol has anti-itching effect,and anti-inflammation is also one of the main effects of(+)Borneol reported in the literature,but its mechanism has not been conclusively determined.Contact allergic dermatitis(ACD)is an inflammatory reaction that occurs at the contact site of skin or mucosa after contact with exogenous substances.The specific manifestations are erythema,swelling,papules,blisters and even bullae.Often accompanied by a strong itching sensation leads to a vicious circle of disease development of "inflammation-Scratch-skin lesion-aggravating inflammation".Therefore,this study explored the anti-inflammatory mechanism of(+)Borneol using ACD chronic itching model.The results showed that(+)Borneol could significantly improve the inflammation phenotype of ACD model in mice.On the basis of the good anti-inflammation effect reflected by HE staining and toluidine blue staining,it was found that(+)Borneol could reduce the levels of inflammatory factors IgE,IL-4,IL-1beta,IL-17,IL-5 and TNF-alpha in serum of ACD mice,and inhibit the mouse model-making Department at the gene level.The expression of TNF-alpha,IL-4,IL-5,IL-17 and IL-23 mrna.It is suggested that(+)Borneol may be involved in Th1/Th2 immunoregulation,reducing the accumulation of inflammatory mediators and thus inhibiting inflammation.To sum up,animal experiments have proved that(+)Borneol has a good anti-inflammatory and anti-itching effect.Calcium ion imaging showed that(+)Borneol could specifically stimulate TRPM8-expressing HEK cells and endogenous TRPM8 channel in rat dorsal root ganglion(DRG).It was proved that(+)Borneol's antipruritic effect was closely related to TRPM8 in mice that inhibited TRPM8 channel.In addition,in mouse ACD model(+)Borneol may participate in Th1/Th2 immune regulation,reduce the accumulation of inflammatory mediators and thus inhibit the effect of inflammation.Our research,using modern scientific means,elaborated the molecular biological mechanism of anti-inflammatory and anti-itching effect of(+)Borneol.At the same time,we hope to make people realize that there are still many treasures of traditional Chinese medicine waiting for us to explore.Through the theory and method of modern biology science,the function of traditional Chinese medicine is clarified,which provides modern theoretical guidance for the development and promotion of traditional Chinese medicine.