| Objective:Amyotrophic lateral sclerosis(ALS)damages the upper and lower motor neurons and gradually leads to the gradual atrophy of the bulbar(muscles innervated by the medulla oblongata),limbs,trunk,chest and abdomen.The pathogenesis is still unclear.Studies have found that 5-HT in patients with amyotrophic lateral sclerosis affects the survival rate of patients.Therefore,we studied the possible mechanism of increased 5-HT levels on the death of spinal cord neurons in the SOD1*G93A transgenic mouse model of ALS.Methods:The experiment was divided into two groups,each with two serotonin reuptake inhibitors(SSRI)intervention,namely Paroxetine(Paroxetine)and Sertraline(Sertraline).In each group,12 SOD1*G93A transgenic mice(TG)and 12 wild-type mice(WT)were divided into 4 groups: drug-treated TG group,saline-treated TG group,drug-treated WT group,and saline-treated WT group.The mice in the SSRI intervention group were given 5mg/kg.d SSRI normal saline suspension,and the control group was given the same volume of normal saline.The TG mice developed ALS-like symptoms and started the administration.The Paroxetine group was administered until the TG mice died.The Sertraline group TG The mice had severe hindlimb paralysis and stopped the administration.At different time points,the mice were observed and recorded their body weight,hanging wire test and ALSTDI score.After the Sertraline group,the spinal cord of each mouse was separated for Western Blot and immunofluorescence analysis.Results:1.After SSRI intervention,there was no significant change in the body weight of wild-type and SOD1 G93 A mice.2.The ALSTDI score showed that the time to reach 1 point for SOD1 G93 A mice in the Paroxetine group was delayed by 4.5 days than the control group(p>0.05),which was not statistically significant;the time to reach 2 points for SOD1G93 A mice in the Paroxetine group was delayed by 4.5 days(P>0.05),no statistical significance;the time to reach 3 points for SOD1 G93 A mice in the Paroxetine group was delayed by 4.5 days(p>0.05),no statistical significance;the time to reach 4points for SOD1 G93 A mice in the Paroxetine group It was postponed for 3 days(p>0.05),which was not statistically significant;The arrival of SOD1 G93 A mice in the Sertraline group was 3 days later than the control group(p>0.05),which was not statistically significant;when the ALSTDI of the mice reached score 2,the intervention group was 4.5 days later than the control group(p>0.05),no statistics Academic significance: At score 3,the intervention group was delayed by 4.5 days compared with the control group(p>0.05),which was not statistically significant.3.The thread-drawing test showed that there was no significant difference between the thread-drawing results of the Paroxetine group and the control group;the thread-drawing results of the Sertraline group were better than those of the control group from 100 days,P<0.05,the difference was statistically significant;4.Western blot analysis Sertraline group SOD1 G93 A mouse lumbar spinal cord TFAM,NRF1 expression significantly decreased,h SOD1,FUS and TDP43 expression significantly increased.After Sertraline intervention,the expressions of TFAM and NRF1 were increased compared with SOD1 G93 A control mice,while the expressions of FUS and TDP43 decreased.5.Immunofluorescence analysis showed that the expressions of IBA1 and GFAP in the spinal cord of SOD1 G93 A mice decreased.After Sertraline intervention,the expressions of IBA1 and GFAP were all decreased compared with SOD1 G93 A control mice.6.Immunohistochemical analysis showed that CHAT in the anterior horn of the spinal cord of SOD1 G93 A mice was reduced;there was no significant difference after Sertraline intervention.Conclusions:In our research,our results show the protective effect of SSRI on the progression of ALS,promote the degradation of ALS-related pathogenic proteins(FUS and TDP43),and inhibit microglia(IBA1)and astrocytes(GFAP).)Activation.In summary,these results show the mitigation and protection effects of SSRI on ALS. |
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