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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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General Review Article

Neurophysiology and Treatment of Disorders of Consciousness Induced by Traumatic Brain Injury: Orexin Signaling as a Potential Therapeutic Target

Author(s): Huiling Tang, Qiumei Zhu, Wei Li, Siru Qin, Yinan Gong, Hong Wang, Seiji Shioda, Shanshan Li, Jin Huang, Baohu Liu, Yuxin Fang, Yangyang Liu, Shenjun Wang, Yongming Guo, Qing Xia, Yi Guo* and Zhifang Xu*

Volume 25, Issue 39, 2019

Page: [4208 - 4220] Pages: 13

DOI: 10.2174/1381612825666191029101830

Price: $65

Abstract

Background: Traumatic brain injury (TBI) can cause disorders of consciousness (DOC) by impairing the neuronal circuits of the ascending reticular activating system (ARAS) structures, including the hypothalamus, which are responsible for the maintenance of the wakefulness and awareness. However, the effectiveness of drugs targeting ARAS activation is still inadequate, and novel therapeutic modalities are urgently needed.

Methods: The goal of this work is to describe the neural loops of wakefulness, and explain how these elements participate in DOC, with emphasis on the identification of potential new therapeutic options for DOC induced by TBI.

Results: Hypothalamus has been identified as a sleep/wake center, and its anterior and posterior regions have diverse roles in the regulation of the sleep/wake function. In particular, the posterior hypothalamus (PH) possesses several types of neurons, including the orexin neurons in the lateral hypothalamus (LH) with widespread projections to other wakefulness-related regions of the brain. Orexins have been known to affect feeding and appetite, and recently their profound effect on sleep disorders and DOC has been identified. Orexin antagonists are used for the treatment of insomnia, and orexin agonists can be used for narcolepsy. Additionally, several studies demonstrated that the agonists of orexin might be effective in the treatment of DOC, providing novel therapeutic opportunities in this field.

Conclusion: The hypothalamic-centered orexin has been adopted as the point of entry into the system of consciousness control, and modulators of orexin signaling opened several therapeutic opportunities for the treatment of DOC.

Keywords: Wakefulness, orexin, disorders of consciousness, traumatic brain injury, ascending reticular activating system, hypothalamus.

« Previous
[1]
Dewan MC, Rattani A, Gupta S, et al. Estimating the global incidence of traumatic brain injury. J Neurosurg 2018; 1-18.
[http://dx.doi.org/10.3171/2017.10.JNS17352] [PMID: 29701556]
[2]
Vanhaudenhuyse A, Demertzi A, Schabus M, et al. Two distinct neuronal networks mediate the awareness of environment and of self. J Cogn Neurosci 2011; 23(3): 570-8.
[http://dx.doi.org/10.1162/jocn.2010.21488] [PMID: 20515407]
[3]
Lopez-Rolon A, Vogler J, Howell K, et al. Severe disorders of consciousness after acquired brain injury: a single-centre long-term follow-up study. NeuroRehabilitation 2017; 40(4): 509-17.
[http://dx.doi.org/10.3233/NRE-171438] [PMID: 28222568]
[4]
Jang SH, Kim OL, Kim SH, Kim JB. The relation between loss of consciousness, severity of traumatic brain injury and injury of ascending reticular activating system in patients with traumatic brain injury. Am J Phys Med Rehabil 2019; 98(12): 1067-7.
[http://dx.doi.org/10.1097/PHM.0000000000001243] [PMID: 31206359]
[5]
de Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998; 95(1): 322-7.
[http://dx.doi.org/10.1073/pnas.95.1.322] [PMID: 9419374]
[6]
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): 573-85.
[http://dx.doi.org/10.1016/S0092-8674(00)80949-6] [PMID: 9491897]
[7]
Haas HL, Lin JS. Waking with the hypothalamus. Pflugers Arch 2012; 463(1): 31-42.
[http://dx.doi.org/10.1007/s00424-011-0996-4] [PMID: 21796339]
[8]
Sakurai T. Orexin deficiency and narcolepsy. Curr Opin Neurobiol 2013; 23(5): 760-6.
[http://dx.doi.org/10.1016/j.conb.2013.04.007] [PMID: 23663890]
[9]
Liblau RS, Vassalli A, Seifinejad A, Tafti M. Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy. Lancet Neurol 2015; 14(3): 318-28.
[http://dx.doi.org/10.1016/S1474-4422(14)70218-2] [PMID: 25728441]
[10]
Dong XY, Feng Z. Wake-promoting effects of vagus nerve stimulation after traumatic brain injury: upregulation of orexin-A and orexin receptor type 1 expression in the prefrontal cortex. Neural Regen Res 2018; 13(2): 244-51.
[http://dx.doi.org/10.4103/1673-5374.226395] [PMID: 29557373]
[11]
Thomasy HE, Opp MR. Hypocretin mediates sleep and wake disturbances in a mouse model of traumatic brain injury. J Neurotrauma 2019; 36(5): 802-14.
[http://dx.doi.org/10.1089/neu.2018.5810] [PMID: 30136622]
[12]
Parvizi J, Damasio AR. Neuroanatomical correlates of brainstem coma. Brain 2003; 126(Pt 7): 1524-36.
[http://dx.doi.org/10.1093/brain/awg166] [PMID: 12805123]
[13]
Schwartz JR, Roth T. Neurophysiology of sleep and wakefulness: basic science and clinical implications. Curr Neuropharmacol 2008; 6(4): 367-78.
[http://dx.doi.org/10.2174/157015908787386050] [PMID: 19587857]
[14]
Gerashchenko D, Salin-Pascual R, Shiromani PJ. Effects of hypocretin-saporin injections into the medial septum on sleep and hippocampal theta. Brain Res 2001; 913(1): 106-15.
[http://dx.doi.org/10.1016/S0006-8993(01)02792-5] [PMID: 11532254]
[15]
Trofimova I, Robbins TW. Temperament and arousal systems: a new synthesis of differential psychology and functional neurochemistry. Neurosci Biobehav Rev 2016; 64: 382-402.
[http://dx.doi.org/10.1016/j.neubiorev.2016.03.008] [PMID: 26969100]
[16]
Edlow BL, Takahashi E, Wu O, et al. Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. J Neuropathol Exp Neurol 2012; 71(6): 531-46.
[http://dx.doi.org/10.1097/NEN.0b013e3182588293] [PMID: 22592840]
[17]
O’Donnell JC, Browne KD, Kilbaugh TJ, Chen HI, Whyte J, Cullen DK. Challenges and demand for modeling disorders of consciousness following traumatic brain injury. Neurosci Biobehav Rev 2019; 98: 336-46.
[http://dx.doi.org/10.1016/j.neubiorev.2018.12.015] [PMID: 17234097]
[18]
Pistoia F, Mura E, Govoni S, Fini M, Sarà M. Awakenings and awareness recovery in disorders of consciousness: is there a role for drugs? CNS Drugs 2010; 24(8): 625-38.
[http://dx.doi.org/10.2165/11535940-000000000-00000] [PMID: 20658796]
[19]
Laureys S. The neural correlate of (un)awareness: lessons from the vegetative state. Trends Cogn Sci (Regul Ed) 2005; 9(12): 556-9.
[http://dx.doi.org/10.1016/j.tics.2005.10.010] [PMID: 16271507]
[20]
Laureys S, Faymonville ME, Luxen A, Lamy M, Franck G, Maquet P. Restoration of thalamocortical connectivity after recovery from persistent vegetative state. Lancet 2000; 355(9217): 1790-1.
[http://dx.doi.org/10.1016/S0140-6736(00)02271-6] [PMID: 10832834]
[21]
Machado C. The minimally conscious state: definition and diagnostic criteria. Neurology 2002; 59(9): 1473.
[http://dx.doi.org/10.1212/WNL.59.9.1473] [PMID: 12434799]
[22]
Young GB. Coma. Ann N Y Acad Sci 2009; 1157: 32-47.
[http://dx.doi.org/10.1111/j.1749-6632.2009.04471.x] [PMID: 19351354]
[23]
Cossu G. Therapeutic options to enhance coma arousal after traumatic brain injury: state of the art of current treatments to improve coma recovery. Br J Neurosurg 2014; 28(2): 187-98.
[http://dx.doi.org/10.3109/02688697.2013.841845] [PMID: 24090192]
[24]
Ciurleo R, Bramanti P, Calabrò RS. Pharmacotherapy for disorders of consciousness: are ‘awakening’ drugs really a possibility? Drugs 2013; 73(17): 1849-62.
[http://dx.doi.org/10.1007/s40265-013-0138-8] [PMID: 24170667]
[25]
Wisor JP. Dopamine and wakefulness: pharmacology, genetics, and circuitry. Handb Exp Pharmacol 2019; 253: 321-35.
[http://dx.doi.org/10.1007/164_2018_95] [PMID: 29616340]
[26]
Chen YH, Huang EY, Kuo TT, Miller J, Chiang YH, Hoffer BJ. Impact of traumatic brain injury on dopaminergic transmission. Cell Transplant 2017; 26(7): 1156-68.
[http://dx.doi.org/10.1177/0963689717714105] [PMID: 28933212]
[27]
Schnakers C, Hustinx R, Vandewalle G, et al. Measuring the effect of amantadine in chronic anoxic minimally conscious state. J Neurol Neurosurg Psychiatry 2008; 79(2): 225-7.
[http://dx.doi.org/10.1136/jnnp.2007.124099] [PMID: 18202217]
[28]
Meythaler JM, Brunner RC, Johnson A, Novack TA. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil 2002; 17(4): 300-13.
[http://dx.doi.org/10.1097/00001199-200208000-00004] [PMID: 12105999]
[29]
Hughes S, Colantonio A, Santaguida PL, Paton T. Amantadine to enhance readiness for rehabilitation following severe traumatic brain injury. Brain Inj 2005; 19(14): 1197-206.
[http://dx.doi.org/10.1080/02699050500309296] [PMID: 16286335]
[30]
Giacino JT, Whyte J, Bagiella E, et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med 2012; 366(9): 819-26.
[http://dx.doi.org/10.1056/NEJMoa1102609] [PMID: 22375973]
[31]
Hammond FM, Malec JF, Zafonte RD, et al. Potential impact of amantadine on aggression in chronic traumatic brain injury. J Head Trauma Rehabil 2017; 32(5): 308-18.
[http://dx.doi.org/10.1097/HTR.0000000000000342] [PMID: 28891908]
[32]
Matsuda W, Matsumura A, Komatsu Y, Yanaka K, Nose T. Awakenings from persistent vegetative state: report of three cases with Parkinsonism and brain stem lesions on MRI. J Neurol Neurosurg Psychiatry 2003; 74(11): 1571-3.
[http://dx.doi.org/10.1136/jnnp.74.11.1571] [PMID: 14617720]
[33]
Joensson M, Thomsen KR, Andersen LM, et al. Making sense: Dopamine activates conscious self-monitoring through medial prefrontal cortex. Hum Brain Mapp 2015; 36(5): 1866-77.
[http://dx.doi.org/10.1002/hbm.22742] [PMID: 25627861]
[34]
Matsuda W, Komatsu Y, Yanaka K, Matsumura A. Levodopa treatment for patients in persistent vegetative or minimally conscious states. Neuropsychol Rehabil 2005; 15(3-4): 414-27.
[http://dx.doi.org/10.1080/09602010443000588] [PMID: 16350982]
[35]
Krimchansky BZ, Keren O, Sazbon L, Groswasser Z. Differential time and related appearance of signs, indicating improvement in the state of consciousness in vegetative state traumatic brain injury (VS-TBI) patients after initiation of dopamine treatment. Brain Inj 2004; 18(11): 1099-105.
[http://dx.doi.org/10.1080/02699050310001646206] [PMID: 15545207]
[36]
Levin H, Troyanskaya M, Petrie J, et al. Methylphenidate Treatment of cognitive dysfunction in adults after mild to moderate traumatic brain injury: rationale, efficacy, and neural mechanisms. Front Neurol 2019; 10: 925.
[http://dx.doi.org/10.3389/fneur.2019.00925] [PMID: 31572283]
[37]
Whyte J, Hart T, Vaccaro M, et al. Effects of methylphenidate on attention deficits after traumatic brain injury: a multidimensional, randomized, controlled trial. Am J Phys Med Rehabil 2004; 83(6): 401-20.
[http://dx.doi.org/10.1097/01.PHM.0000128789.75375.D3] [PMID: 15166683]
[38]
Moein H, Khalili HA, Keramatian K. Effect of methylphenidate on ICU and hospital length of stay in patients with severe and moderate traumatic brain injury. Clin Neurol Neurosurg 2006; 108(6): 539-42.
[http://dx.doi.org/10.1016/j.clineuro.2005.09.003] [PMID: 16226371]
[39]
Kim YW, Shin JC, An YS. Effects of methylphenidate on cerebral glucose metabolism in patients with impaired consciousness after acquired brain injury. Clin Neuropharmacol 2009; 32(6): 335-9.
[http://dx.doi.org/10.1097/WNF.0b013e3181b40678] [PMID: 19667974]
[40]
Mura E, Pistoia F, Sara M, Sacco S, Carolei A, Govoni S. Pharmacological modulation of the state of awareness in patients with disorders of consciousness: an overview. Curr Pharm Des 2014; 20(26): 4121-39.
[http://dx.doi.org/10.2174/13816128113196660658] [PMID: 24025054]
[41]
Leonard BE, McCartan D, White J, King DJ. Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects. Hum Psychopharmacol 2004; 19(3): 151-80.
[http://dx.doi.org/10.1002/hup.579] [PMID: 15079851]
[42]
Sanger DJ, Benavides J, Perrault G, et al. Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes. Neurosci Biobehav Rev 1994; 18(3): 355-72.
[http://dx.doi.org/10.1016/0149-7634(94)90049-3] [PMID: 7984354]
[43]
Machado C, Estévez M, Rodríguez R, et al. Zolpidem arousing effect in persistent vegetative state patients: autonomic, EEG and behavioral assessment. Curr Pharm Des 2014; 20(26): 4185-202.
[http://dx.doi.org/10.2174/13816128113196660646] [PMID: 24025063]
[44]
Calabrò RS, Aricò I, De Salvo S, Conti-Nibali V, Bramanti P. Transient awakening from vegetative state: is high-dose zolpidem more effective? Psychiatry Clin Neurosci 2015; 69(2): 122-3.
[http://dx.doi.org/10.1111/pcn.12215] [PMID: 24965312]
[45]
Clauss RP, Güldenpfennig WM, Nel HW, Sathekge MM, Venkannagari RR. Extraordinary arousal from semi-comatose state on zolpidem. A case report. S Afr Med J 2000; 90(1): 68-72.
[http://dx.doi.org/10.1016/S0248-8663(01)00464-7] [PMID: 10721397]
[46]
Du B, Shan A, Zhang Y, Zhong X, Chen D, Cai K. Zolpidem arouses patients in vegetative state after brain injury: quantitative evaluation and indications. Am J Med Sci 2014; 347(3): 178-82.
[http://dx.doi.org/10.1097/MAJ.0b013e318287c79c] [PMID: 23462249]
[47]
Kim H, Shin C, Ko YH, Han C. Comorbid zolpidem dependence and over-the-counter compound analgesic abuse. Clin Psychopharmacol Neurosci 2019; 17(2): 323-5.
[http://dx.doi.org/10.9758/cpn.2019.17.2.323] [PMID: 30905134]
[48]
Lei J, Wang L, Gao G, Cooper E, Jiang J. Right median nerve electrical stimulation for acute traumatic coma patients. J Neurotrauma 2015; 32(20): 1584-9.
[http://dx.doi.org/10.1089/neu.2014.3768] [PMID: 25664378]
[49]
Peri CV, Shaffrey ME, Farace E, et al. Pilot study of electrical stimulation on median nerve in comatose severe brain injured patients: 3-month outcome. Brain Inj 2001; 15(10): 903-10.
[http://dx.doi.org/10.1080/02699050110065709] [PMID: 11595086]
[50]
Cooper EB, Cooper JB. Electrical treatment of coma via the median nerve. Acta Neurochir Suppl (Wien) 2003; 87: 7-10.
[http://dx.doi.org/10.1007/978-3-7091-6081-7_2] [PMID: 14518514]
[51]
Wu X, Zhang C, Feng J, Mao Q, Gao G, Jiang J. Right median nerve electrical stimulation for acute traumatic coma (the Asia Coma Electrical Stimulation trial): study protocol for a randomised controlled trial. Trials 2017; 18(1): 311.
[http://dx.doi.org/10.1186/s13063-017-2045-x] [PMID: 28693604]
[52]
Giacino JT, Trott CT. Rehabilitative management of patients with disorders of consciousness: grand rounds. J Head Trauma Rehabil 2004; 19(3): 254-65.
[http://dx.doi.org/10.1097/00001199-200405000-00006] [PMID: 15247847]
[53]
Mitchell S, Bradley VA, Welch JL, Britton PG. Coma arousal procedure: a therapeutic intervention in the treatment of head injury. Brain Inj 1990; 4(3): 273-9.
[http://dx.doi.org/10.3109/02699059009026177] [PMID: 2390654]
[54]
Padilla R, Domina A. Effectiveness of sensory stimulation to improve arousal and alertness of people in a coma or persistent vegetative state after traumatic brain injury: a systematic review Am J Occup Ther 2016; 70(3): 7003180030p1-8.
[http://dx.doi.org/10.5014/ajot.2016.021022] [PMID: 27089287]
[55]
Vanhoecke J, Hariz M. Deep brain stimulation for disorders of consciousness: systematic review of cases and ethics. Brain Stimul 2017; 10(6): 1013-23.
[http://dx.doi.org/10.1016/j.brs.2017.08.006] [PMID: 28966051]
[56]
Cohadon F, Richer E. Deep cerebral stimulation in patients with post-traumatic vegetative state. 25 cases. Neurochirurgie 1993; 39(5): 281-92.
[http://dx.doi.org/10.1185/030079906X100050] [PMID: 8065486]
[57]
Chudy D, Deletis V, Almahariq F, Marčinković P, Škrlin J, Paradžik V. Deep brain stimulation for the early treatment of the minimally conscious state and vegetative state: experience in 14 patients. J Neurosurg 2018; 128(4): 1189-98.
[http://dx.doi.org/10.3171/2016.10.JNS161071] [PMID: 28621620]
[58]
Kanno T, Kamel Y, Yokoyama T, Shoda M, Tanji H, Nomura M. Effects of dorsal column spinal cord stimulation (DCS) on reversibility of neuronal function-experience of treatment for vegetative states. Pacing Clin Electrophysiol 1989; 12(4 Pt 2): 733-8.
[http://dx.doi.org/10.1111/j.1540-8159.1989.tb02724.x] [PMID: 2470059]
[59]
Sharova EV, Mel’nikov AV, Novikova MR, et al. Changes in spontaneous brain bioelectrical activity during transcranial electrical and electromagnetic stimulation. Neurosci Behav Physiol 2007; 37(5): 451-7.
[http://dx.doi.org/10.1007/s11055-007-0034-3] [PMID: 17505794]
[60]
Seledtsov VI, Rabinovich SS, Parlyuk OV, et al. Cell transplantation therapy in re-animating severely head-injured patients. Biomed Pharmacother 2005; 59(7): 415-20.
[http://dx.doi.org/10.1016/j.biopha.2005.01.012] [PMID: 16084057]
[61]
Scammell TE, Winrow CJ. Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol 2011; 51: 243-66.
[http://dx.doi.org/10.1146/annurev-pharmtox-010510-100528] [PMID: 21034217]
[62]
Nauta WJ. Hypothalamic regulation of sleep in rats; an experimental study. J Neurophysiol 1946; 9: 285-316.
[http://dx.doi.org/10.1152/jn.1946.9.4.285] [PMID: 20991815]
[63]
Moruzzi G. The sleep-waking cycle. Ergeb Physiol 1972; 64: 1-165.
[http://dx.doi.org/10.1007/3-540-05462-6_1] [PMID: 4340664]
[64]
Wilson CL, Motter BC, Lindsley DB. Influences of hypothalamic stimulation upon septal and hippocampal electrical activity in the cat. Brain Res 1976; 107(1): 55-68.
[http://dx.doi.org/10.1016/0006-8993(76)90095-0] [PMID: 1268724]
[65]
Lin JS, Sakai K, Vanni-Mercier G, Jouvet M. A critical role of the posterior hypothalamus in the mechanisms of wakefulness determined by microinjection of muscimol in freely moving cats. Brain Res 1989; 479(2): 225-40.
[http://dx.doi.org/10.1016/0006-8993(89)91623-5] [PMID: 2924157]
[66]
Sakai K. Physiological properties and afferent connections of the locus coeruleus and adjacent tegmental neurons involved in the generation of paradoxical sleep in the cat Prog Brain Res 1991; 88: 31-45.
[http://dx.doi.org/10.1016/S0079-6123(08)63798-X] [PMID: 1687620]
[67]
Steriade M. Sleep, epilepsy and thalamic reticular inhibitory neurons. Trends Neurosci 2005; 28(6): 317-24.
[http://dx.doi.org/10.1016/j.tins.2005.03.007] [PMID: 15927688]
[68]
Heiss JE, Yamanaka A, Kilduff TS. Parallel arousal pathways in the lateral hypothalamus. eNeuro 2018; 5(4): 5.
[http://dx.doi.org/10.1523/ENEURO.0228-18.2018] [PMID: 30225361]
[69]
Sakurai T, Mieda M, Tsujino N. The orexin system: roles in sleep/wake regulation. Ann N Y Acad Sci 2010; 1200: 149-61.
[http://dx.doi.org/10.1111/j.1749-6632.2010.05513.x] [PMID: 20633143]
[70]
Saito YC, Tsujino N, Abe M, Yamazaki M, Sakimura K, Sakurai T. Serotonergic input to orexin neurons plays a role in maintaining wakefulness and REM sleep architecture. Front Neurosci 2018; 12: 892.
[http://dx.doi.org/10.3389/fnins.2018.00892] [PMID: 30555297]
[71]
Tabuchi S, Tsunematsu T, Kilduff TS, et al. Influence of inhibitory serotonergic inputs to orexin/hypocretin neurons on the diurnal rhythm of sleep and wakefulness. Sleep (Basel) 2013; 36(9): 1391-404.
[http://dx.doi.org/10.5665/sleep.2972] [PMID: 23997373]
[72]
Edwards CM, Abusnana S, Sunter D, Murphy KG, Ghatei MA, Bloom SR. The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin. J Endocrinol 1999; 160(3): R7-R12.
[http://dx.doi.org/10.1677/joe.0.160r007] [PMID: 10077743]
[73]
Haynes AC, Jackson B, Chapman H, et al. A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul Pept 2000; 96(1-2): 45-51.
[http://dx.doi.org/10.1016/S0167-0115(00)00199-3] [PMID: 11102651]
[74]
Date Y, Ueta Y, Yamashita H, et al. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci USA 1999; 96(2): 748-53.
[http://dx.doi.org/10.1073/pnas.96.2.748] [PMID: 9892705]
[75]
Yamanaka A, Beuckmann CT, Willie JT, et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 2003; 38(5): 701-13.
[http://dx.doi.org/10.1016/S0896-6273(03)00331-3] [PMID: 12797956]
[76]
Hoang QV, Bajic D, Yanagisawa M, Nakajima S, Nakajima Y. Effects of orexin (hypocretin) on GIRK channels. J Neurophysiol 2003; 90(2): 693-702.
[http://dx.doi.org/10.1152/jn.00001.2003] [PMID: 12702704]
[77]
Nepovimova E, Janockova J, Misik J, et al. Orexin supplementation in narcolepsy treatment: a review. Med Res Rev 2019; 39(3): 961-75.
[http://dx.doi.org/10.1002/med.21550] [PMID: 30426515]
[78]
Peyron C, Tighe DK, van den Pol AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998; 18(23): 9996-10015.
[http://dx.doi.org/10.1523/JNEUROSCI.18-23-09996.1998] [PMID: 9822755]
[79]
Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 1998; 438(1-2): 71-5.
[http://dx.doi.org/10.1016/S0014-5793(98)01266-6] [PMID: 9821961]
[80]
Jöhren O, Neidert SJ, Kummer M, Dendorfer A, Dominiak P. Prepro-orexin and orexin receptor mRNAs are differentially expressed in peripheral tissues of male and female rats. Endocrinology 2001; 142(8): 3324-31.
[http://dx.doi.org/10.1210/endo.142.8.8299] [PMID: 11459774]
[81]
Mileykovskiy BY, Kiyashchenko LI, Siegel JM. Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 2005; 46(5): 787-98.
[http://dx.doi.org/10.1016/j.neuron.2005.04.035] [PMID: 15924864]
[82]
Zeitzer JM, Buckmaster CL, Parker KJ, Hauck CM, Lyons DM, Mignot E. Circadian and homeostatic regulation of hypocretin in a primate model: implications for the consolidation of wakefulness. J Neurosci 2003; 23(8): 3555-60.
[http://dx.doi.org/10.1523/JNEUROSCI.23-08-03555.2003] [PMID: 12716965]
[83]
Kummangal BA, Kumar D, Mallick HN. Intracerebroventricular injection of orexin-2 receptor antagonist promotes REM sleep. Behav Brain Res 2013; 237: 59-62.
[http://dx.doi.org/10.1016/j.bbr.2012.09.015] [PMID: 22989413]
[84]
Yamanaka A, Tsujino N, Funahashi H, et al. Orexins activate histaminergic neurons via the orexin 2 receptor. Biochem Biophys Res Commun 2002; 290(4): 1237-45.
[http://dx.doi.org/10.1006/bbrc.2001.6318] [PMID: 11811995]
[85]
Huang ZL, Qu WM, Li WD, et al. Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci USA 2001; 98(17): 9965-70.
[http://dx.doi.org/10.1073/pnas.181330998] [PMID: 11493714]
[86]
Mieda M, Tsujino N, Sakurai T. Differential roles of orexin receptors in the regulation of sleep/wakefulness. Front Endocrinol (Lausanne) 2013; 4: 57.
[http://dx.doi.org/10.3389/fendo.2013.00057] [PMID: 23730297]
[87]
Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A. Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 2006; 49(4): 589-601.
[http://dx.doi.org/10.1016/j.neuron.2006.01.016] [PMID: 16476667]
[88]
Borgland SL, Storm E, Bonci A. Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons. Eur J Neurosci 2008; 28(8): 1545-56.
[http://dx.doi.org/10.1111/j.1460-9568.2008.06397.x] [PMID: 18793323]
[89]
Liu RJ, van den Pol AN, Aghajanian GK. Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci 2002; 22(21): 9453-64.
[http://dx.doi.org/10.1523/JNEUROSCI.22-21-09453.2002] [PMID: 12417670]
[90]
Mieda M. The roles of orexins in sleep/wake regulation. Neurosci Res 2017; 118: 56-65.
[http://dx.doi.org/10.1016/j.neures.2017.03.015] [PMID: 28526554]
[91]
Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000; 27(3): 469-74.
[http://dx.doi.org/10.1016/S0896-6273(00)00058-1] [PMID: 11055430]
[92]
Sasaki K, Suzuki M, Mieda M, Tsujino N, Roth B, Sakurai T. Pharmacogenetic modulation of orexin neurons alters sleep/wakefulness states in mice. PLoS One 2011; 6(5)e20360
[http://dx.doi.org/10.1371/journal.pone.0020360] [PMID: 21647372]
[93]
Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999; 98(4): 437-51.
[http://dx.doi.org/10.1016/S0092-8674(00)81973-X] [PMID: 10481909]
[94]
Marcus JN, et al. Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice. Proc Natl Acad Sci USA 2011; 108: 4471-6.
[http://dx.doi.org/dx.doi: 10.1073/pnas.1012456108 ] [PMID: 21368172]
[95]
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; 59(10): 1553-62.
[http://dx.doi.org/10.1001/archneur.59.10.1553] [PMID: 12374492]
[96]
Duchna HW. Sleep-related breathing disorders-a second edition of the International Classification of Sleep Disorders (ICSD-2) of the American Academy of Sleep Medicine (AASM). Pneumologie 2006; 60(9): 568-75.
[http://dx.doi.org/10.1055/s-2006-944248] [PMID: 17006794]
[97]
Baumann CR, Stocker R, Imhof HG, et al. Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury. Neurology 2005; 65(1): 147-9.
[http://dx.doi.org/10.1212/01.wnl.0000167605.02541.f2] [PMID: 16009905]
[98]
Mieda M, Willie JT, Hara J, Sinton CM, Sakurai T, Yanagisawa M. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci USA 2004; 101(13): 4649-54.
[http://dx.doi.org/10.1073/pnas.0400590101] [PMID: 15070772]
[99]
Roecker AJ, Cox CD, Coleman PJ. Orexin receptor antagonists: new therapeutic agents for the treatment of insomnia. J Med Chem 2016; 59(2): 504-30.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00832] [PMID: 26317591]
[100]
Janockova J, Dolezal R, Nepovimova E, et al. Investigation of new orexin 2 receptor modulators using in silico and in vitro methods. Molecules 2018; 23(11): 23.
[http://dx.doi.org/10.3390/molecules23112926] [PMID: 30423961]
[101]
Coleman PJ, Gotter AL, Herring WJ, Winrow CJ, Renger JJ. The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia. Annu Rev Pharmacol Toxicol 2017; 57: 509-33.
[http://dx.doi.org/10.1146/annurev-pharmtox-010716-104837] [PMID: 27860547]
[102]
Holman L Available at:. http://imbriumthera.com/news/eisai-and-imbrium-therapeuticsannounce-u-s-filing-acceptanceof-new-drug-applicationfor-lemborexant-for-thetreatment-of-insomnia/2019
[103]
Kumar A, Chanana P, Choudhary S. Emerging role of orexin antagonists in insomnia therapeutics: an update on SORAs and DORAs. Pharmacol Rep 2016; 68(2): 231-42.
[http://dx.doi.org/10.1016/j.pharep.2015.09.002] [PMID: 26922522]
[104]
Bettica P, Squassante L, Zamuner S, Nucci G, Danker-Hopfe H, Ratti E. The orexin antagonist SB-649868 promotes and maintains sleep in men with primary insomnia. Sleep (Basel) 2012; 35(8): 1097-104.
[http://dx.doi.org/10.5665/sleep.1996] [PMID: 22851805]
[105]
Chow M, Cao M. The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress. Nat Sci Sleep 2016; 8: 81-6.
[http://dx.doi.org/10.2147/NSS.S76711] [PMID: 27051324]
[106]
Weinhold SL, Seeck-Hirschner M, Nowak A, Hallschmid M, Göder R, Baier PC. The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy. Behav Brain Res 2014; 262: 8-13.
[http://dx.doi.org/10.1016/j.bbr.2013.12.045] [PMID: 24406723]
[107]
Hagan JJ, Leslie RA, Patel S, et al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci USA 1999; 96(19): 10911-6.
[http://dx.doi.org/10.1073/pnas.96.19.10911] [PMID: 10485925]
[108]
Zeitzer JM, Nishino S, Mignot E. The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends Pharmacol Sci 2006; 27(7): 368-74.
[http://dx.doi.org/10.1016/j.tips.2006.05.006] [PMID: 16766052]
[109]
Willie JT, Renthal W, Chemelli RM, et al. Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates. Neuroscience 2005; 130(4): 983-95.
[http://dx.doi.org/10.1016/j.neuroscience.2004.10.005] [PMID: 15652995]
[110]
Mitchell HA, Bogenpohl JW, Liles LC, et al. Behavioral responses of dopamine beta-hydroxylase knockout mice to modafinil suggest a dual noradrenergic-dopaminergic mechanism of action. Pharmacol Biochem Behav 2008; 91(2): 217-22.
[http://dx.doi.org/10.1016/j.pbb.2008.07.014] [PMID: 18703079]
[111]
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; 114(22): 5731-6.
[http://dx.doi.org/10.1073/pnas.1700499114] [PMID: 28507129]
[112]
Prober DA. Discovery of hypocretin/orexin ushers in a new era of sleep research. Trends Neurosci 2018; 41(2): 70-2.
[http://dx.doi.org/10.1016/j.tins.2017.11.007] [PMID: 29405929]
[113]
Nagahara T, Saitoh T, Kutsumura N, et al. Design and synthesis of non-peptide, selective orexin receptor 2 agonists. J Med Chem 2015; 58(20): 7931-7.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00988] [PMID: 26267383]
[114]
Irukayama-Tomobe Y, Yanagisawa M. [Development of a therapeutic drug for narcolepsy Brain Nerve 2018; 70(11): 1255-63.
[http://dx.doi.org/10.11477/mf.1416201171] [PMID: 30416119]
[115]
Arias-Carrión O, Drucker-Colín R, Murillo-Rodríguez E. Survival rates through time of hypocretin grafted neurons within their projection site. Neurosci Lett 2006; 404(1-2): 93-7.
[http://dx.doi.org/10.1016/j.neulet.2006.05.017] [PMID: 16762505]
[116]
Gravett N, Bhagwandin A, Fuxe K, Manger PR. Distribution of orexin-A immunoreactive neurons and their terminal networks in the brain of the rock hyrax, Procavia capensis. J Chem Neuroanat 2011; 41: 86-96.
[http://dx.doi.org/10.1016/j.jchemneu.2010.11.005] [PMID: 21126575]
[117]
Arias-Carrión O, Murillo-Rodríguez E. Effects of hypocretin/orexin cell transplantation on narcoleptic-like sleep behavior in rats. PLoS One 2014; 9(4)e95342
[http://dx.doi.org/10.1371/journal.pone.0095342] [PMID: 24736646]
[118]
Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355(9197): 39-40.
[http://dx.doi.org/10.1016/S0140-6736(99)05582-8] [PMID: 10615891]
[119]
Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000; 6(9): 991-7.
[http://dx.doi.org/10.1038/79690] [PMID: 10973318]
[120]
Carter ME, de Lecea L. Optogenetic investigation of neural circuits in vivo. Trends Mol Med 2011; 17(4): 197-206.
[http://dx.doi.org/10.1016/j.molmed.2010.12.005] [PMID: 21353638]
[121]
Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98(3): 365-76.
[http://dx.doi.org/10.1016/S0092-8674(00)81965-0] [PMID: 10458611]
[122]
Kalogiannis M, Hsu E, Willie JT, et al. Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. PLoS One 2011; 6(4)e18697
[http://dx.doi.org/10.1371/journal.pone.0018697] [PMID: 21533254]
[123]
Liu M, Thankachan S, Kaur S, et al. Orexin (hypocretin) gene transfer diminishes narcoleptic sleep behavior in mice. Eur J Neurosci 2008; 28(7): 1382-93.
[http://dx.doi.org/10.1111/j.1460-9568.2008.06446.x] [PMID: 18973565]
[124]
Blanco-Centurion C, Liu M, Konadhode R, Pelluru D, Shiromani PJ. Effects of orexin gene transfer in the dorsolateral pons in orexin knockout mice. Sleep (Basel) 2013; 36(1): 31-40.
[http://dx.doi.org/10.5665/sleep.2296] [PMID: 23288969]
[125]
Kantor S, Mochizuki T, Lops SN, et al. Orexin gene therapy restores the timing and maintenance of wakefulness in narcoleptic mice. Sleep (Basel) 2013; 36(8): 1129-38.
[http://dx.doi.org/10.5665/sleep.2870] [PMID: 23904672]
[126]
Feng Z, Zhong YJ, Wang L, Wei TQ. Resuscitation therapy for traumatic brain injury-induced coma in rats: mechanisms of median nerve electrical stimulation. Neural Regen Res 2015; 10(4): 594-8.
[http://dx.doi.org/10.4103/1673-5374.155433] [PMID: 26170820]
[127]
Zhong YJ, Feng Z, Wang L, Wei TQ. Wake-promoting actions of median nerve stimulation in TBI-induced coma: an investigation of orexin-A and orexin receptor 1 in the hypothalamic region. Mol Med Rep 2015; 12(3): 4441-7.
[http://dx.doi.org/10.3892/mmr.2015.3898] [PMID: 26059340]
[128]
Jia X, Yan J, Xia J, et al. Arousal effects of orexin A on acute alcohol intoxication-induced coma in rats. Neuropharmacology 2012; 62(2): 775-83.
[http://dx.doi.org/10.1016/j.neuropharm.2011.08.047] [PMID: 21924278]
[129]
Modi HR, Wang Q, Gd S, et al. Intranasal post-cardiac arrest treatment with orexin-A facilitates arousal from coma and ameliorates neuroinflammation. PLoS One 2017; 12(9)e0182707
[http://dx.doi.org/10.1371/journal.pone.0182707] [PMID: 28957432]
[130]
Winrow CJ, Renger JJ. Discovery and development of orexin receptor antagonists as therapeutics for insomnia. Br J Pharmacol 2014; 171(2): 283-93.
[http://dx.doi.org/10.1111/bph.12261] [PMID: 23731216]
[131]
Fujiki N, Yoshida Y, Ripley B, Mignot E, Nishino S. 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; 26(8): 953-9.
[http://dx.doi.org/10.1093/sleep/26.8.953] [PMID: 14746374]
[132]
Dhuria SV, Hanson LR, Frey WH II. Intranasal drug targeting of hypocretin-1 (orexin-A) to the central nervous system. J Pharm Sci 2009; 98(7): 2501-15.
[http://dx.doi.org/10.1002/jps.21604] [PMID: 19025760]
[133]
Spetter MS, Hallschmid M. Intranasal neuropeptide administration to target the human brain in health and disease. Mol Pharm 2015; 12(8): 2767-80.
[http://dx.doi.org/10.1021/acs.molpharmaceut.5b00047] [PMID: 25880274]
[134]
Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 2012; 64(7): 614-28.
[http://dx.doi.org/10.1016/j.addr.2011.11.002] [PMID: 22119441]
[135]
Al-Barazanji KA, Wilson S, Baker J, Jessop DS, Harbuz MS. Central orexin-A activates hypothalamic-pituitary-adrenal axis and stimulates hypothalamic corticotropin releasing factor and arginine vasopressin neurones in conscious rats. J Neuroendocrinol 2001; 13(5): 421-4.
[http://dx.doi.org/10.1046/j.1365-2826.2001.00655.x] [PMID: 11328451]
[136]
Hang CH, Shi JX, Li JS, Wu W, Li WQ, Yin HX. Levels of vasoactive intestinal peptide, cholecystokinin and calcitonin gene-related peptide in plasma and jejunum of rats following traumatic brain injury and underlying significance in gastrointestinal dysfunction. World J Gastroenterol 2004; 10(6): 875-80.
[http://dx.doi.org/10.3748/wjg.v10.i6.875] [PMID: 15040036]

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