Rat model of Parkinson's disease: chronic central delivery of 1-methyl-4-phenylpyridinium (MPP+).
Mitochondrial dysfunction is observed in sporadic Parkinson's disease (PD) and may contribute to progressive neurodegeneration. While acute models of mitochondrial dysfunction have been used for many years to investigate PD, chronic models may better replicate the cellular disturbances caused by long-standing mitochondrial derangements and may represent a better model for neurotherapeutic testing. This study sought to develop a chronic model of PD that has the advantages of continuous low level toxin delivery, low mortality, unilateral damage to minimize aphagia and adipsia as well as minimal animal handling to reduce stress-related confounds. Infusion by osmotic minipump of the complex I toxin, 1-methyl-4-phenylpyridinium (MPP+), for 28 days into the left cerebral ventricle in rats caused a selective ipsilateral loss of nigral tyrosine hydroxylase immunoreactive somata (35% loss). In animals that were sacrificed 14 days after the chronic MPP+ administration, there was an even greater loss of nigral tyrosine hydroxylase cells (65% loss). Lewy-body-like structures that stained positive for ubiquitin and alpha-synuclein were found in striatal neurons near the infusion site but were not observed in nigral neurons. At the electron microscope level, however, swollen and abnormal mitochondria were observed in the nigral dopamine neurons, which may represent the early formation of an inclusion body. There were no animal deaths with the chronic treatment regimen that was utilized, and the magnitude of nigrostriatal neuronal loss was relatively consistent among the animals. This model of progressive neurodegeneration of nigrostriatal dopamine neurons may be useful for studying neuroprotective therapeutic agents for PD.
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
U
U
Yazdani
D C
DC
German
C-L
CL
Liang
L
L
Manzino
P K
PK
Sonsalla
G D
GD
Zeevalk
D015655:1-Methyl-4-phenylpyridinium / Q000008:administration & dosage* / Q000633:toxicity; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007276:Injections, Intraventricular; D008297:Male; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000401:mortality / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate
D015655:1-Methyl-4-phenylpyridinium