The Role Of Distribution Of Vesicular Monoamine Transporter In Brain Tissue In The Pathogenesis Of Parkinson Disease

Parkinson disease(PD) is a progressive neurodegenerative disorder characterized by a preferential loss of dopaminergic neurons of the substantia nigra pars compacta(SNc) and its projections to the striatum.The etiology of PD is unclear.There are several hypothesis about the pathogenesis of PD,such as genetic and environmental factors.But these hypothesis could not explain the progressive and selective characteristic of PD. Recently,neurotransmitter transporter has been the study hotspot of neuroscience. The hypothesis about maladjustment of transporters can explain preferably the mechanism of selective loss of the dopaminergic cell in SNc,and Vesicular Monoamine Transporter(VMAT) may play a key role in the pathogenesis of PD.The neurotoxin 1-methyl-4-phenyl-l ,2,3,6-tetrahydropyridine(MPTP) that can produce a parkinsonian syndrome in man has been used to produce an animal model of Parkinson disease.The toxic metabolite of MPTP, 1-methy-4-phenylpyridinium(MPP) inhibits mitochondrial function of the dopaminergic cells in SNc, impairing the production of ATP, and causes neurodegeneration. VMAT2 can sequester MPP+ and Dopamin within synaptic vesicles andseparate their toxin from cytoplasm, and play a role in protecting dopaminergic neurons from neurodegeneration. Thus, VMAT may play an important role in avoiding PD deterioration and improving its prognosis.In this study we investigated the distribution of VMAT in the of brain PD model of C57BL mice and in human embryonic brain and their relationship with PD and studied the possible role of apoptosis in the pathogenesis of PD.Depend on this study we may reasonably illuminate an pathogenesis which can interpret the progressive and selective characteristic of PD. Methods: 1. PD models of C57BL mice induced by reserpine or MPTP or reserpine plus MPTP were used respectively . The distribution of VMAT and TH in substantia nigra pars compacta(SNc),striatum,ventral tegmental ares(VTA) and locus coeruleus(LC) was examined by immunohistochemical staining.2. The distribution of VMAT and TH in SNc, striatum, VTA and LC was examined by immunohistochemical staining in human embryonic brains of different gestational age.3. TUNEL technique was used to detect the apoptotic dopaminergic neurons in PD model of C57BL mice. Results:1. The number of VMAT2-positive neurons and the number of TH-positive neurons in SNc were significantly reduced in PD model than the control,but there was no significant difference in VTA and LC between PD model and the control. VMAT2-positive neuron fibers and TH-positive neuron fibers in the striatum region were significantly reduced in PD model. The distribution of VMAT2 in the control in SNc was less than that in both VTA and LC.2. The distribution of VMAT2 in SNc was less than that in both VTA and LC inhuman embryonic brain.S.TUNEL staining showed apoptotic neurons with typical DNA fragmentation in SNc. Conclusion: l.In both mouse brain and human embryonic brain ,the amount of VMAT1 that has protective effect on the DA neurons in SNc is less than that in VTA and LC.The weak of the protecting function of VMAT in SNc may be the important cause of the selective lose of DA neurons.2.Nigral neuronal apoptosis may be involved in the pathogenesis of PD and the apoptotic effect of MPTP in vivo on the nigral neurons is realized through its intermediate MPP.