Progressive changes of orexin system in a rat model of 6-hydroxydopamine-induced Parkinson's disease

Sleep disturbance, which is characterized by excessive daytime sleepiness and sleep attacks, is frequently observed in patients with Parkinson's disease (PD). Loss of orexin neurons in hypothalamus and the resultant decreased level of orexin in cerebrospinal fluid (CSF) found in narcolepsy patients may also play an essential role in the pathogenesis of sleep disturbance. The present study aimed to investigate the possible changes in the orexin system during PD progression.

After the establishment of a rat PD model by injecting 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, the numbers of orexin-A- and tyrosine hydroxylase (TH)-positive neurons, and the levels of orexin-A fibers and orexin-A in CSF were examined by immunohistochemistry and ELISA assay, respectively.

Compared to the TH-containing neurons that exhibited fast degeneration in response to 6-OHDA, orexin-A-containing neurons were less sensitive to 6-OHDA. The number of orexin-A-positive neurons began to decrease at day 21 after operation, and at day 49, it decreased by 30% of the initial level. The orexin-A level in CSF of PD rats did not show any obvious fluctuations compared to the control, and there was no obvious reduction in the density of orexin-A-positive fibers in brain areas such as tuberomammillary nucleus.

These results reveal for the first time the dynamic changes of orexin system during the progression of PD. This may provide valuable information for drug development to reverse the loss of orexin neurons and sleep disturbance in PD patients.