Continuous intrathecal orexin delivery inhibits cataplexy in a murine model of narcolepsy
Continuous intrathecal orexin delivery inhibits cataplexy in a murine model of narcolepsy
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连续鞘内注射食欲素可抑制发作性睡病小鼠模型的猝倒
DOI：
10.1073/pnas.1722686115
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Yanagisawa Masashi
中科院分区：
文献类型：
--
作者：
Kaushik Mahesh K.;Aritake Kosuke;Imanishi Aya;Kanbayashi Takashi;Ichikawa Tadashi;Shimizu Tetsuo;Urade Yoshihiro;Yanagisawa Masashi
发作性睡病是一种慢性神经系统疾病，由产生食欲素（下丘脑泌素）的神经元丢失引起，与白天过度嗜睡、睡眠发作、昏厥、睡眠麻痹、临睡幻觉和夜间睡眠片段有关。目前，人类发作性睡病的治疗方法是提供对症治疗，这可能与一系列副作用有关。虽然外周给药的食欲素不能有效地穿透血脑屏障，但中枢递送的食欲素可以有效地缓解动物模型中的发作性睡眠症状。通过植入式泵进行慢性鞘内药物输注是治疗许多神经系统疾病的临床可用策略。在这里，我们证明了食欲素基因敲除小鼠的发作性睡眠症状可以通过腰部鞘内给予食欲素来逆转。通过在上腰椎水平长期植入鞘内导管输送食欲素。计算机断层扫描证实，鞘内注射的造影剂迅速从脊髓移动到大脑。通过放射免疫测定法在脑中检测到鞘内递送的食欲素，其水平与内源性食欲素水平相当。在缓慢输注食欲素（1 nmol/1 µL/h）期间和之后很长一段时间内，食欲素敲除小鼠的紧张症和睡眠发作REM睡眠显著减少。睡眠/觉醒状态在数量和质量上都保持不变。鞘内促食欲素未能诱导双促食欲素受体-1和-2敲除小鼠的任何变化。本研究支持鞘内给予食欲素作为治疗发作性睡病的一种潜在疗法，以改善患者的健康状况。
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. Currently, human narcolepsy is treated by providing symptomatic therapies, which can be associated with an array of side effects. Although peripherally administered orexin does not efficiently penetrate the blood–brain barrier, centrally delivered orexin can effectively alleviate narcoleptic symptoms in animal models. Chronic intrathecal drug infusion through an implantable pump is a clinically available strategy to treat a number of neurological diseases. Here we demonstrate that the narcoleptic symptoms of orexin knockout mice can be reversed by lumbar-level intrathecal orexin delivery. Orexin was delivered via a chronically implanted intrathecal catheter at the upper lumbar level. The computed tomographic scan confirmed that intrathecally administered contrast agent rapidly moved from the spinal cord to the brain. Intrathecally delivered orexin was detected in the brain by radioimmunoassay at levels comparable to endogenous orexin levels. 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). Sleep/wake states remained unchanged both quantitatively as well as qualitatively. Intrathecal orexin failed to induce any changes in double orexin receptor-1 and -2 knockout mice. This study supports the concept of intrathecal orexin delivery as a potential therapy for narcolepsy–cataplexy to improve the well-being of patients.
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影响因子：
17.1
作者：
Dagdeviren C;Ramadi KB;Joe P;Spencer K;Schwerdt HN;Shimazu H;Delcasso S;Amemori KI;Nunez-Lopez C;Graybiel AM;Cima MJ;Langer R
通讯作者：
Langer R
DOI：
10.1073/pnas.0400590101
发表时间：
2004-03-30
影响因子：
11.1
作者：
Mieda, M;Willie, JT;Yanagisawa, M
通讯作者：
Yanagisawa, M
下丘脑分泌素替代疗法对患有发作性睡病的 3 岁威玛猎犬的效果。
影响因子：
2.6
作者：
S. Schatzberg;K. Cutter;D. Nydam;J. Barrett;R. Penn;J. Flanders;A. Delahunta;Ling Lin;E. Mignot
通讯作者：
E. Mignot
影响因子：
1
作者：
C. Inocente;I. Arnulf;H. Bastuji;A. Thibault-Stoll;A. Raoux;R. Reimão;Jian-Sheng Lin;P. Franco
通讯作者：
C. Inocente;I. Arnulf;H. Bastuji;A. Thibault-Stoll;A. Raoux;R. Reimão;Jian-Sheng Lin;P. Franco
全身给予hypocretin-1可减少发作性睡病犬的猝倒并使睡眠和清醒持续时间正常化。
DOI：
--
发表时间：
2000
期刊：
Sleep research online : SRO
影响因子：
--
作者：
John,J;Wu,MF;Siegel,JM
通讯作者：
Siegel,JM