Objective To study the apoptotic effects of 1 methyl 4 phenyl 1,2,3,6 tetrahydropyridine (MPTP) on the nigral dopaminergic neurons of mice and 1 methyl 4 phenylpyridium ion (MPP +) on pheochromocytoma (P...Objective To study the apoptotic effects of 1 methyl 4 phenyl 1,2,3,6 tetrahydropyridine (MPTP) on the nigral dopaminergic neurons of mice and 1 methyl 4 phenylpyridium ion (MPP +) on pheochromocytoma (PC12) cells, as well as the antagonism of Eldepryl against MPTP's apoptotic effect Methods Three groups of C 57 BL mice were treated with MPTP, Eldepryl plus MPTP and normal saline, respectively, for 7 days before performing TUNEL (terminal deoxyneucleotidyl transferase mediated dUTP x nick end labeling) and FACS (fluorescence activated cell sorting) analyses of neuronal apoptosis in the substantia nigra The same tests were employed in cell culture to examine apoptosis in PC12 cells treated with MPP +, MPTP or PBS Results Intraperitoneal administration of MPTP 30?mg/kg could induce nigral apoptosis, and oral use of Eldepryl prior to MPTP treatment could completely prevent the nigral apoptosis caused by MPTP MPP +, an intermediate metabolite of MPTP, could lead to the apoptosis of PC12 cells, whereas MPTP itself had no such effect on PC12 cells Conclusions The experiment indicated that the neurotoxin, MPTP, might cause the death of nigral neurons through a mechanism of apoptosis and this effect might be mediated by its bioactive intermediate metabolite MPP + Eldepryl could protect the neurotoxicity from MPTP展开更多
A spontaneous mutation in the Albino Swiss (AS) rat has been shown to be a single point mutation (agu) in the gene coding for the gamma isoform of protein kinase C (PKC-γ). The characteristics of the mutant include m...A spontaneous mutation in the Albino Swiss (AS) rat has been shown to be a single point mutation (agu) in the gene coding for the gamma isoform of protein kinase C (PKC-γ). The characteristics of the mutant include movement disorders, a failure to release dopamine in the striatum and elevations of molecules such as parkin and ubiquitin in the substantia nigra pars compacta (SNC). This present study examined SNC cell bodies and dopaminergic synaptic terminals within the caudate-putamen. Cell volume and nuclear volume were reduced in the AS/AGU mutant compared to the AS control, but the volume fractions of mitochondria and rough endoplasmic reticulum were significantly higher. No Lewy bodies were present in the mutant, although microglia were found adjacent to some SNC cells. Dopaminergic terminals were identified in the caudate-putamen by electron microscopy with low-glutaraldehyde fixation and immunohistochemistry for tyrosine hydroxylase using immuno-gold visualisation. AS/AGU mutant rats had less than half of the synaptic vesicles of AS controls;this was not only true of “readily-releasable” zones adjacent to the synaptic cleft but also “storage pool” zones. The findings support the hypothesis that the initial bar to dopamine availability in the striatum is the reduced release, with nigral cell death being a later phenomenon.展开更多
Background Dorsal nigral hyperintensity(DNH)abnormality associated with excessive iron deposition in the substantia nigra,is recognized as an imaging characteristic of Parkinson’s disease(PD)and can be effectively vi...Background Dorsal nigral hyperintensity(DNH)abnormality associated with excessive iron deposition in the substantia nigra,is recognized as an imaging characteristic of Parkinson’s disease(PD)and can be effectively visualized using 7T MRI.This study was aimed to develop and validate the optimal DNH assessment method as a biomarker for PD,idiopathic rapid eye movement sleep behavior disorder(iRBD),and Parkinson-plus syndromes,and to explore the nigral iron deposition patterns in these diseases.Methods Three-dimensional gradient-echo T2*-weighted images were acquired by 7T MRI from a total of 402 patients and 100 healthy controls(HCs)in two independent cohorts(development and validation cohorts).Seven methods,including four dichotomous methods and three DNH rating scales,were used to assess DNH and evaluate their diagnostic performance.R2*mapping and principal component analysis were performed to assess nigral iron deposition patterns.Results Bilateral DNH detection rates in the development cohort were 22.6%for early-stage PD,3.7%for advanced PD,93.5%for iRBD,5.7%for MSA-parkinsonian type,78.8%for MSA-cerebellar type,11.8%for progressive supranuclear palsy(PSP),and 100%for HC,with similar rates in the validation cohort.A cut-off of 6 on the 6-point visibility scale demonstrated a 100%accuracy for diagnosing early-stage PD in both the development and the validation cohorts.This scale exhibited moderate differential diagnostic performance between early-stage PD and iRBD(area under the curve[AUC]=0.940)or MSA-C(AUC=0.892).Iron deposition was predominantly in the dorsal and posterior substantia nigra of PD and PSP,the intermediate and posterior substantia nigra of MSA-P,and the ventral substantia nigra of MSA-C.Conclusion DNH may be preserved in approximately one-quarter of early-stage PD and most MSA-C cases.The 6-point visibility scale on 7T effectively distinguished PD from HC,iRBD,and MSA-C.The nigral iron deposition pattern in PD may help distinguish PD from MSA-P and MSA-C,although it overlaps with that of PSP.展开更多
文摘Objective To study the apoptotic effects of 1 methyl 4 phenyl 1,2,3,6 tetrahydropyridine (MPTP) on the nigral dopaminergic neurons of mice and 1 methyl 4 phenylpyridium ion (MPP +) on pheochromocytoma (PC12) cells, as well as the antagonism of Eldepryl against MPTP's apoptotic effect Methods Three groups of C 57 BL mice were treated with MPTP, Eldepryl plus MPTP and normal saline, respectively, for 7 days before performing TUNEL (terminal deoxyneucleotidyl transferase mediated dUTP x nick end labeling) and FACS (fluorescence activated cell sorting) analyses of neuronal apoptosis in the substantia nigra The same tests were employed in cell culture to examine apoptosis in PC12 cells treated with MPP +, MPTP or PBS Results Intraperitoneal administration of MPTP 30?mg/kg could induce nigral apoptosis, and oral use of Eldepryl prior to MPTP treatment could completely prevent the nigral apoptosis caused by MPTP MPP +, an intermediate metabolite of MPTP, could lead to the apoptosis of PC12 cells, whereas MPTP itself had no such effect on PC12 cells Conclusions The experiment indicated that the neurotoxin, MPTP, might cause the death of nigral neurons through a mechanism of apoptosis and this effect might be mediated by its bioactive intermediate metabolite MPP + Eldepryl could protect the neurotoxicity from MPTP
文摘A spontaneous mutation in the Albino Swiss (AS) rat has been shown to be a single point mutation (agu) in the gene coding for the gamma isoform of protein kinase C (PKC-γ). The characteristics of the mutant include movement disorders, a failure to release dopamine in the striatum and elevations of molecules such as parkin and ubiquitin in the substantia nigra pars compacta (SNC). This present study examined SNC cell bodies and dopaminergic synaptic terminals within the caudate-putamen. Cell volume and nuclear volume were reduced in the AS/AGU mutant compared to the AS control, but the volume fractions of mitochondria and rough endoplasmic reticulum were significantly higher. No Lewy bodies were present in the mutant, although microglia were found adjacent to some SNC cells. Dopaminergic terminals were identified in the caudate-putamen by electron microscopy with low-glutaraldehyde fixation and immunohistochemistry for tyrosine hydroxylase using immuno-gold visualisation. AS/AGU mutant rats had less than half of the synaptic vesicles of AS controls;this was not only true of “readily-releasable” zones adjacent to the synaptic cleft but also “storage pool” zones. The findings support the hypothesis that the initial bar to dopamine availability in the striatum is the reduced release, with nigral cell death being a later phenomenon.
基金supported by the National Natural Science Foundation of China(No.82271459 and No.82071422).
文摘Background Dorsal nigral hyperintensity(DNH)abnormality associated with excessive iron deposition in the substantia nigra,is recognized as an imaging characteristic of Parkinson’s disease(PD)and can be effectively visualized using 7T MRI.This study was aimed to develop and validate the optimal DNH assessment method as a biomarker for PD,idiopathic rapid eye movement sleep behavior disorder(iRBD),and Parkinson-plus syndromes,and to explore the nigral iron deposition patterns in these diseases.Methods Three-dimensional gradient-echo T2*-weighted images were acquired by 7T MRI from a total of 402 patients and 100 healthy controls(HCs)in two independent cohorts(development and validation cohorts).Seven methods,including four dichotomous methods and three DNH rating scales,were used to assess DNH and evaluate their diagnostic performance.R2*mapping and principal component analysis were performed to assess nigral iron deposition patterns.Results Bilateral DNH detection rates in the development cohort were 22.6%for early-stage PD,3.7%for advanced PD,93.5%for iRBD,5.7%for MSA-parkinsonian type,78.8%for MSA-cerebellar type,11.8%for progressive supranuclear palsy(PSP),and 100%for HC,with similar rates in the validation cohort.A cut-off of 6 on the 6-point visibility scale demonstrated a 100%accuracy for diagnosing early-stage PD in both the development and the validation cohorts.This scale exhibited moderate differential diagnostic performance between early-stage PD and iRBD(area under the curve[AUC]=0.940)or MSA-C(AUC=0.892).Iron deposition was predominantly in the dorsal and posterior substantia nigra of PD and PSP,the intermediate and posterior substantia nigra of MSA-P,and the ventral substantia nigra of MSA-C.Conclusion DNH may be preserved in approximately one-quarter of early-stage PD and most MSA-C cases.The 6-point visibility scale on 7T effectively distinguished PD from HC,iRBD,and MSA-C.The nigral iron deposition pattern in PD may help distinguish PD from MSA-P and MSA-C,although it overlaps with that of PSP.
