Morphological and Metabolic Changes in the Nigro-Striatal Pathway of Synthetic Proteasome Inhibitor (PSI)-Treated Rats: A MRI and MRS Study

Abstract

Systemic administration of a Synthetic Proteasome Inihibitor (PSI) in rats has been described as able to provide a model of Parkinson’s disease (PD), characterized by behavioral and biochemical modifications, including loss of dopaminergic neurons in the substantia nigra (SN), as assessed by post-mortem studies. With the present study we aimed to assess in-vivo by Magnetic Resonance (MR) possible morphological and metabolic changes in the nigro-striatal pathway of PSI-treated rats. 10 animals were subcutaneously injected with PSI 6.0 mg/kg dissolved in DMSO 100%. Injections were made thrice weekly over the course of two weeks. 5 more animals injected with DMSO 100% with the same protocol served as controls. The animals underwent MR sessions before and at four weeks after the end of treatment with either PSI or vehicle. MR Imaging was performed to measure SN volume and Proton MR Spectroscopy (1H-MRS) was performed to measure metabolites changes at the striatum. Animals were also assessed for motor function at baseline and at 4 and 6 weeks after treatment. Dopamine and dopamine metabolite levels were measured in the striata at 6 weeks after treatment. PSI-treated animals showed volumetric reduction of the SN (p<0.02) at 4 weeks after treatment as compared to baseline. Immunofluorescence analysis confirmed MRI changes in SN showing a reduction of tyrosine hydroxylase expression as compared to neuron-specific enolase expression. A reduction of N-acetyl-aspartate/total creatine ratio (p = 0.05) and an increase of glutamate-glutamine-γ amminobutirrate/total creatine were found at spectroscopy (p = 0.03). At 6 weeks after treatment, PSI-treated rats also showed motor dysfunction compared to baseline (p = 0.02), accompanied by dopamine level reduction in the striatum (p = 0.02). Treatment with PSI produced morphological and metabolic modifications of the nigro-striatal pathway, accompanied by motor dysfunction. MR demonstrated to be a powerful mean to assess in-vivo the nigro-striatal pathway morphology and metabolism in the PSI-based PD animal model.

Dopamine Reduction in the Substantia Nigra of Parkinson's Disease Patients Confirmed by In Vivo Magnetic Resonance Spectroscopic Imaging

“…In this study we could non-invasively detect these expected de- and increases in vivo for the first time using an optimized 3D MRSI method. Furthermore, the observed decrease in NAA, Cho, Cr, Ins, GSH and dopamine and slightly increase in Glu+Gln and GABA are in good agreement with post-mortem results from Gerlach et al [2] and Sofic et al [15] as well as with findings from PD rat model based on proteasome inhibition [20]. Only in the case of HVA did we find a slight elevation that is in contradiction to the post-mortem data [2].…”

Modeling nigrostriatal degeneration in organotypic cultures, a new ex vivo model of Parkinson’s disease

“…Within this line, axonal regeneration (Ishihara et al, 2011) and glial response (Ziemka-Nalecz et al, 2013) after axotomy could be studied in the model presented here. Moreover, using MRI that produces detailed images of a living brain tissue over time without using radioactive ligands (Petridou et al, 2006), fiber tracts can be visualized in organotypic slices and pathway integrity assessed by calculation of FA and the study of neuronal metabolism using magnetic resonance spectroscopy (Delli Pizzi et al, 2013). This could be used to evaluate the neuroregenerative potential of axonal growth therapeutics among others (Ullrich et al, 2011).…”

GABA levels in the ventromedial prefrontal cortex during the viewing of appetitive and disgusting food images

“…After autophasing, baseline and frequency shifts correction, a priori knowledge database (N-acetyl aspartate = NAA, 2.02 ppm; total creatine = tCr, 3.03 ppm) was created to put constraints on the Advanced Magnetic Resonance (AMARES) fitting algorithm within the jMRUI package. Using the PRESS sequence, the water signal was quantified to use it as internal reference standard to calculated the absolute tCr quantification (Christiansen et al, 1993;Delli Pizzi et al, 2012, 2013, 2015, 2016). Peak shifts were restricted to ±5 ppm of the theoretical location.…”