Activation Of Dectin-1 By β-glucan From Yunnan Fungus Enhances Synaptic Excitability And Produces Antidepressant Effect

Depression is a common mood disorder affecting millions of people in China.The incidence of depression is increasing,and the patients with major depressive disorder experience suicidal thoughts.The pain caused by these diseases to the patients and their families,and the cost to the society,are tremendous.However,at present,the majority of the first-line drugs for depression in China are imported and/or produced by joint-venture.Most of these drugs share the common disadvantages,including slow-onset,low-efficiency and multiple side-effects.Therefore,scientists have struggled to develop novel antidepressant drugs with properties of rapid onset,novel pharmacological mechanism,and less side-effects.From the perspectives of traditional Chinese medicine,many edible fungi have medicinal effects on physical rehabilitation and they have been used as herbal medicine for prevention and treatment of diseases.My doctoral research projects include three separate studies based on the activation of Dectin-1 receptor by β-glucan from Yunnan fungus as the target,which investigated the antidepressant effect of 1)edible and medicinal wild fungus Grifola frondosa rich inβ-glucan,2)Grifola frondosa proteo β-glucan,and 3)Lentinus edodes P-glucan,and their possible mechanisms.In the studies above,male CD-1 mice were used as the animal models.The mice were treated with Grifola frondosa rich in β-glucan,Grifola frondosa proteo β-glucan,or Lentinus edodes β-glucan respectively for various time periods and tail suspension and forced swim tests,were carried out to evaluate the antidepressant effect of the these"drugs".Open field test were conducted to evaluate their safety.Then,the protein expression levels of the β-glucan receptor Dectin-1,as well as the levels of AMPA receptor GluA1 S845 phosphorylation,GluAl,GluA2 and GluA3 in the prefrontal cortex and synaptic components were determined by Western blot analysis.Finally,the Dectin-1 or AMPA receptor-specific antagonists were used to further determine whether the antidepressant effect of the Grifola frondosa,Grifola frondosa proteo P-glucan,and Lentinus edodes P-glucan were mediated through Dectin-1 receptor and/or AMPA receptors or not.(1)The results of the study on Grifola frondosa rich in β-glucan demonstrated that Grifola frondosa-containing chow(1:4,1:2,1:1)significantly reduced the immobility time in the tail suspension and forced swim tests afte 1 day or 5 consecutive days of treatment in mice(P<0.01);And Grifola frondosa did not show a hyperactive effect in open field test(P>0.05);Compared with the same dose of Pleurotus ostreatus(1:2),Grifola frondosa showed a strong antidepressant effect(P<0.01);The consumption of Grifola frondosa-containing food were significantly higher than that of normal food(P<0.01);Moreover,AMPA specific antagonist GYKI 52466 was able to block the antidepressant effect of Grifola frondosa(P<0.01).(2)The results of the study on Grifola frondosa proteo P-glucan indicated that treatment with different dosages(5,8,12.5 mg/kg)of Grifola frondosa proteo P-glucan in the tail suspension and forced swim tests showed that Grifola frondosa proteo P-glucan demonstrated a rapid and stable antidepressant effect after 60 minutes or 5 consecutive days of treatment in mice(P<0.01);And Grifola frondosa proteo P-glucan did not show a hyperactive effect in open field test(P>0.05);The results of immunoblotting showed that the Grifola frondosa proteo P-glucan significantly increased the expression of its receptor Dectin-1 in the prefrontal lobe after 5 consecutive days of treatment(P<0.01);Dectin-1 specific antagonist Laminarin was able to effectively block the antidepressant effect of Grifola frondosa proteo P-glucan(P<0.01);Grifola frondosa proteo P-glucan significantly increased the phosphorylation level of GluA1 S845(P<0.01),but not GluAl,GluA2 and GluA3(P>0.05)in the prefrontal lobe and synaptic components after 60 minutes of treatment in mice;Grifola frondosa proteo β-glucan significantly increased the expression of the phosphorylation level of GluA1 S845,and GluAl in the prefrontal lobe,as well as the phosphorylation level of GluA1 S845,GluA1,GluA2,and GluA3 in synaptic components after 5 consecutive days of treatment in mice(P<0.01);Moreover,Grifola frondosa proteo β-glucan’s antidepressant effects and the increase of the phosphorylation level of GluAl S845 and GluAl lasted for 3 days after stopping treatment(P<0.01);AMPA noncompetitive antagonist GYKI 52466 was able to effectively block the antidepressant effect of Grifola frondosa proteo β-glucan(P<0.01).(3)The results of the study on Lentinus edodes P-glucan showed that Lentinus edodes P-glucan(20 mg/kg)significantly reduced the immobility time in the tail suspension and forced swim tests afte 60 minutes of treatment in mice(P<0.01);The results of immunoblotting showed that the Lentinus edodes P-glucan significantly increased the expression of its receptor Dectin-1(P<0.01),but not TLR2(P>0.05)in the prefrontal lobe after 5 consecutive days of treatment;Moreover,Dectin-1 specific antagonist Laminarin was able to effectively block the antidepressant effect of Lentinus edodes P-glucan(P<0.01).All these studies showed that Grifola frondosa rich in β-glucan,Grifola frondosa proteo β-glucan,or Lentinus edodes β-glucan are novel antidepressants of clinical potential with the rapid and prolonged antidepressant effects.Their antidepressant effects are mainly mediated through the activation of Dectin-1 and by enhancement of the AMPA synaptic excitability.These findings will provide a new theoretical basis for the development of novel antidepressant drugs.