Hyperlipidemia Induce Rat Depression Like Effects And The Possible Mechanism

With the quick rhythm of modern social life,the incidence of depression is higher and higher,which has become one of the main harmful diseases for human beings.There is variety of reasons in the pathogenesis of depression.However,in recent years,epidemiological studies showed that blood lipid disorder was closely related to depression.In order to investigate the relationship between serum lipids and depression,based on the previous research,we further study the role of hyperlipidemic in depression and the possible mechanism.We established the hyperlipidemic rat model by feeding high fat diet.The changes of blood lipid and depression index were detected.The results showed that TC,TG and LDLC level increased in hyperlipidemic rats,while HDLC,which meant that the model was established successfully.Hyperlipidemic rats appeared some changes related with depression,such as decreasing of the percentage of drinking sugar water in sucrose preference test(SPT)and Serum brain-derived neurotrophic factor(BDNF)level(P<0.05),and increasing of serum corticosterone(CORT)(P<0.05)and the content of aspartate,glutamate and lipoprotein lipase in hippocampus(P<0.05).But the forced swimming test(FST)data and the content of monoamine neurotransmitters(dopamine(DA)),norepinephrine(NE),5-hydroxytryptamine(5-HT))and inhibitory neurotransmitter(glycine and r-amino butyric acid(GABA))didn' t show any obvious difference.At the same time,simvastatin treatment could decrease the serum level of corticosterone(P<0.05)and the content of aspartate and glutamate in hippocampus(p<0.05),increase the serum level of BDNF(P<0.05)and the percentage of drinking sugar water in SPT(P<0.05).These results indicated that the hyperlipidemia could cause some depression-like effects in rats.In order to verify the effect of hyperlipidemia on depression,we established the hyperlipidemia-depression hybrid models with the chronic unpredictable stimulation.We find that hybrid model rats kept high levels of blood lipids,and appeared more signs of depression.Compared with the pure depression model group,hybrid model rats showed more obvious effects in increasing serum corticosterone(CORT)and the content of hippocampus aspartate,glutamate and lipoprotein lipase,and in decreasing serum BDNF and 5-HT in hippocampus.And in histopathology,the pyramidal cells become significantly fewer,disordered in hippocampal C2 and C3 regions,and even the emergence of glial cells in C1 and C2 area in hybrid model rats.These results suggested that hyperlipidemia aggravated the symptoms of depression.The above study demonstrated that the hyperlipidemia can cause the early slight change of depression(anhedonia)and increase the depressed lesions.But its mechanism maintained unclear.Due to the phenomenon that hyperlipidemia couldn' t regulate the content of 5-HT in hippocampus,hyperlipidemia should affect depression through other signal pathway.In recent years,many researchers revealed the effect of inflammation theory in depression.We surmised the inflammatory pathways may be a bridge in hyperlipidemia inducing depressive-like change.Based on this assumption,we explored the changes of P2X7/NLRP3 inflammasome pathways in hyperlipidemia rats.The result showed that both of mRNA and protein level of P2X7,NLRP3,ASC,Caspase 1 and IL-1? increased,which led higher IL-1 ? content in hippocampus.Correlation analysis revealed the close link between the hippocampus IL-1 ? content and hyperlipidemia-induced depression.To further investigate the role of IL-1?,we used P2X7 receptor antagonist brilliant blue G(BBG),and caspase 1 inhibitor V-YVAD-FMK to observe the inflammatory pathways and depression indicator changes in hyperlipidemia rats.And we found blocking treatment of any step in inflammatory pathway could reduce IL-1(3 production and brain tissue injury,inhibit rat behavior changes and promote BDNF induction,which could enhance nerve cells growth and reconstruction.Theses date supported our assumption,namely,hyperlipidemia induced depression through P2X7/NLRP3 inflammasome pathway activation and IL-1?expression increase.In conclusion,(1)this study found that hyperlipidemia could induce depression like effects in rats.(2)hyperlipidemia could aggravate depression in rats.(2)Further research revealed that inflammasome pathway activation and IL-1? expression increase was the potential mechanism of hyperlipidemia-inducing depression.These results would provide the theoretical basis for the prevention and cure of depression,and new targets for anti-depression drug R&D..