Detection Of Metabolic Changes In The Striatum And The Hippocampus Of Proteasome Inhibition-induced Parkinson's Disease In Rats And The Relationship With The Memory Disorders

Parkinson's disease(PD)is a neurodegenerative disorder that is characterized pathologically by the selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta(SNc)and the consequent deficiency of dopamine in the striatum and the Lewy bodies in the surviving neurons.The ubiquitin proteasome system(UPS)is responsible for clearance of damaged intracellular proteins.Dysfunction of the UPS disturbs protein homeostasis and leads to accumulation and aggregation of unwanted proteins which has been observed in Lewy body inclusions and aggregated alpha-synuclein(?-syn)which are characteristically present in Parkinson's disease(PD).Rodent models of PD which are proteasome inhibition-induced have been widely used.Lactacystin is one selective inhibitor.A single injection with lactacystin in rats can reproduce dopamine cell loss and protein accumulation and aggregation associated with motor impairments in PD.Although it might have effect on the proteasomal systems of other cells in the local region,and could possible affect the long-term enzymes,it was considered as a potential contributor to cell death in PD and might be linked to the accumulation of both non-ubiquitinated and ubiquitinated proteins in the SNpc and in Lewy bodies of PD models.Proton magnetic resonance spectroscopy(MRS)enables the measurement of several low-molecular-weight metabolites in brain noninvasively and can be repeated over time in the same animal.MRS can monitor changes in chemical markers,which cannot be detected by conventional MRI.Most prior MRS studies reported few neurochemicals or ratios,measured at 1.5tesla(T)or 3T.From previous studies,MRS signatures obtained from the nigrostriatal region were variable,and most of them reported no differences between PD and controls.Compared to the low magnetic field,higher magnetic field MRS possesses higher resolving power.Recent studies demonstrated that higher magnetic fields MRS of animal models of PD found alterations in several other metabolites,including the neurotransmitters glutamate(Glu)and ?-aminobutyric acid(GABA).The feasibility of quantifying “neurochemical profiles” in the PD model at the high field of 9.4T has been demonstrated previously.If metabolite changes can be monitored in PD animal models,this monitoring could lead to increased understanding of PD pathogenesis and can provide a theoretical basis for screening and neuroimaging biological markers.Therefore,the goal of the current study was to investigate neurochemical alterations in the striatum region that are thought to be progressively involved in PD pathology with MRS at 9.4T.Objective: Parkinson's disease(PD)is a progressive disorder.To investigate the biochemical alterations in the striatum of rats with different stages of PD induced by proteasome inhibition,we quantified neurochemical profiles of the striatum using proton magnetic resonance spectroscopy using 9.4 T ultra-high field imaging.Methods: In this study,10?g/2?l lactacystin,a selective proteasome inhibitor,was unilaterally injected stereotaxically into the left substantia nigra pars compacta of rats.An equal volume of saline was injected into the same region and side in the control group.Changes in motor behavior were observed.The morphological changes of THpositive cells in substantia nigra pars compacta were visualized using immunohistochemistry.TH-positive cells were quantified.Alterations of Nacetylaspartate,choline,creatine,taurine in the different stages of PD rats were detected using proton MRS.Results: Application of in-vivo 1H magnetic resonance spectroscopy(1H MRS)was repeated in both the six PD rats and the six control rats three times during the first,second and fourth weekend after administration.In PD rats,increased N-acetylaspartate and decreased taurine concentrations were observed in the left striatum at the first week after administration.The increased N-acetylaspartate and choline concentrations were observed at the second weekend.At the fourth weekend,increased creatine concentrations in the left side were observed,while other metabolites were not significantly changed.Conclusions: Neurochemical alterations occurred in the striatum during different stages of the PD model in rats.Also,9.4T 1H MRS may be a useful tool for elucidating the progression of PD disease through the variation of these metabolites.