Environmental neurotoxin-induced progressive model of parkinsonism in rats.
OBJECTIVE
Exposure to a number of drugs, chemicals, or environmental factors can cause parkinsonism. Epidemiologic evidence supports a causal link between the consumption of flour made from the washed seeds of the plant Cycas micronesica by the Chamorro population of Guam and the development of amyotrophic lateral sclerosis/parkinsonism dementia complex.


METHODS
We now report that consumption of washed cycad flour pellets by Sprague-Dawley male rats induces progressive parkinsonism.


RESULTS
Cycad-fed rats displayed motor abnormalities after 2 to 3 months of feeding such as spontaneous unilateral rotation, shuffling gait, and stereotypy. Histological and biochemical examination of brains from cycad-fed rats revealed an initial decrease in the levels of dopamine and its metabolites in the striatum (STR), followed by neurodegeneration of dopaminergic (DAergic) cell bodies in the substantia nigra (SN) pars compacta (SNc). alpha-Synuclein (alpha-syn; proteinase K-resistant) and ubiquitin aggregates were found in the DAergic neurons of the SNc and neurites in the STR. In addition, we identified alpha-syn aggregates in neurons of the locus coeruleus and cingulate cortex. No loss of motor neurons in the spinal cord was found after chronic consumption of cycad flour. In an organotypic slice culture of the rat SN and the striatum, an organic extract of cycad causes a selective loss of dopamine neurons and alpha-syn aggregates in the SN.


CONCLUSIONS
Cycad-fed rats exhibit progressive behavioral, biochemical, and histological hallmarks of parkinsonism, coupled with a lack of fatality.
Shen
Wei-Bin
WB
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201, USA.
McDowell
Kimberly A
KA
Siebert
Aubrey A
AA
Clark
Sarah M
SM
Dugger
Natalie V
NV
Valentino
Kimberly M
KM
Jinnah
H A
HA
Sztalryd
Carole
C
Fishman
Paul S
PS
Shaw
Christopher A
CA
Jafri
M Samir
MS
Yarowsky
Paul J
PJ
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D029784:Cycas / Q000633:toxicity*; D004032:Diet; D004195:Disease Models, Animal; D018450:Disease Progression; D020820:Dyskinesias / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005433:Flour / Q000633:toxicity; D066298:In Vitro Techniques; D008297:Male; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D010936:Plant Extracts / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
D009498:Neurotoxins; D010936:Plant Extracts