1,106
Views
3
CrossRef citations to date
0
Altmetric
Review

An overview of hypocretin based therapy in narcolepsy

, , , , &
Pages 389-406 | Received 15 Mar 2018, Accepted 28 Mar 2018, Published online: 09 Apr 2018

References

  • ICSD-3. ed. International classification of sleep disorders. 3rd ed. American Sleep Disorders Association: Rochester (MN), 2014.
  • Hublin C, Kaprio J, Partinene M, et al. The prevalence of narcolepsy: an epidemiological study of the Finnish twin cohort. Ann Neurol. 1994;35:709–716.
  • Tashiro T, Kanbayashi T, Hishikawa Y An epidemiological study of narcolepsy in Japanese. The 4th International Symposium on Narcolepsy; 1994; Tokyo, Japan; p. 13.
  • Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology. 2001 Dec 11;57(11):2029–2033.
  • Mignot E, Hayduk R, Grumet FC, et al. HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients. Sleep. 1997;20(11):1012–1020.
  • Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002 Oct;59(10):1553–1562.
  • Nishino S, Ripley B, Overeem S, et al. (Orexin) deficiency in human narcolepsy. Lancet. 2000;355(9197):39–40.
  • Nishino S, Mignot E. Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol. 1997 May;52(1):27–78.
  • Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet. 2007 Feb 10;369(9560):499–511.
  • Scammell TE. Narcolepsy. N Engl J Med. 2015 Dec 31;373(27):2654–2662.
  • Serlin Y, Shelef I, Knyazer B, et al. Physiology of the blood-brain barrier. Semin Cell Dev Biol. 2015 Feb 11;38:2–6.
  • Dhuria SV, Hanson LR, Frey WH 2nd. Intranasal drug targeting of hypocretin-1 (orexin-A) to the central nervous system. J Pharm Sci. 2009 Jul;98(7):2501–2515.
  • Deadwyler SA, Porrino L, Siegel JM, et al. Systemic and nasal delivery of orexin-A (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci. 2007 Dec 26; 27(52):14239–14247.
  • Baier PC, Hallschmid M, Seeck-Hirschner M, et al. Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy. Sleep Med. 2011 Dec;12(10):941–946. Epub 11 Oct 28.
  • Weinhold SL, Seeck-Hirschner M, Nowak A, et al. The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy. Behav Brain Res. 2014 Apr 01;262:8–13. Epub 14 Jan 7.
  • Dhuria SV, Hanson LR, Frey WH 2nd. Novel vasoconstrictor formulation to enhance intranasal targeting of neuropeptide therapeutics to the central nervous system. J Pharmacol Exp Ther. 2009 Jan;328(1):312–320. Epub 2008 Oct 22.
  • Nagahara T, Saitoh T, Kutsumura N, et al. Design and synthesis of non-peptide, selective orexin receptor 2 agonists. J Med Chem. 2015 Oct 22;58(20):7931–7937. Epub 2015 Aug 26.
  • Irukayama-Tomobe Y, Ogawa Y, Tominaga H, et al. Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. Proc Natl Acad Sci USA. 2017 May 30;114(22):5731–5736. Epub 2017 May 15.
  • Mieda M, Willie JT, Hara J, et al. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci USA. 2004 Mar 16; 101(13):4649–4654.
  • Liu M, Thankachan S, Kaur S, et al. Orexin (hypocretin) gene transfer diminishes narcoleptic sleep behavior in mice. Eur J Neurosci. 2008 Oct;28(7):1382–1393.
  • Liu M, Blanco-Centurion C, Konadhode R, et al. Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice. J Neurosci. 2011 Apr 20;31(16):6028–6040.
  • Blanco-Centurion C, Liu M, Konadhode R, et al. Effects of orexin gene transfer in the dorsolateral pons in orexin knockout mice. Sleep. 2013 Jan 1;36(1):31–40.
  • Liu M, Blanco-Centurion C, Konadhode RR, et al. Orexin gene transfer into the amygdala suppresses both spontaneous and emotion-induced cataplexy in orexin-knockout mice. Eur J Neurosci. 2016 Mar;43(5):681–688. Epub 2016 Feb 3.
  • Arias-Carrion O, Murillo-Rodriguez E, Xu M, et al. Transplant of hypocretin neurons into the pontine reticular formation: preliminary results. Sleep. 2004;27:1465–1470.
  • Arias-Carrion O, Murillo-Rodriguez E. Effects of hypocretin/orexin cell transplantation on narcoleptic-like sleep behavior in rats. PLoS One. 2014 Apr 15;9(4):e95342. eCollection 2014.
  • Hayakawa K, Hirosawa M, Tabei Y, et al. Epigenetic switching by the metabolism-sensing factors in the generation of orexin neurons from mouse embryonic stem cells. J Biol Chem. 2013 Jun 14;288(24):17099–17110. Epub 2013 Apr 26.
  • Wang L, Meece K, Williams DJ, et al. Differentiation of hypothalamic-like neurons from human pluripotent stem cells. J Clin Invest. 2015 Feb 2;125:796–808. Epub 2015 Jan 2.
  • Merkle FT, Maroof A, Wataya T, et al. Generation of neuropeptidergic hypothalamic neurons from human pluripotent stem cells. Development. 2015 Feb 15;142(4):633–643.
  • Niewoehner J, Bohrmann B, Collin L, et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron. 2014 Jan 8;81(1):49–60.
  • Dauvilliers Y, Abril B, Mas E, et al. Normalization of hypocretin-1 in narcolepsy after intravenous immunoglobulin treatment. Neurology. 2009 Oct 20;73(16):1333–1334.
  • Dauvilliers Y, Carlander B, Rivier F, et al. Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset. Ann Neurol. 2004 Dec;56(6):905–908.
  • Plazzi G, Poli F, Franceschini C, et al. Intravenous high-dose immunoglobulin treatment in recent onset childhood narcolepsy with cataplexy. J Neurol. 2008 Oct;255(10):1549–1554.
  • Chen W, Black J, Call P, et al. Late-onset narcolepsy presenting as rapidly progressing muscle weakness: response to plasmapheresis. Ann Neurol. 2005 Sep;58(3):489–490.
  • Hecht M, Lin L, Kushida CA, et al. Report of a case of immunosuppression with prednisone in an 8-year-old boy with an acute onset of hypocretin-deficiency narcolepsy. Sleep. 2003 Nov 1;26(7):809–810.
  • Coelho FM, Pradella-Hallinan M, Alves GR, et al. Report of two narcoleptic patients with remission of hypersomnolence following use of prednisone. Arq Neuropsiquiatr 2007 Jun;65(2A):336–7.
  • Donjacour CE, Lammers GJ. A remarkable effect of alemtuzumab in a patient suffering from narcolepsy with cataplexy. J Sleep Res. 2012 Aug;21(4):479–480. Epub 2011 Dec 5.
  • Nishino S, Kanbayashi T. Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med Rev. 2005;9(4):269–310.
  • Arand D, Bonnet M, Hurwitz T, et al. The clinical use of the MSLT and MWT. Sleep. 2005 Jan;28(1):123–144.
  • Murray BJ. A practical approach to excessive daytime sleepiness: a focused review. Can Respir J. 2016;2016:4215938. Epub 2016 May 12.
  • Akimoto H, Honda Y, Takahashi Y. Pharmacotherapy in narcolepsy. Dis Nerv Syst. 1960 Dec;21:704–706.
  • Guilleminault C, Carskadon M, Dement WC. On the treatment of rapid eye movement narcolepsy. Arch Neurol. 1974 Jan;30(1):90–93.
  • Parkes JD, Baraitser M, Marsden CD, et al. Natural history, symptoms and treatment of the narcoleptic syndrome. Acta Neurol Scand. 1975 Nov;52(5):337–353.
  • Passouant P, Billiard M. [Narcolepsy]. Rev Prat. 1976 May 11;26(27):1917–1923.
  • Dauvilliers Y, Billiard M, Montplaisir J. Clinical aspects and pathophysiology of narcolepsy. Clin Neurophysiol. 2003 Nov;114(11):2000–2017.
  • Guilleminault C, Kryger MH, Roth T, et al. Narcolepsy syndrome. Principles and practice of sleep medicine. 2nd ed. Chicago: Elsevier; 1994. p. 549–561.
  • Juji T, Satake M, Honda Y, et al. HLA antigens in Japanese patients with narcolepsy. All the patients were DR2 positive. Tissue Antigens. 1984 Nov;24(5):316–319.
  • Hishikawa Y, Wakamatsu H, Furuya E, et al. Sleep satiation in narcoleptic patients. Electroencephalogr Clin Neurophysiol. 1976;41:1–18.
  • Broughton R, Dunham W, Newman J, et al. Ambulatory 24 hour sleep-wake monitoring in narcolepsy-cataplexy compared to matched control. Electroenceph Clin Neurophysiol. 1988;70:473–481.
  • Montplaisir J, Billard M, Takahashi S, et al. Twenty-four-hour recording in REM-narcoleptics with special reference to nocturnal sleep disruption. Biol Psych. 1978;13(1):78–89.
  • Godbout R, Montplaisir J. Comparison of sleep parameters in narcoleptics with and without periodic movements of sleep. In: Koella WP, Ruther E, Schulz H, editors. Sleep ‘84. Stuttgart, Germany: Fischer Verlag; 1985. p. 380–382.
  • Mosko SS, Shampain DS, Sassin JF. Nocturnal REM latency and sleep disturbance in narcolepsy. Sleep. 1984;7:115–125.
  • Mayer G, Pollmächer T, Meier-Ewert K, et al. Zur Einschätzung des Behinderungsgrades bei Narkolepsie. Gesundh-Wes. 1993;55:337–342.
  • Schenck CH, Mahowald MW. Motor dyscontrol in narcolepsy: rapid-eye-movement (REM) sleep without atonia and REM sleep behavior disorder. Annals of Neurology. 1992;32(1):3–10.
  • Chokroverty S. Sleep apnea in narcolepsy. Sleep. 1986;9(1):250–253.
  • Guilleminault C, Dement WC, Passouant P, eds. Narcolepsy. New York: Spectrum Publications; 1976.
  • Ferri R, Franceschini C, Zucconi M, et al. Searching for a marker of REM sleep behavior disorder: submentalis muscle EMG amplitude analysis during sleep in patients with narcolepsy/cataplexy. Sleep. 2008 Oct;31(10):1409–1417.
  • Juji T, Matsuki K, Tokunaga K, et al. Narcolepsy and HLA in the Japanese. Ann N Y Acad Sci. 1988;540:106–114.
  • Hirtz C, Vialaret J, Gabelle A, et al. From radioimmunoassay to mass spectrometry: a new method to quantify orexin-A (hypocretin-1) in cerebrospinal fluid. Sci Rep. 2016;6:25162.
  • Liguori C, Placidi F, Albanese M, et al. CSF beta-amyloid levels are altered in narcolepsy: a link with the inflammatory hypothesis? J Sleep Res. 2014 Aug;23(4):420–424. Epub 2014 Feb 19.
  • Schmidt FM, Kratzsch J, Gertz HJ, et al. Cerebrospinal fluid melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) in Alzheimer’s disease. PLoS One. 2013 May 7;8(5):e63136. Print 2013.
  • Ono T. 0668 Evaluation of commercial RIA and ELISA for measuring CSF orexin-A (hypocretin-1). Sleep. 2017;40(suppl_1):A247–A47.
  • ICSD-2. ed. ICSD-2-International classification of sleep disorders. 2nd ed. Diagnostic and coding manual. Westchester, Illinois: American Academy of Sleep Medicine;2005.
  • Tsai S, Santamaria P. MHC class II polymorphisms, autoreactive T-cells, and autoimmunity. Front Immunol. 2013 Oct 10;4: 321.
  • Dauvilliers Y, Maret S, Bassetti C, et al. A monozygotic twin pair discordant for narcolepsy and CSF hypocretin-1. Neurology. 2004 Jun 8;62(11):2137–2138.
  • Bardage C, Persson I, Ortqvist A, et al. Neurological and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a monovalent adjuvanted vaccine: population based cohort study in Stockholm, Sweden. BMJ. 2011 Oct 12;343:d5956.
  • Partinen M, Saarenpaa-Heikkila O, Ilveskoski I, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One. 2012;7(3):e33723. Epub 2012 Mar 28.
  • Nohynek H, Jokinen J, Partinen M, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One. 2012;7(3):e33536. Epub 2012 Mar 28.
  • Han F, Lin L, Warby SC, et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol. 2011 Sep;70(3):410–417. Epub 2011 Aug 22.
  • Picchioni D, Hope CR, Harsh JR. A case-control study of the environmental risk factors for narcolepsy. Neuroepidemiology. 2007;29(3–4):185–192. Epub 2007 Nov 27.
  • Aran A, Lin L, Nevsimalova S, et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep. 2009 Aug;32(8):979–983.
  • Ambati A, Poiret T, Svahn BM, et al. Increased beta-haemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular immune responses in Swedish narcolepsy cases. J Intern Med. 2015 Sep;278(3):264–276. Epub 2015 Mar 22.
  • Dauvilliers Y, Arnulf I, Lecendreux M, et al. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain. 2013;136(8):2486–2496.
  • Winstone AM, Stellitano L, Verity C, et al. Clinical features of narcolepsy in children vaccinated with AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in England. Dev Med Child Neurol. 2014 Nov;56(11):1117–1123. Epub 2014 Jul 10.
  • O’Flanagan D, Barret AS, Foley M, et al. Investigation of an association between onset of narcolepsy and vaccination with pandemic influenza vaccine, Ireland April 2009-December 2010. Euro Surveill. 2014 May 1;19(17):15–25.
  • Duffy J, Weintraub E, Vellozzi C, et al. Narcolepsy and influenza A(H1N1) pandemic 2009 vaccination in the United States. Neurology. 2014 Nov 11;83(20):1823–1830. Epub 2014 Oct 15.
  • Montplaisir J, Petit D, Quinn M-J, et al. Risk of narcolepsy associated with inactivated adjuvanted (AS03) A/H1N1 (2009) pandemic influenza vaccine in Quebec. Plos One. 2014;9(9):e108489.
  • Ahmed SS, Schur PH, MacDonald NE, et al. Narcolepsy, 2009 A(H1N1) pandemic influenza, and pandemic influenza vaccinations: what is known and unknown about the neurological disorder, the role for autoimmunity, and vaccine adjuvants. J Autoimmun. 2014 May;50:1–11. Epub 14 Feb 19.
  • Ahmed SS, Volkmuth W, Duca J, et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl Med. 2015 Jul 1;7(294):294ra105.
  • Nakamura M, Nishida S, Hayashida K, et al. Differences in brain morphological findings between narcolepsy with and without cataplexy. Plos One. 2013;8(11):e81059.
  • Ripley B, Fujiki N, Okura M, et al. Hypocretin levels in sporadic and familial cases of canine narcolepsy. Neurobiol of Dis. 2001 Jun;8(3):525–534.
  • Thannickal TC, Nienhuis R, Siegel JM. Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep. 2009 Aug 1;32(8):993–998.
  • Garma L, Marchand F. Non-pharmacological approaches to the treatment of narcolepsy. Sleep. 1994 Dec;17(8 Suppl):S97–102.
  • Roehrs T, Zorick F, Wittig R, et al. Alerting effects of naps in patients with narcolepsy. Sleep. 1986;9(1):194–199.
  • Rogers AE. Problems and coping strategies identified by narcoleptic patients. J Neurosurg Nurs. 1984 Dec;16(6):326–334.
  • Morgenthaler TI, Kapur VK, Brown T, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep. 2007 Dec;30(12):1705–1711.
  • Hirai N, Nishino S. Recent advances in the treatment of narcolepsy. Curr Treat Options Neurol. 2011 Oct;13(5):437–457.
  • JUSTICE DEAUSDO. Scheduling actions - alphabetical order. [ cited 2017 Sep27]. Available from: https://www.deadiversion.usdoj.gov/schedules/orangebook/a_sched_alpha.pdf
  • Moldofsky H, Broughton RJ, Hill JD. A randomized trial of the long-term, continued efficacy and safety of modafinil in narcolepsy. Sleep Med. 2000 Apr 1;1(2):109–116.
  • Drakatos P, Lykouras D, D’Ancona G, et al. Safety and efficacy of long-term use of sodium oxybate for narcolepsy with cataplexy in routine clinical practice. Sleep Med. 2017 Jul;35:80–84. Epub 17 May 6.
  • Mahowald MW, Bornemann MA. Stimulants and narcolepsy. Sleep. 2005 Jun;28(6):663.
  • Rogers AE, Aldrich MS, Berrios AM, et al. Compliance with stimulant medications in patients with narcolepsy. Sleep. 1997 Jan;20(1):28–33.
  • Auger RR, Goodman SH, Silber MH, et al. Risks of high-dose stimulants in the treatment of disorders of excessive somnolence: a case-control study. Sleep. 2005 Jun 1;28(6):667–672.
  • Nishino S, Ripley B, Mignot E, et al. CSF hypocretin-1 levels in schizophrenics and controls: relationship to sleep architecture. Psychiatry Res. 2002 May 15;110(1):1–7.
  • Shiba T. Wake promoting effects of thioperamide, a histamine H3 antagonist in orexin/ataxin-3 narcoleptic mice. Sleep. 2004;27(suppl):A241–A42.
  • Parmentier R, Anaclet C, Guhennec C, et al. The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders. Biochem Pharmacol. 2007 Apr 15;73(8):1157–1171.
  • Dauvilliers Y, Bassetti C, Lammers GJ, et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013 Nov;12(11):1068–1075.
  • Nishino S, Mao J, Sampathkumaran R, et al. Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants. Sleep Res Online. 1998;1(1):49–61.
  • Kanbayashi T, Honda K, Kodama T, et al. Implication of dopaminergic mechanisms in the wake-promoting effects of amphetamine: a study of D- and L-derivatives in canine narcolepsy. Neuroscience. 2000;99(4):651–659.
  • Bogan RK, Feldman N, Emsellem HA, et al. Effect of oral JZP-110 (ADX-N05) treatment on wakefulness and sleepiness in adults with narcolepsy. Sleep Med. 2015 Sep;16(9):1102–1108. Epub 15 Jun 3.
  • Ruoff C, Swick TJ, Doekel R, et al. Effect of oral JZP-110 (ADX-N05) on wakefulness and sleepiness in adults with narcolepsy: a phase 2b study. Sleep. 2016 Jul 1;39(7):1379–1387.
  • Schweitzer PK, Rosenberg R, Zammit GK, et al. 0641 A phase 3, randomized, placebo-controlled, double-blind, 12-week, multicenter study of the efficacy and safety of JZP-110 for the treatment of excessive sleepiness in patients with obstructive sleep apnea. Sleep. 2017;40(suppl_1):A237–A37.
  • ADMINISTRATION USFD. Xyrem (sodium oxybate) information. [ cited 2017 Sep 27]. Available from: https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm332408.htm
  • Mamelak M, Black J, Montplaisir J, et al. A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep. 2004 Nov 1;27(7):1327–1334.
  • Swick TJ. Treatment paradigms for cataplexy in narcolepsy: past, present, and future. Nat Sci Sleep. 2015 Dec 11;7:159–169.
  • Santarsieri D, Schwartz TL. Antidepressant efficacy and side-effect burden: a quick guide for clinicians. Drugs Context. 2015 Oct 8;4:212290.
  • Thase ME. Depression, sleep, and antidepressants. J Clin Psychiatry. 1998;59(Suppl 4):55–65.
  • Sakurai T. Roles of orexins in regulation of feeding and wakefulness. Neuroreport. 2002;13(8):987–995.
  • Brown RE, Basheer R, McKenna JT, et al. Control of sleep and wakefulness. Physiological Reviews. 2012;92(3):1087–1187.
  • Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci. 2007 Mar;8(3):171–181. Epub 2007 Feb 14.
  • Marcus JN, Aschkenasi CJ, Lee CE, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol. 2001;435(1):6–25.
  • Willie JT, Chemelli RM, Sinton CM, et al. Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice: molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron. 2003 Jun 5;38(5):715–730.
  • Mieda M, Hasegawa E, Kisanuki YY, et al. Differential roles of orexin receptor-1 and −2 in the regulation of non-REM and REM sleep. J Neurosci. 2011 Apr 27;31(17):6518–6526.
  • Fujiki N, Yoshida Y, Ripley B, et al. Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog. Sleep. 2003 Dec 15; 26(8):953–959.
  • Mishima K, Fujiki N, Yoshida Y, et al. Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy. Sleep. 2008 Aug 1;31(8):1119–1126.
  • Schatzberg SJ, Barrett J, Cutter K, et al. Effect of hypocretin replacement therapy in a 3-year-old Weimaraner with narcolepsy. J Vet Internal Med. 2004;18(4):586–588.
  • Yoshida Y, Fujiki N, Maki RA, et al. Differential kinetics of hypocretins in the cerebrospinal fluid after intracerebroventricular administration in rats. Neurosci Lett. 2003 Aug 7;346(3):182–186.
  • Kastin AJ, Akerstrom V. Orexin A but not orexin B rapidly enters brain from blood by simple diffusion. JPET. 1999;289:219–223.
  • Prokai L. Peptide drug delivery into the central nervous system. In: Jucker E, editor. Progress in drug research. Basel, Switzerland: Birkhäuser Verlag. 1998. p. 95–131.
  • Darker JG, Porter RA, Eggleston DS, et al. Structure-activity analysis of truncated orexin-A analogues at the orexin-1 receptor. Bioorg Med Chem Lett. 2001;11(5):737–740.
  • Asahi S, Egashira S, Matsuda M, et al. Structure-activity relationship studies on the novel neuropeptide orexin. In: Fujii N, editor. The Japanese Peptide Society. Saga, Japan: the Japanese Peptide Society; 2000:37–40.
  • Begley DJ, Brightman MW. Structural and functional aspects of the blood-brain barrier. Prog Drug Res. 2003;61:39–78.
  • Laterra J, Keep R, Betz AL, et al. Blood-brain-cerebrospinal fluid barriers. Basic neurochemistry: molecular, cellular and medical aspects. Philadelphia, USA: Lippincott-Raven Publishers; 1999. p. 671–689.
  • Brightman MW. Morphology of blood-brain interfaces. Exp Eye Res. 1977;25(Suppl):1–25.
  • Johanson C. Ventricles and cerebrospinal fluid. In: Conn PM, editor. Neuroscience in medicine. Philadelphia, USA: J.B Lippincott Company; 1995. p. 171–196.
  • Stanimirovic DB, Bani-Yaghoub M, Perkins M, et al. Blood-brain barrier models: in vitro to in vivo translation in preclinical development of CNS-targeting biotherapeutics. Expert Opin Drug Discov. 2015 Feb;10(2):141–155. Epub 2014 Nov 12.
  • Prokai-Tatrai K, Prokai L. Modifying peptide properties by prodrug design for enhanced transport into the CNS. Prog Drug Res. 2003;61:155–188.
  • Grondin R, Zhang Z, Ai Y, et al. Intracranial delivery of proteins and peptides as a therapy for neurodegenerative diseases. Prog Drug Res. 2003;61:101–123.
  • Kim HY, Hong E, Kim JI, et al. Solution structure of human orexin-A: regulator of appetite and wakefulness. J Biochem Mol Biol. 2004 Sep 30;37(5):565–573.
  • Lee JH, Bang E, Chae KJ, et al. Solution structure of a new hypothalamic neuropeptide, human hypocretin-2/orexin-B. Eur J Biochem. 1999 Dec;266(3):831–839.
  • Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 1997 Jan 15;23(1):3–25.
  • Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92(4):573–585.
  • Frey WH, Liu J, Chen X, et al. Delivery of 125I-NGF to the brain via the olfactory route. Drug Delivery. 1997;4(2):87–92.
  • Dhanda DS, Frey W, Leopold D, et al. Approaches for drug deposition in the human olfactory epithelium. Drug Deliv Technol. 2005;5(4):64–72.
  • Frey WH. Intranasal delivery: bypassing the blood-brain barrier to deliver therapeutic agents to the brain and spinal cord. Drug Deliv Technol. 2002;2(5):46–49.
  • Thorne RG, Frey WH 2nd. Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations. Clin Pharmacokinet. 2001;40(12):907–946.
  • Chen XQ, Fawcett JR, Rahman YE, et al. Delivery of nerve growth factor to the brain via the olfactory pathway. J Alzheimers Dis. 1998 Mar;1(1):35–44.
  • Thorne RG, Pronk GJ, Padmanabhan V, et al. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience. 2004;127(2):481–496.
  • Ross TM, Martinez PM, Renner JC, et al. Intranasal administration of interferon beta bypasses the blood-brain barrier to target the central nervous system and cervical lymph nodes: a non-invasive treatment strategy for multiple sclerosis. J Neuroimmunol. 2004 Jun;151(1–2):66–77.
  • Hanson LR, Fine JM, Svitak AL, et al. Intranasal administration of CNS therapeutics to awake mice. J Vis Exp. 2013 Apr 08(74). DOI:10.3791/4440
  • Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. 2012 Nov;32(11):1959–1972. Epub 12 Aug 29.
  • Wang D, El-Amouri SS, Dai M, et al. Engineering a lysosomal enzyme with a derivative of receptor-binding domain of apoE enables delivery across the blood-brain barrier. Proc Natl Acad Sci USA. 2013 Feb 19;110(8):2999–3004. Epub 2013 Feb 4.
  • Pardridge WM, Boado RJ. Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier. Methods Enzymol. 2012;503:269–92.
  • Yu YJ, Zhang Y, Kenrick M, et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med. 2011 May 25;3(84):84ra44.
  • Hruby VJ. Designing peptide receptor agonists and antagonists. Nat Rev Drug Discov. 2002 Nov;1(11):847–858.
  • Yin J, Babaoglu K, Brautigam CA, et al. Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors. Nat Struct Mol Biol. 2016 Apr;23(4):293–299. Epub 2016 Mar 7.
  • Kantor S, Mochizuki T, Lops SN, et al. Orexin gene therapy restores the timing and maintenance of wakefulness in narcoleptic mice. Sleep. 2013 Aug 1;36(8):1129–1138.
  • Perlow MJ, Freed WJ, Hoffer BJ, et al. Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine system. Science. 1979;204(4393):643–647.
  • Dunnett SB, Bjorklund A, Schmidt RH. Intracerebral grafting of neuronal cell suspensions. V. Behavioural recovery in rats with bilateral 6-OHDA lesions following implantation of nigral cell suspensions. Acta Physiologica Scandinavica. 1983;118(SUPPL. 522):39–47.
  • Dunnett SB, Hernandez TD, Summerfield A, et al. Graft-derived recovery from 6-OHDA lesions: specificity of ventral mesencephalic graft tissues. Exp Brain Res. 1988;71(2):411–424.
  • Björklund A, Schmidt RH, Stenevi U. Functional reinnervation of the neostriatum in the adult rat by use of intraparenchymal grafting of dissociated cell suspensions from the substantia nigra. Cell and Tissue Research. 1980;212(1):39–45.
  • Kefalopoulou Z, Politis M, Piccini P, et al. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol. 2014 Jan;71(1):83–87.
  • Aldrin-Kirk P, Heuer A, Wang G, et al. DREADD modulation of transplanted DA neurons reveals a novel parkinsonian dyskinesia mechanism mediated by the serotonin 5-HT6 receptor. Neuron. 2016 Jun 01;90(5):955–968. Epub 16 May 5.
  • Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27(3):469–474.
  • Borlongan CV, Stahl CE, Cameron DF, et al. CNS immunological modulation of neural graft rejection and survival. Neurol Res. 1996 Aug;18(4):297–304.
  • Kawashima M, Lin L, Tanaka S, et al. Anti-Tribbles homolog 2 (TRIB2) autoantibodies in narcolepsy are associated with recent onset of cataplexy. Sleep. 2010 Jul 1;33(7):869–874.
  • Partinen M, Kornum BR, Plazzi G, et al. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol. 2014 Jun;13(6):600–613.
  • Arias-Carrion O, Murillo-Rodriguez E. Cell transplantation: a future therapy for narcolepsy? CNS Neurol Disord Drug Targets. 2009. 8. Aug(4):309–314.
  • Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006 Aug 25;126(4):663–676. Epub 2006 Aug 10.
  • Cai S, Hou J, Fujino M, et al. iPSC-derived regulatory dendritic cells inhibit allograft rejection by generating alloantigen-specific regulatory T cells. Stem Cell Reports. 2017 May 09;8(5):1174–1189. Epub 17 Apr 20.
  • Mahlios J, De La Herran-Arita AK, Mignot E. The autoimmune basis of narcolepsy. Curr Opin Neurobiol. 2013 Oct;23(5):767–773. Epub 13 May 29.
  • Knudsen S, Biering-Sorensen B, Kornum BR, et al. Early IVIg treatment has no effect on post-H1N1 narcolepsy phenotype or hypocretin deficiency. Neurology. 2012 Jul 3;79(1):102–103. Epub 2012 Jun 20.
  • Knudsen S, Mikkelsen JD, Bang B, et al. Intravenous immunoglobulin treatment and screening for hypocretin neuron-specific autoantibodies in recent onset childhood narcolepsy with cataplexy. Neuropediatrics. 2010 Oct 5;41:217–222.
  • Valko PO, Khatami R, Baumann CR, et al. No persistent effect of intravenous immunoglobulins in patients with narcolepsy with cataplexy. J Neurol. 2008 Dec;255(12):1900–1903. Epub 2008 Sep 25.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.