| Aim: To study the detoxification effect of high expression NQO1 on toxicity of quinone,and on Parkinson’s disease and levodopa induced dyskinesia,to further explore the prevention and treatment of levodopa induced dyskinesia.Methods: The highly expressed NQO1(NAD(P)H quinone oxidoreductase 1)transgenic mice successfully constructed in our laboratory were bred and amplified.In addition,C57BL/6J wild-type mice were intraperitoneally injected with sulforaphane(SF),in order to induce high expression of NQO1 in vivo.The acute toxicity test of hydroquinone(HQ)was performed on transgenic mice with high expression of NQO1,wild-type mice and wild-type mice induced by intraperitoneal injection of sulforaphane.The model of Parkinson’s disease was established by injecting 6-OHDA into the one side of the striatum.The behavioral indexes of mice with Parkinson’s disease were measured and recorded by cylinder test and amphetamine-induced ipsilateral rotation test of injured side.The damage degree of dopamine cells in the substantia nigra was observed and compared by immunohistochemical examination of paraffin sections in different groups of mice.Mice with similar behavioral data in Parkinson’s disease model were selected and the model of levodopa induced dyskinesia was established by long-term intraperitoneal administration of levodopa(L-DOPA)and Benserazide Hydrochloride.During administration,the severity of dyskinesia among mice with high expression of NQO1,wild-type mice and wild-type mice injected with SF were compared by the cylinder test and AIM behavioral experiments.The damage of dopamine cel s in the brain of each group was observed by immunohistochemistry.Results:1.In acute hydroquinone toxicity test,the survival time of Tg27 and Tg39 in the NQO1 transgenic mice was longer than that of the wild-type mice(P<0.05),and the survival time of the wild-type mice induced by sulforaphane was more longer than that of the wild-type mice(P<0.01).The results showed that the high expression of NQO1 had obvious preventive effect on the toxicity of hydroquinone.2.Two weeks after the model of 6-OHDA Parkinson’s disease,the percentage of use of left forelimb in each experimental group was lower than that in sham-operated group,and the percentage of use of left forelimb in Tg39 group was lower than that in the sham-operated group(P<0.05),the wild-type experimental group was significantly lower than that in the sham-operated group(P< 0.01).In amphetamine-induced rotation test,the number of rotation circles to the right in the experimental group was more than that in the sham-operated group,and the number of right rotations of Tg27 and SF groups were more higher(P<0.05),Tg39 mice was much more higher than that in the sham-operated group(P< 0.05),the number of right rotations of wild-type experimental group was significantly higher than that in the sham-operated group(P< 0.001).The results of immunohistochemistry showed that compared with sham-operated mice,the damage degree of the right side of substantia nigra dopaminergic cells of each experimental group was significantly higher than that of the sham-operated mice(P< 0.001).The loss of dopaminergic cells in substantia nigra of Tg27 and SF(50 mg/kg)group was more lower than that of wild-type experimental group(P< 0.05).The behavioral and immunohistochemical results indicated that the Parkinson’s disease model mice were successfully constructed.3.During the establishment of levodopa-induced dyskinesia model,with the increase of dose of levodopa,there was no abnormal involuntary movement in normal saline group and sham-operation group,and the degree of dyskinesia in the experimental group became more and more serious.Compared with wild-type mice,the degree of levodopa-induced dyskinesia of Tg27 and Tg39 in NQO1 transgenic mice was lower,and there was a significant difference between the two groups(P< 0.01).The degree of dyskinesia in sulforaphane(50 mg/kg)group was much lower,there was a significant difference compared with wild-type(P< 0.001).The immunehistochemical results of paraffin sections showed that the number of dopamine cells in the substantia nigra of the lesion side of saline group,Tg27,Tg39 and sulforaphane(50 mg/kg)groups were significantly higher than that of wild-type experimental mice(P<0.001).Conclusions : By comparing the survival time of NQO1 transgenic mice,wild-type mice and wild-type mice injected by sulforaphane,the results showed that the high expression of NQO1 in mice and the induction of sulforaphane which has certain protective effect on the toxicity of hydroquinone oxidation to quinones in vivo.A mouse model of Parkinson’s disease was successfully established by microinjection of 6-OHDA into the right striatum of the mice.Transgenic mice with high expression of NQO1 and wild-type mice induced by sulforaphane could reduce the neurotoxicity of 6-OHDA to a certain extent.In the model of Parkinson’s disease mice,the high expression of NQO1 transgenic mice and the wild-type mice induced b y sulforaphane had a lower degree of levodopa-induced dyskinesia,which had a certain preventive effect on levodopa dyskinesia. |
