Murine and canine narcolepsy can be caused by mutations of the hypocretin (Hcrt) (orexin) precursor or Hcrt receptor genes. In contrast to these animal models, most human narcolepsy is not familial, is discordant in identical twins, and has not been linked to mutations of the Hcrt system. Thus, the cause of human narcolepsy remains unknown. Here we show that human narcoleptics have an 85%-95% reduction in the number of Hcrt neurons. Melanin-concentrating hormone (MCH) neurons, which are intermixed with Hcrt cells in the normal brain, are not reduced in number, indicating that cell loss is relatively specific for Hcrt neurons. The presence of gliosis in the hypocretin cell region is consistent with a degenerative process being the cause of the Hcrt cell loss in narcolepsy.

Sleep deprivation by the disk-over-water technique results in a predictable syndrome of physiological changes in rats. It has been proposed that reactive oxygen species (ROS) may be responsible for some of these effects. A variety of antioxidative enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) help to regulate the level of ROS. In this study we investigated the effects of prolonged (5-11 days) sleep deprivation on the activities of SOD and GPx as well as the metabolic activity of the mitochondria (using alamar blue) in several brain regions (cortex, hippocampus, hypothalamus, brainstem and cerebellum). We show that prolonged sleep deprivation significantly decreased Cu/Zn-SOD activity in the hippocampus and brainstem, suggesting an alteration in the metabolism of ROS resulting in oxidative stress.

Narcolepsy without cataplexy can be caused by a partial loss of hypocretin cells.

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