On the other hand, intrathecal drug delivery has proven effective in humans for various other conditions, e.g., intrathecal delivery of baclofen for severe pain and spastic paresis ( 19– 22). Although it is effective in rodents, its feasibility and effectiveness in higher animals is not known. Recently, a miniaturized “neural” system has been developed for chronic and local intracerebral drug delivery ( 18).
Highly invasive methods such as ICV administration is nonpractical for human use. Since orexin peptide is unable to cross the blood–brain barrier (BBB) upon peripheral administration ( 6), it needs to be delivered centrally. Orexin replacement therapy that restores orexin signaling by intracerebroventricular (ICV) administration prevents cataplexy in ligand-deficient mice ( 17). Orexin has widespread projections to the brain areas that are involved in sleep/wake regulation, including specific nuclei in the brainstem, hypothalamus, and basal forebrain ( 1, 16). The neuropeptides orexin-A and orexin-B, also known as hypocretins, are produced from the common precursor preproorexin and act via two G protein-coupled receptors OX1R and OX2R ( 14, 15). This study supports the concept of intrathecal orexin delivery as a potential therapy for narcolepsy–cataplexy to improve the well-being of patients. Intrathecal orexin failed to induce any changes in double orexin receptor-1 and -2 knockout mice. Sleep/wake states remained unchanged both quantitatively as well as qualitatively. Cataplexy and sleep-onset REM sleep were significantly decreased in orexin knockout mice during and long after slow infusion of orexin (1 nmol/1 µL/h). Intrathecally delivered orexin was detected in the brain by radioimmunoassay at levels comparable to endogenous orexin levels. The computed tomographic scan confirmed that intrathecally administered contrast agent rapidly moved from the spinal cord to the brain. Orexin was delivered via a chronically implanted intrathecal catheter at the upper lumbar level. Here we demonstrate that the narcoleptic symptoms of orexin knockout mice can be reversed by lumbar-level intrathecal orexin delivery. Chronic intrathecal drug infusion through an implantable pump is a clinically available strategy to treat a number of neurological diseases. Although peripherally administered orexin does not efficiently penetrate the blood–brain barrier, centrally delivered orexin can effectively alleviate narcoleptic symptoms in animal models. Currently, human narcolepsy is treated by providing symptomatic therapies, which can be associated with an array of side effects. Narcolepsy–cataplexy is a chronic neurological disorder caused by loss of orexin (hypocretin)-producing neurons, associated with excessive daytime sleepiness, sleep attacks, cataplexy, sleep paralysis, hypnagogic hallucinations, and fragmentation of nighttime sleep.
0 kommentar(er)
