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Hypocretin-saporin (Hcrt-sap) as a tool to examine hypocretin function.

Gerashchenko D, Kohls MD, Greco MA, Waleh NS, Salin-Pascual R, Kilduff TS, Lappi DA, Shiromani PJ (2001) Hypocretin-saporin (Hcrt-sap) as a tool to examine hypocretin function. Neuroscience 2001 Abstracts 410.7. Society for Neuroscience, San Diego, CA.

Summary: The hypocretin (Hcrt) peptides are linked to narcolepsy. Humans with narcolepsy have decreased numbers of Hcrt neurons and Hcrt-null mice have narcoleptic symptoms. Hcrt neurons are located only in the lateral hypothalamus (LH) but neither lesions of this nor any other brain region have produced narcoleptic-like sleep, suggesting that specific neurons need to be destroyed. To facilitate lesioning the Hcrt neurons, the ribosome inactivating protein, saporin (SAP), was conjugated to Hcrt-2/orexin B. In vitro binding studies indicated specificity of Hcrt-SAP since it preferentially bound to CHO-cells containing the HcrtR2/OX2 receptor compared to the HcrtR1/OX1 receptor, but not to KNRK cells stably transfected with the NK1 receptor. In vivo specificity was confirmed since administration of the toxin to the LH eliminated some neurons (Hcrt, MCH, and histamine) but not others (alpha-MSH). When the toxin was administered to the LH, rats (n=19) had increased slow wave sleep, REM sleep, and sleep-onset REM sleep periods at night. These were negatively correlated with the loss of Hcrt-containing neurons (r=-0.74; p<0.01). Toxin applied to hypothalamic neurons that are not Hcrt positive but contain the Hcrt receptor lesioned the neurons but did not produce narcoleptic-like sleep. These findings indicate the utility of Hcrt-SAP as a tool and also demonstrate that damage to the LH that also includes a substantial loss of Hcrt neurons is likely to produce the sleep disturbances that occur in narcolepsy.

Related Products: Orexin-B-SAP (Cat. #IT-20)

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