A highly reproducible rotenone model of Parkinson's disease.
The systemic rotenone model of Parkinson's disease (PD) accurately replicates many aspects of the pathology of human PD and has provided insights into the pathogenesis of PD. The major limitation of the rotenone model has been its variability, both in terms of the percentage of animals that develop a clear-cut nigrostriatal lesion and the extent of that lesion. The goal here was to develop an improved and highly reproducible rotenone model of PD. In these studies, male Lewis rats in three age groups (3, 7 or 12-14 months) were administered rotenone (2.75 or 3.0 mg/kg/day) in a specialized vehicle by daily intraperitoneal injection. All rotenone-treated animals developed bradykinesia, postural instability, and/or rigidity, which were reversed by apomorphine, consistent with a lesion of the nigrostriatal dopamine system. Animals were sacrificed when the PD phenotype became debilitating. Rotenone treatment caused a 45% loss of tyrosine hydroxylase-positive substantia nigra neurons and a commensurate loss of striatal dopamine. Additionally, in rotenone-treated animals, alpha-synuclein and poly-ubiquitin positive aggregates were observed in dopamine neurons of the substantia nigra. In summary, this version of the rotenone model is highly reproducible and may provide an excellent tool to test new neuroprotective strategies.
Cannon
Jason R
JR
Pittsburgh Institute for Neurodegenerative Diseases, Department of Neurology, University of Pittsburgh, PA 15260, USA.
Tapias
Victor
V
Na
Hye Mee
HM
Honick
Anthony S
AS
Drolet
Robert E
RE
Greenamyre
J Timothy
JT
D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency; D004409:Dyskinesia, Drug-Induced / Q000473:pathology / Q000503:physiopathology*; D018476:Hypokinesia / Q000139:chemically induced; D007274:Injections, Intraperitoneal; D008297:Male; D009127:Muscle Rigidity / Q000139:chemically induced; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D011917:Rats, Inbred Lew; D015203:Reproducibility of Results; D012402:Rotenone / Q000633:toxicity*; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism; D014452:Ubiquitins / Q000187:drug effects / Q000378:metabolism; D014475:Uncoupling Agents / Q000633:toxicity; D051844:alpha-Synuclein / Q000187:drug effects / Q000378:metabolism
D009498:Neurotoxins; D014452:Ubiquitins; D014475:Uncoupling Agents; D051844:alpha-Synuclein; D012402:Rotenone; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine