Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Effects of inflammation produced by chronic lipopolysaccharide administration on the survival of hypocretin neurons and sleep. 1530 50

Hypocretin, also known as orexin, maintains the vigilance state and regulates various physiological processes, such as arousal, sleep, food intake, energy expenditure, and reward. Previously, we found that when wild-type mice and hypocretin/ataxin-3 littermates (which are depleted of hypothalamic hypocretin-expressing neurons postnatally) were administered lipopolysaccharide (LPS), the two genotypes exhibited significant differences in their sleep/wake cycle, including differences in the degree of increase in sleep periods and in recovery from sickness behaviour. In the present study, we examined changes in the hypothalamic vigilance system and in the hypothalamic expression of inflammatory factors in response to LPS in hypocretin/ataxin-3 mice. Peripheral immune challenge with LPS affected the hypothalamic immune response and vigilance states. This response was altered by the loss of hypocretin. Hypocretin expression was inhibited after LPS injection in both hypocretin/ataxin-3 mice and their wild-type littermates, but expression was completely abolished only in hypocretin/ataxin-3 mice. Increases in the number of histidine decarboxylase (HDC)-positive cells and in Hdc mRNA expression were found in hypocretin/ataxin-3 mice, and this increase was suppressed by LPS. Hypocretin loss did not impact the change in expression of hypothalamic inflammatory factors in response to LPS, except for interferon gamma and colony stimulating factor 3. The number of c-Fos-positive/HDC-positive cells in hypocretin/ataxin-3 mice administered LPS injections was elevated, even during the rest period, in all areas, suggesting that there is an increase in the activity of histaminergic neurons in hypocretin/ataxin-3 mice following LPS injection. Taken together, our results suggest a novel role for hypocretin in the hypothalamic response to peripheral immune challenge. Our findings contribute to the understanding of the pathophysiology of narcolepsy.
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PMID:Hypocretin/orexin loss changes the hypothalamic immune response. 2731 95

Narcolepsy is caused by the loss of hypocretin (Hcrt) neurons and is associated with multiple genetic and environmental factors. Although abnormalities in immunity are suggested to be involved in the etiology of narcolepsy, no decisive mechanism has been established. We previously reported chemokine (C-C motif) receptor 3 (CCR3) as a novel susceptibility gene for narcolepsy. To understand the role of CCR3 in the development of narcolepsy, we investigated sleep-wake patterns of Ccr3 knockout (KO) mice. Ccr3 KO mice exhibited fragmented sleep patterns in the light phase, whereas the overall sleep structure in the dark phase did not differ between Ccr3 KO mice and wild-type (WT) littermates. Intraperitoneal injection of lipopolysaccharide (LPS) promoted wakefulness and suppressed both REM and NREM sleep in the light phase in both Ccr3 KO and WT mice. Conversely, LPS suppressed wakefulness and promoted NREM sleep in the dark phase in both genotypes. After LPS administration, the proportion of time spent in wakefulness was higher, and the proportion of time spent in NREM sleep was lower in Ccr3 KO compared to WT mice only in the light phase. LPS-induced changes in sleep patterns were larger in Ccr3 KO compared to WT mice. Furthermore, we quantified the number of Hcrt neurons and found that Ccr3 KO mice had fewer Hcrt neurons in the lateral hypothalamus compared to WT mice. We found abnormalities in sleep patterns in the resting phase and in the number of Hcrt neurons in Ccr3 KO mice. These observations suggest a role for CCR3 in sleep-wake regulation in narcolepsy patients.
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PMID:Narcolepsy susceptibility gene CCR3 modulates sleep-wake patterns in mice. 2918 5