Impact Of Iron And MPTP On Dopamine Metabolism

Parkinson’s disease（PD）is the second major neurodegenerative disease with about6 million patients worldwide.Its prevalence rate is 0.3%in the general population and1%in the population over 60 years old.The non-motor symptoms of PD patients were anosmia,constipation,sleep disturbance and depression,while the motor symptoms are tremor,rigidity and imbalance.The main pathological feature of PD is the progressive degeneration of dopaminergic neuronal cells,which results in reduced dopamine（DA）secretion.DA is an important neurotransmitter,which can be easily oxidized due to its low oxidation potential.DA oxidation produces a series of catechol substances,for instance,norepinephrine（NE）.Thus,DA is strictly regulated in the brain and stored in vesicles.The DA molecules released by exocytosis are rapidly captured by the DA receptor molecules of postsynaptic neurons.The excessive DA molecules either re-enter the presynaptic neurons through endocytosis or are metabolized through enzymatic and non-enzymatic pathways.DA metabolism involves many pathways that produce neurotoxic substances,such as 6-hydroxydopamine（6-OHDA）,nonsalsolinol（NSA）and salsolinol（SA）.In addition,the DA metabolism is influenced by iron and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）.MPTP exposure can induce motor symptoms similar to PD,which are commonly used to generate animal model.Additionally,the deposition of iron in the brain will lead to the generation of cytotoxic free radicals,thus damaging catecholamine neurotransmitters and producing cognitive impairment.Therefore,the overload of brain iron content is considered to be closely related to the pathogenesis of several neurodegenerative diseases.At the same time,the treatment of iron overload combined with MPTP will lead to functional and neurochemical defects.The consequences are beyond the simple accumulation of the two chemicals,which will have an important impact on PD neurodegenerative disease.In reported studies of catecholamine neurotransmitters in the brain tissue of mice,the detection of each main brain region was relatively simple,and the two metabolites i.e.,SA and NSA,were generally ignored.Both SA and NSA have been proved to be cytotoxic both in vivo and in vitro.SA and NSA can inhibit tyrosine hydroxylase and monoamine oxidase activities.Moreover,they alter the activity of mitochondrial respiratory chain complex I and II,thus inhibiting the energy supply of mitochondria to cells and leading to the death of dopaminergic neurons.Therefore,it is of great significance to detect the contents of SA and NSA in brain tissue.The purpose of this research is to quantify the main neurotransmitters,including DA,NE,SA and NSA,and their metabolites in clearly partitioned brain regions of mice,and to further assess the effects of iron addition on SA and NSA by establishing Fe³⁺+MPTP mouse model.In addition,based on the effects of iron and MPTP on the main neurotransmitters and their metabolites in the brain tissue of mice,this research revealed the enhancement effect of MPTP in the presence of iron.