Environmental neurotoxin‐induced progressive model of parkinsonism in rats

Abstract

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 (ALS/PDC). 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 two to three 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 pars compacta (SNc). α-synuclein (α-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 α-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 substantia nigra and the striatum, an organic extract of cycad causes a selective loss of DA neurons and α-synuclein aggregates in the substantia nigra. Interpretation Cycad-fed rats exhibit progressive behavioral, biochemical, and histological hallmarks of parkinsonism, coupled with a lack of fatality.

Sleep alterations in an environmental neurotoxin-induced model of parkinsonism

“…Furthermore, these animals did not show advanced symptoms (i.e., motor disturbances) of the disease. It is only at later time points (thirty-six weeks after cycad exposure) that cycad-fed rats display a significant loss of DA neurons in the SN and the presence of α-synuclein aggregation, a classical histological hallmark of PD (Shen et al, 2010). In other words, cycad consumption in rats induces a hypersomnia that precedes the development of parkinsonian symptoms.…”

“…Flour made from the seeds of the plant C ycas micronesica was fed in pellet form to induce a Parkinsonian-like behavior in rats (Shen et al, 2010, in press). Briefly, pellet batches were prepared every other week for control and experimental rats, using unbleached wheat flour or washed cycad flour, respectively.…”

“…Importantly, washing of the seeds removes acute toxins such as β- N -methylamino-L-alanine which has been shown to induce motor neuron loss in culture (Rao et al, 2006). We found that cycad-fed rats display a progressive parkinsonian phenotype with no signs of ALS (Shen et al, 2010). Here, we report an in-depth analysis of the sleep architecture in cycad-fed and control rats.…”

Is Neurodegenerative Disease a Long-Latency Response to Early-Life Genotoxin Exposure?

“…Studies of adult rodents have focused on the carcinogenic potential of cycad and cycasin, although cerebellar pathology was reported in a study of rats fed L-BMAA [55]. A recent experimental study of rats fed cycad materials (cycasin content unknown) found neuropathological changes in the substantia nigra, striatum, locus coeruleus and cingulate cortex [56] which, as the authors note, supports the proposed role of cycad in western Pacific ALS-PDC, a proposal first made by Whiting and Kurland, later resurrected by Spencer and colleagues, and now once again the subject of intense biomedical interest. Shaw and his colleagues, the authors of the recent rodent study, propose that cycad sitosterols—either as the free sterol or the glucoside—are likely etiological agents; this seems unlikely since these compounds are used to treat prostatic hypertrophy without reported neurological disease, and controlled toxicological studies have given these sterols a clean bill of health [57].…”

Therapeutic role of terbutaline in a rat whole-lung lavage model

“…After 5 days, lung samples were inflated, fixed in formalin, paraffin-embedded, and sectioned for histological analysis. Slides were washed and counterstained with hematoxylin and eosin [21].…”