| OBJECTIVE:Abnormally elevated excitatory neurotransmitter glutamate is neurotoxic,breaking the balance between excitatory neurotransmitters and inhibitory neurotransmitters,and then inducing nervous system dysfunction.Glutamate exerts its physiological regulation mainly through glutamate receptors.Glutamate receptor 5(mGluR5)belongs to group I metabolic glutamate receptor.It is highly expressed in the striatum of the brain and plays an important role in regulating glutamate release and affecting synaptic plasticity.Its specific antagonist,MPEP,can inhibit glutamate neurotoxic and has been proved to have brain protective effects in animal models of various nervous system diseases.This study,we used homocysteine-induced preeclampsia rat model to detect the behavioral changes of pregnant rats,and the changes of plasma inflammatory factors,oxidative stress factors,brain tissue apoptosis and related signaling pathway proteins,For investigating the molecular mechanism of mGluR5 antagonist MPEP regulation in preeclampsia-induced brain injury,so as to find a new direction for the treatment of brain damage of preeclampsia and the development of brain protective drugs.Methods: 60 SD female rats were caged at 3:1 ratio of male to female every evening.After pregnancy,pregnant rats were randomly divided into six groups:pregnancy control group(PN group),pregnancy homocysteine group(PH group),pregnancy homocysteine-MPEP group(PHM group),pregnancy homocysteine-MPEP-U0126 group(PHM + U0126 group),pregnancy homocysteine-MPEP-SB202190 group(PHM + SB202190 group),pregnancy homocysteine-MPEP-SP600125 group(PHM+SP600125 group),10 rats in each group.From the tenth day to the twentieth day of pregnancy,the PN group received intraperitoneal injection of the same amount of saline and 1% DMSO daily;the rest group used homocysteine to induce preeclampsia in rats;the PHM group received intraperitoneal injection of MPEP(1.5 mg/kg)daily;the remaining three groupsreceived intraperitoneal injection of U0126(4 mg/kg),SB202190(20 mg/kg)and SP600125(30 mg/kg)1 hour before MPEP injection to block the signal.Systolic blood pressure of caudal artery in rats was measured from the 8th day of pregnancy,once a day until the 20 th day of pregnancy;urine protein was collected by standard metabolic cage on the 8th,15 th and 19 th day of pregnancy;Morris water maze test was performed from the 15 th to 20 th day of pregnancy during the intervention period.On the 20 th day of pregnancy,the hippocampus was sacrificed and HE staining was performed to observe the changes of neurons;the expression of inflammatory factors IL-1,IL-6 and TNF-alpha in plasma and the activity of NO,NOS,SOD and GSH-Px in brain tissue were detected by ELISA;the apoptosis of brain tissue was detected by TUNEL;the behavioral changes of rats were detected by Morris water maze test;the phosphorylation of p38,JNK and ERK were detected by immunohistochemistry and Western blot.Result: 1.With pregnancy goes,Compared with PH group,proteinuria and blood pressure in PHM group decreased with the increase of gestational days(p < 0.05).HE staining of hippocampal tissue showed that the hippocampal tissue in PHM group was slightly tidy and the number of apoptotic neurons decreased compared with that in PH group.2.TUNEL results showed that the apoptosis of neurons in PHM group was significantly lower than that in PH group(P < 0.05).After inhibiting the MAPK pathway,the number of apoptotic neurons increased compared with PHM group(P <0.05).Compared with PH group,the activity time of original platform quadrant in PHM group was significantly longer(P < 0.05)and the number of times of crossing platform was increased(P < 0.05).Inhibiting the MAPK pathway could reduce the effect of MPEP..3.Compared with PH group,the levels of IL-1,IL-6 and TNF-alpha in PHM group were significantly lower(P < 0.05),and the activities of NO,NOS,SOD and GSH-Px in rat brain tissue were also decreased.After inhibiting the MAPK pathway,the effect of MPEP was basically offset.4.Immunohistochemical and Western blot results showed that the expression of ERK,JNK and p38 protein was significantly increased in PH group.After the administration of MPEP,the expression of ERK,JNK and p38 protein was decreased,suggesting that the activity of MAPK pathway was decreased.After the inhibition of MAPK signaling pathway,the expression of ERK,JNK and p38 protein was restored.CONCLUSION: This study found that mGluR5 antagonist MPEP can alleviate brain damage in preeclampsia rats,and its mechanism may be achieved by inhibiting the activity of MAPK signaling pathway. |
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