A phenotypic model recapitulating the neuropathology of Parkinson's disease

Brain and Behavior

Craig F. Ferris¹  Mathieu Marella²  Brian Smerkers³  Thomas M. Barchet¹  Benjamin Gershman⁴  Akemi Matsuno-Yagi² 

[1] Center for Translational NeuroImaging, Northeastern University, Boston, Massachusetts;Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California;State University of New York Upstate Medical University, Syracuse, New York;InviCRO, LLC, Boston, Massachusetts

关键词: DNA oxidation;    dopamine transporter;    Lewy bodies;    oxidative stress;    rotenone;    tyrosine hydroxylase;    vesicular monoamine transporter;   

DOI  :  10.1002/brb3.138

来源: Wiley

【 摘 要 】

Abstract

This study was undertaken to develop a phenotypic model recapitulating the neuropathology of Parkinson's disease (PD). Such a model would show loss of dopamine in the basal ganglia, appearance of Lewy bodies, and the early stages of motor dysfunction. The model was developed by subcutaneously injecting biodegradable microspheres of rotenone, a complex I inhibitor in 8–9 month old, ovariectomized Long–Evans rats. Animals were observed for changes in body weight and motor activity. At the end of 11–12 weeks animals were euthanized and the brains examined for histopathological changes. Rotenone treated animals gain weight and appear normal and healthy as compared to controls but showed modest hypokinesia around 5–6 weeks posttreatment. Animals showed loss of dopaminergic (DA) neurons and the appearance of putative Lewy bodies in the substantia nigra. Neuroinflammation and oxidative stress were evidenced by the appearance of activated microglia, iron precipitates, and 8-oxo-2′-deoxyguanosine a major product of DNA oxidation. The dorsal striatum, the projection site of midbrain DA neurons, showed a significant reduction in tyrosine hydroxylase immunostaining, together with an increase in reactive astrocytes, an early sign of DA nerve terminal damage. Levels of vesicular monoamine transporter 2 (VMAT2) were significantly reduced in the dorsal striatum; however, there was an unexpected increase in dopamine transporter (DAT) levels. Old, ovariectomized females treated with rotenone microspheres present with normal weight gain and good health but a modest hypokinesia. Accompanying this behavioral phenotype are a constellation of neuropathologies characteristic of PD that include loss of DA neurons, microglia activation, oxidative damage to nuclear DNA, iron deposition, and appearance of putative Lewy bodies. This phenotypic model recapitulating the neuropathology of Parkinson's disease could provide insight into early mechanisms of pathogenesis and could aid in the identification of biomarkers to identify patients in early stage, PD.

【 授权许可】

CC BY   
© 2013 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

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