The Cycad Hypothesis: Sleep alterations in a progressive, environmental neurotoxin-induced model of parkinsonism.

摘要

Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, current attention has focused on the early, non-motor symptoms. Sleep disorders, such as excessive daytime sleepiness (EDS), are one of the most prominent initial symptoms in PD. Recently there have been studies revealing that the orexin-containing neurons of the hypothalamus, a cell type vital to sleep regulation, also degenerate in PD and may contribute to these associated sleep disorders. However, the role of orexin neurons in the development of PD remains controversial and relatively unstudied since few animal models can replicate both the motor and non-motor symptoms of the disease. We have developed a novel, progressive, neurotoxin-induced rat model of parkinsonism that accesses this subject. Epidemiological studies elucidated a fundamental connection between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant, Cycas micronesica (cycad). We have examined the effects of prolonged cycad consumption on male, Sprague-Dawley rats. Cycad-fed rats displayed a behavioral phenotype resembling that of parkinsonism. Briefly, we found that cycad consumption induced multiple, classical symptoms of PD including locomotor deficits, neurodegeneration of dopamine (DA) cell bodies and aggregation of alpha-synuclein in the remaining neurons of the substantia nigra pars compacta (SNc). Uniquely, preceding these alterations we found that cycad-fed rats displayed a hypersomnolent behavior. Analysis of sleep architecture revealed an increase in the length and/or the number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep during the active period of cycad-fed rats when compared to control rats. In addition, we found a significant reduction in orexin-A (ORX-A) neurons of cycad-fed rats. Lastly, dose response curves of NMDA-induced DA release in the striatum and SN provide a method to elucidate some of the neurochemical changes behind the early, non-motor symptoms of cycad-fed rats.