Variable effects of chronic subcutaneous administration of rotenone on striatal histology.
When infused in rats, rotenone, a mitochondrial complex I inhibitor, induces alterations that resemble the histological changes of Parkinson's disease, particularly degeneration of the nigrostriatal dopaminergic system. However, the specificity of rotenone effects has been challenged recently. We have re-examined the alterations caused by rotenone in the substantia nigra and the striatum of rats after infusion of rotenone (2 mg/kg per day s.c.) for 21 days. Three patterns of striatal tyrosine-hydroxylase immunoreactivity (TH-IR) were observed: 46% of animals showed no reduction, and 46% of animals showed diffuse reduction in TH-IR, whereas one animal presented a focal loss of TH-IR in the striatum. Confocal microscopy analysis showed that the vesicular monoamine transporter (VMAT2) was decreased in parallel with TH-IR, strongly suggesting a loss of striatal DA nerve terminals in animals with diffuse or central TH-IR loss. However, no significant loss of TH-IR neurons was observed in the substantia nigra. Analysis of NeuN and DARPP-32 immunoreactivity, and Nissl staining, in the striatum showed no striatal neuronal loss in animals with either preserved TH-IR or diffuse TH-IR reduction. However, in the animal with focal TH-IR loss, severe neuronal loss was evident in the center and the periphery of the striatum, together with microglial activation detected by OX-6 and OX-42 staining. Thus, in most cases, chronic subcutaneous infusion of low doses of rotenone does not induce significant striatal neuronal loss, despite TH-IR and VMAT-IR reduction in a subset of animals, supporting the use of rotenone as a model of Parkinson's disease under carefully controlled experimental conditions.
Zhu
Chunni
C
Departments of Neurology and Neurobiology, The David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095-1769, USA.
Vourc'h
Patrick
P
Fernagut
Pierre-Olivier
PO
Fleming
Sheila M
SM
Lacan
Sanja
S
Dicarlo
Cheryl D
CD
Seaman
Ronald L
RL
Chesselet
Marie-Françoise
MF
D000818:Animals; D003342:Corpus Striatum / Q000737:chemistry* / Q000187:drug effects* / Q000473:pathology; D007279:Injections, Subcutaneous; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D012402:Rotenone / Q000008:administration & dosage* / Q000633:toxicity
D012402:Rotenone