title: Evaluation of a multiple system atrophy model in rats using multitracer microPET.
abstract: BACKGROUND
  A double toxin-double lesion strategy is appropriate for mimicking of striatonigral degeneration. Because knowledge of human pathology is limited, animal models must be well characterized prior to testing of therapeutic approaches to treat multiple system atrophy. In double-toxin animal models, however, reduced contralateral rotation after apomorphine injection is restored within a few weeks via an unknown mechanism; the animals thus revert to PD status. We assessed this phenomenon using multitracer microPET and tissue staining.
  
  
  METHODS
  Five adult male Wistar rats received injections of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle (MFB), followed 3 weeks later by injections of quinolinic acid (QA) into the ipsilateral striatum. Apomorphine-induced rotation tests were performed 1 week after each injection, and 6 and 10 weeks after QA injection. Rotarod tests were performed weekly after 6-OHDA injection. MSA-p status was characterized by microPET 5 and 10 weeks after QA injection using the tracers 2-deoxy-2-[(18)F]-fluoro-D-glucose ([(18)F]-FDG) and [(18)F]-N-(3-fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl)nortropane ([(18)F]-FP-CIT). Histological changes were evaluated by tyrosine hydroxylase (TH) and cresyl violet staining.
  
  
  RESULTS
  The numbers of apomorphine-induced rotations increased contralaterally after 6-OHDA lesions were created, but decreased significantly after QA administration (p = 0.007). Five weeks after QA injection, however, contralateral rotation again increased and persisted for 1 month. Rotarod rotation differed significantly between the intact and PD states (p < 0.05), but not between the PD and MSA-p states. MicroPET revealed glucose hypometabolism and dopamine transporter (DAT) impairment on the lesioned side of the striatum 1 and 2 months after QA lesion surgery. Loss of nigral cells was confirmed by TH immunostaining, and striatal atrophy was observed upon cresyl violet staining.
  
  
  CONCLUSIONS
  Pathological changes consistent with MSA-p can be generated by the double toxin-double lesion method and persist during follow-up. Behavioral tests, such as drug-induced rotation and rotarod tests, are not appropriate for long-term follow-up in the MSA-p model, suggesting the need for development of more appropriate behavioral tests.
authors.affiliation: Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Korea.
authors.forename: Hyung Ho
authors.initials: HH
authors.lastname: Yoon
authors.forename: Chong Sik
authors.initials: CS
authors.lastname: Lee
authors.forename: Seok Ho
authors.initials: SH
authors.lastname: Hong
authors.forename: Joongkee
authors.initials: J
authors.lastname: Min
authors.forename: Yong Hwan
authors.initials: YH
authors.lastname: Kim
authors.forename: Onyou
authors.initials: O
authors.lastname: Hwang
authors.forename: Sang Ryong
authors.initials: SR
authors.lastname: Jeon
mesh_terms: D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000502:physiology; D019578:Multiple System Atrophy / Q000139:chemically induced / Q000378:metabolism*; D049268:Positron-Emission Tomography; D051381:Rats; D017208:Rats, Wistar; D020955:Striatonigral Degeneration / Q000139:chemically induced / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins