Exoplre The Potential Mechanism Of Mesenchymal Stem Cells-derived Exosomes And Nature Productions In The Treatment Of Depression Based On Neuroinflammation

Depression is a severe mental disorder,which affects more than 10% population over the world.However,current antidepressants are only effective for 50% of depressed patients with many serious side effects.A large number of studies have shown that peripheral immune inflammation and subsequent central inflammation can affect the occurrence and development of depression.Clinical studies have demonstrated that the expression of pro-inflammatory cytokines,tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),IL-6 and interferon γ in depression patients are higher than those in normal people,which can be attenuated by antidepressant.Moreover,treatments with antidepressants can increase the content of anti-inflammatory cytokines,such as IL-10 and IL-4.Therefore,the inhibition of inflammation becomes a new target for the development of antidepressant drugs.Mesenchymal stem cells(MSCs)are pluripotent stem cells with self-renewal,multiple differentiation,regulation of immune cell activity and stimulation of tissue repair.The MSCs derived exosomes(MSCs-Exo)can inhibit the inflammation.However,there is little research on Exo for treatment of neuroinflammation and depression.The present study explored whether Exo exerts a therapeutic effect on neuroinflammation and depression in LPS-induced neuroinflammation,as well as on chronic mild unpredictable stress(CUMS)-induced depression-like changes.Previous studies have reported that phosphatidylserine(PS),one of the lipid components of exosomes,have various biological activities,such as increasing learning and memory functions and improving depression symptoms.The n-3 polyunsaturated fatty acids(n-3 PUFAs)are one of the components of cell membrane phospholipids among which docosapentaenoic acid(DPA)is mainly enriched in phosphatidylethanolamine and PS.It is known that Exo can be modified in vitro to enhance its biological activity due to containing more benefitial substance and information.Therefore,this study aimed to examine whether DPA can enhance the antiinflammatory and antidepressant activities of MSCs-Exo.The results showed that exosomes obtained from DPA treatment of MSCs(DPAExo)conform to the morphological and structural characteristics of exosomes.Moreover,DPA could significantly increase the concentration of EPA,DPA and DHA in MSCs and Exo.In the BV2 cell,DPA-Exo significantly inhibited LPS-induced inflammation,such as expression of IL-1β,TNF-α and microglia activation through regulating of the NF-κB signaling pathway.In paralle,DPA-Exo markedly prevented SH-SY5 Y from apoptosis induced by LPS pre-treated BV2 culture medium(LPS-CM).Furthermore,our results of differential mi RNA showed that DPA significantly increased mi R125b-5p,which modulated NF-κB to reinforce the anti-inflammatory of exosome.As a sequence,DPA-Exo rescued the CUMS induced depression and anxietylike phenotypes.Thses results included that DPA-Exo increased the travel distance,rearing times and entries into the central area in the open field experiment.Also,the duration and entries into the open arms in the elevated plus maze were increased after DPA-Exo treatment,but the immobility time in the tail suspension test was shorten.The modulation of behavioural changes were associated with DPA-Exo attenuation of the reduction of monoamine transmitters in the brain caused by CUMS exposure.The content of monoamine neurotransmitters(5-HT,DA)and the ratio of 5-HT/5-HIAA and DA/DOPAC were increased after DPA-Exo treated in the CUMS model.Again,DPAExo could inhibit the inflammatory response caused by CUMS since DPA-Exo treatment reduced the serum,prefrontal cortex and hippocampus IL-1β and TNF-α,and increase IL-10 expression in the CUMS mice.By contrast,DPA-Exo decreased the expression of Iba1 and i NOS,increased the expression of Arg1 and CD206,and inhibited the protein level of TRAF6,My D88 and NF-κB in the hippocampus.More interesting,the effect of DPA-Exo was better than Exo in anti-inflammation and antidepressive effects.In another experiment,isoginkgetin(Iso)was used to explore the role of neuroinflammation in the treatment of depression.The present study showed that Iso markedly rescued LPS-induced depression and anxiety-like phenotypes,which included the increase in total distance,the rearing times and entries into central area in the open field test in LPS mice,increase in the time duration and number of entries to the open arms in the elevated puls tes;and decrease the immobility time in the tail suspension test.In correlation,isoginkgetin reversed the changes in the concentration of monoamine neurotransmitters(5-HT and NE)and the ratio of 5-HT/5-HIAA,NE/MHPG in hippocampus of depression model.With regards to the anti-inflammatory effects,Isoginkgetin reduced serum IL-1β concentration,which was associated with the inhibition of the expression of inflammation related pathway,p38,NF-κB phosphorylation and the microglial protein level of Iba1 in the hippocampus.Furthermore,the pretreatment with isoginkgetin significantly inhibited LPS-induced neuroinflammation of BV2 cells,including reduction of NF-κB/p65 protein transferred from cytoplasm to nucleus in BV2 cells;and suppression of inflammatory cells activation.Thus,the expression levels of IL-1β,IL-6,i NOS,ROS and COX2 could be restored by isoginkgetin.Therefore,isoginkgetin could protect SHSY5 Y apoptosis from LPS induced BV2 culture medium.In conclusion,our results indicated that DPA-Exo and Iso could inhibit neuroinflammation and produce the anti-depressive effect.This study may further enrich the role of neuroinflammation in the progression and treatment of depression,as well as provided a theoretical basis for the prevention and treatment of depression(exosomes,natural medicines or functional foods).