| Objective:Amyotrophy lateral sclerosis(ALS)is a kind of gradual progress,serious fatal neurodegenerative disorders,with no effective treatments available at present.It is reported that all-trans retinoic acid(ATRA)possesses the preventive effect on the progression of ALS,however,still has not acquired the exact studied data to determine the hypothesis up to now.To this end,we investigated possible effects of ATRA on neurons death of spinal cord in Tg(SOD1*G93A)1Gur mice.Methods:Twelve Tg(SOD1*G93A)1Gur mice(TG)mice and 12 wild-type(WT)mice were divided into 4 groups: The ATRA+olive oil treatment TG group,the olive oil treatment TG control group,the ATRA+olive oil treatment WT group,the olive oils treatment WT control group.ATRA treatment mice were given 3mg/kg body weight ATRA per day and non ATRA treatment mice given same volume of olive oil for the same time by oral gavage,continued to the sacrifice time point from 85 to 118 days of life time.Spinal cord were isolated at different experimental time point for Western blot and immunofluorescence analysis after performed to evaluate the body weight,the wire hand test(Motor function)and the ALS Therapy Development Institute(ALSTDI)score at the design time schedule.Results:1.No significant changes in body weight were observed in wild-type and SOD1 G93 A mice after ATRA treatment.2.SOD1 G93 A mice in ATRA group began to use the drug at the age of 85 days,and the ALSTDI score of SOD1 G93 A mice in ATRA group reached 2 points two days later than that in the control group(ATRA intervention group: 97+2.45days;Control group: 95+3.32 days;P > 0.05);The ALSTDI score of SOD1 G93 A mice in ATRA group reached 3,which was delayed for 7 days(ATRA intervention group: 113+3.32 days;Control group: 106+3.87 days;P >0.05),but there was no statistical difference in the above.3.The hanging wire test showed that SOD1 G93 A mice in ATRA intervention group were treated at 115 days(ATRA intervention group: 57+5 sec;Control group:45+3 sec;P <0.05)and 118 days(ATRA intervention group: 31+6 sec;Control group:22+3 sec;P <0.05)was significantly better than the control group.4.Western blotting analysis showed that the expressions of RAR,ALDH1A2,UBE3 A,NNT and NGF in the lumbar cord of SOD1 G93 A mice were significantly decreased,and the expressions of SOD1,FUS and TDP43 were significantly increased.The expressions of RAR,ALDH1A2,UBE3 A,NNT and NGF in mice treated with ATRA were increased compared with those in the control group of SOD1 G93 A,while the expressions of SOD1 and TDP43 were decreased.5.Immunofluorescence analysis showed that the expression of NeuN and NGFR in the spinal cord of SOD1 G93 A mice was decreased,while the expression of GFAP was increased.NeuN and NGF expression were both increased and GFAP expression was decreased after ATRA treatment compared with SOD1 G93 A control group.Conclusions:In our study,our data determined that preventive and/or suppressed effects of ATRA in the progression of ALS actualized through regulating the abnormal alteration of RA signal transduction pathway(RAR?,ALDH1A2),ALS pathogenic proteins(SOD1,TDP43),the protein degradation enzyme(UBE3A),the oxidative stress(NNT,TRX),neurotrophic factors(NGF and NGFR)and the neurons death in ALS-like mice.In conclusion,these results demonstrated prevent and/or suppress effects on ALS. |
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