Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation.
Previous studies demonstrated that chronic systemic exposure to the pesticide and mitochondrial toxin rotenone through jugular vein cannulation reproduced many features of Parkinson's disease (PD) in rats, including nigrostriatal dopaminergic degeneration and formation of alpha-synuclein-positive cytoplasmic inclusions in nigral neurons (R. Betarbet et al., 2000, Nat. Neurosci. 3, 1301-1306). Although novel and conceptually important, the rotenone model of PD suffered from being extremely labor-intensive. The current paper demonstrates that these same features of PD can be reproduced by chronic, systemic exposure to rotenone following implantation of subcutaneous osmotic pumps. Chronic subcutaneous exposure to low doses of rotenone (2.0-3.0 mg/kg/day) caused highly selective nigrostriatal dopaminergic lesions. Striatal neurons containing DARPP-32 (dopamine and cAMP-regulated phosphoprotein) remained intact with normal morphology, and NeuN staining revealed normal neuronal nuclear morphology. Neurons of the globus pallidus and subthalamic nucleus were spared. Subcutaneous rotenone exposure caused alpha-synuclein-positive cytoplasmic aggregates in nigral neurons. This new protocol for chronic rotenone administration is a substantial improvement in terms of simplicity and throughput.
Sherer
Todd B
TB
Center for Neurodegenerative Disease, Department of Neurology, Emory University, Atlanta, GA 30032, USA.
Kim
Jin Ho
JH
Betarbet
Ranjita
R
Greenamyre
J Timothy
JT
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009434:Neural Pathways / Q000187:drug effects / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D012402:Rotenone / Q000008:administration & dosage / Q000633:toxicity*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051843:Synucleins; D013995:Time; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein
D007306:Insecticides; D009419:Nerve Tissue Proteins; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D012402:Rotenone; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine