Effects of inflammation produced by chronic lipopolysaccharide administration on the survival of hypocretin neurons and sleep.
The number of hypocretin-containing neurons is markedly decreased in most patients with the sleep disorder narcolepsy. It is presently not known why the loss of hypocretin neurons occurs in these patients. In the present study, we tested the role of inflammation in the degeneration of hypocretin neurons. The proinflammagen lipopolysaccharide (LPS) was infused chronically for 30 days (flow rate=0.22 microg/h) into the lateral hypothalamus in rats. Compared with chronic infusions of phosphate-buffered saline (PBS), LPS infusions produced a decline in the number of hypocretin (29.7% reduction), melanin concentrating hormone (MCH; 24.7% reduction), and neuronal nuclear antigen (NeuN)-immunoreactive neurons, as well as a dense distribution of reactive astrocytes and microglia within the lateral hypothalamus. LPS infusions also produced a large increase in the amounts of wakefulness 6 days after the onset of infusion (72.5+/-8.7% of wakefulness during lights-on period compared with 45.3+/-1.8% in PBS-treated rats). Amounts of wakefulness returned to control levels in all LPS-treated rats 30 days after the onset of infusion. A single injection of LPS (1, 5, or 10 microg) did not produce a significant decline in the number of hypocretin, MCH, or NeuN-positive neurons. The loss of hypocretin neurons produced by chronic LPS administration suggests that inflammation may play a role in the loss of hypocretin neurons in narcolepsy.
West Roxbury VA Medical Center and Harvard Medical School, 1400 VFW Parkway, West Roxbury, MA 02132, USA. dmitri_gerachtchenko@hms.harvard.edu
Dmitry
D
Gerashchenko
Priyattam J
PJ
Shiromani
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000187:drug effects / Q000502:physiology*
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D009479:Neuropeptides; D000068797:Orexins