280612.pdf

REVIEW (BASIC SCIENCE FOR THE CLINICIAN)
Emerging Therapies in Narcolepsy-Cataplexy Emmanuel Mignot, MD, PhD1,2; Seiji Nishino, MD, PhD2 1Howard Hughes Medical Research Institute, Stanford University School of Medicine, Stanford, CA; 2Stanford Center for Narcolepsy Stanford Univer-sity School of Medicine, Stanford, CA Abstract: In the past, narcolepsy was primarily treated using amphet-
not target hypocretin, a major neurotransmitter involved in the pathophysi- amine-like stimulants and tricyclic antidepressants. Newer and novel ology of narcolepsy. In this review, we discuss emerging therapies in the agents, such as the wake-promoting compound modafinil and more se- area of narcolepsy. These include novel antidepressant or anticataplectic, lective reuptake inhibitors targeting the adrenergic, dopaminergic, and/or wake-promoting, and hypnotic compounds. We also report on novel strat- serotoninergic reuptake sites (ie, venlafaxine, atomoxetine) are better-tol- egies designed to compensate for hypocretin deficiency and on the use of erated available alternatives. The development of these agents, together immunosupression at the time of narcolepsy onset. with sodium oxybate (a slow-wave sleep-enhancing agent that consoli- Key Words: Treatment, narcolepsy, cataplexy
dates nocturnal sleep, reduces cataplexy, and improves sleepiness), has Citation: Mignot E; Nishino S. Emerging therapies in narcolepsy-cata-
led to improved functioning and quality of life for many patients with the plexy. SLEEP 2005;28(6):754-763.
disorder. However, these treatments are all symptomatically based and do INTRODUCTION
stimulant structurally distinct of catecholamines, has no effect on granular DA storage and primarily blocks DA reuptake.8-11 Activa- CURRENTLY AVAILABLE TREATMENTS FOR HUMAN tion of DA transmission after methylphenidate is thus dependent NARCOLEPSY ACT SYMPTOMATICALLY AND DO NOT of the underlying DA activity (ie, no increase in DA transmission TARGET THE HYPOCRETIN (OREXIN) NEUROPEPTIDE in the absence of firing).9,11 Other effects may be involved, for ex- SYSTEM, the primary neurotransmitter system involved in the ample stimulation of adrenergic transmission (Table 1). In canine cause of narcolepsy-cataplexy. In the last few years, however, narcolepsy, selective DA reuptake inhibitors such as GBR12909 much has been learned regarding the mode of action of currently (vanoxerine) have strong wake-promoting effects but no impact available agents in the treatment of narcolepsy, thanks mostly to on cataplexy.12 Modafinil, a recently developed wake-promoting pharmacologic studies in a canine model of the disorder (see for compound with lower abuse potential and probably fewer car- review1). This well-characterized model, studied for more than 20 diovascular effects13,14 has similar effects in canine6,15 and mice years,1 has hypocretin receptor-2 (hcrtr-2) mutations2 or sporadic narcolepsy.16 It has a debated mode of action but is also likely to hypocretin deficiency.3 More recently, similar pharmacologic ex- periments are being conducted in murine models of narcolepsy The mode of action of anticataplectic antidepressants has also genetically engineered to lack the hypocretin gene4 or the hypo- been studied in animal models of narcolepsy. These compounds reduce cataplexy in both the murine (evaluated as rapid eye move- Amphetamine-like stimulants are primarily believed to improve ment-like transitions from wake19) and the canine model. 1,12,20,21 In sleepiness via presynaptic stimulation of dopaminergic transmis- canine, reduction is mediated by the inhibition of adrenergic and, sion.6-8 For amphetamine, these effects are mediated through the to a lesser extent, serotonergic (5-HT) reuptake.12,20 Differently inhibition of the vesicular monoamine transporter (VMAT), an ef- from DA reuptake inhibitors, however, pure adrenergic and 5-HT fect resulting in the emptying of vesicular dopamine (DA) stores reuptake inhibitors have only modest wake-promoting effects in in the cytoplasm, and reverse efflux of DA through the dopamine animals.1,6 Novel anticataplectic reuptake inhibitors available in reuptake site (also called the DA transporter, DAT).8-10 This effect humans include compounds with adrenergic (eg, atomoxetine) or produces a net increase in DA release and an associated reduction of dual adrenergic/serotoninergic (eg, venlafaxine) reuptake prop- presynaptic DA stores. Methylphenidate, another commonly used erties that do not have anticholinergic or alpha-adrenergic ef-fects.13,21 Sodium oxybate (GHB), the most recent addition to our thera- Disclosure Statement
peutic arsenal in narcolepsy (see reference 22), is currently indi- Dr. Mignot is a consultant and stockowner of Hypnion, Inc., a company de- cated for cataplexy. It also reduces daytime sleepiness and has veloping hypnotics and stimulants; and occasionally speaks on narcolepsy an effect on disturbed nocturnal sleep.22-25 The mode of action of at engagements supported by Orphan Medical. Dr. Nishino has received GHB is debated and may involve stimulation of GABA-B recep- research support from The Robert Wood Johnson Pharmaceutical Research tors and possibly other GHB-specific receptors.22,26 Interestingly, Institute and Cortex Pharmaceuticals, Inc.
GHB has strong effects on DA transmission (probably mediated via GABA-B receptors on DA cells), acutely reducing cell firing, Submitted for publication January 2005
but with an uncoupling of DA synthesis, thereby resulting in in- Accepted for publication February 2005
creased DA store in animals.27 Whether or not a reduction of DA Address correspondence to: Emmanuel Mignot; [email protected]. transmission is important for sleep induction and the subsequent Stanford University Center For Narcolepsy, 701 Welch Road B, Basement, increased DA store is important for daytime vigilance has been Room 145, Palo Alto CA 94304-5742; Tel: (650) 725-6517; Fax: (650)725- speculated.22 The compound has been shown to be efficacious in narcolepsy but, like amphetamine-like stimulants, is also abused Novel Narcolepsy Therapies—Mignot and Nishino Table 1—Currently Available Narcolepsy Treatments and Their Pharmacologic Properties
Compound
Pharmacologic Properties
Increases monoamine release (DA>NE>>5-HT). Primary effects due to reverse efflux of DA through the DAT. Inhibi- tion of monoamine storage through the VMAT and other effects occur at higher doses. The D-isomer is more specific for DA transmission and is a better stimulant compound. Some effects on cataplexy (especially for the L-isomer) sec- ondary to adrenergic effects occur at higher doses. Available as racemic mixture or pure D-isomer; various time-release Profile similar to amphetamine but more lipophilic with increased central penetration. Blocks monoamine (DA>NE>>5-HT) uptake. No effect on reverse efflux or on VMAT. Short half-life. Available as racemic mixture or as pure D-isomer and in various time-release formulations.
DA uptake inhibition. Low potency. Rarely used due to occasional hepatotoxicity.
MAO B inhibitor with in vivo conversion into L-amphetamine and L-methamphetamine. Mode of action debated but probably involves relative selec tive DA reuptake inhibition. Fewer peripheral side ef- fects. Low-potency compound. Available as a racemic mixture. Little if any addictive potential but less efficacious than amphetamine or methyphenidate. The R-isomer has a longer half-life and is in development. Anticataplectic compoundsProtryptiline Tricyclic antidepressant. Monoaminergic uptake blocker (NE>5-HT>DA). Anticholinergic effects; all antidepressants have immediate effects on cataplexy, but abrupt cessation of treatment can induce very severe rebound in cataplexy Tricyclic antidepressant. Monoaminergic uptake blocker (NE=5-HT>DA). Anticholinergic effects. Desipramine is an Tricyclic antidepressant. Monoaminergic uptake blocker NE>>5-HT>DA). Anticholinergic effects. Tricyclic antidepressant. Monoaminergic uptake blocker (5-HT>NE>>DA). Anticholinergic effects. Desmethylclomip- ramine (NE>>5-HT>DA) is an active metabolite. No specificity in vivo. Dual serotonin and adrenergic reuptake blocker (5-HT≥NE): very effective but some nausea. May have less sexual side effects than other antidepressants. Slightly stimulant, short half-life, extended-release formulation preferred.
Specific adrenergic reuptake blocker (NE) normally indicated for attention-deficit/hyperactivity disorder. Slightly stimulant, short half-life, and reduces appetite.
Specific serotonin uptake blocker (5-HT>>NE=DA). Active metabolite norfluoxetine has more adrenergic effects. High therapeutic doses are often needed.
OtherSodium Oxybate* (GHB) May act via GABA-B or specific GHB receptors. Reduces DA release. Need binightly dosing with immediate effects on disturbed nocturnal sleep; therapeutic effects on cataplexy and daytime sleepiness often delayed.
DA refers to dopamine; NE, norepinephrine; 5-HT, serotonin; DAT, dopamine transporter; MAO, monoamine oxidase; VMAT, vesicular mono-amine transporter. *Recent compounds that can be considered as first-intention treatments in narcolepsy-cataplexy, considering their benefit and side-effect profiles when compared to other older medications. and inexpensive, but recent alternatives such as sodium oxybate/ At a recent meeting of the National Institute of Health entitled GHB, modafinil, and novel reuptake inhibitors (Table 1) should “Frontiers of Knowledge in Sleep & Sleep Disorders: Opportuni- be more frequently considered. Thanks to the recent progress and ties for Improving Health and Quality of Life,” one key recom- renewed interest in this area, novel therapies are also emerging, mendation pertained to the education of physicians on the use of novel antidepressants and stimulants in the treatment of narcolep-sy (http://www.nhlbi.nih.gov/ meetings/slp_front.htm). Indeed, NOVEL ADRENERGIC, SEROTONINERGIC, AND DOPAMINERGIC
old tricyclic antidepressants, such as clomipramine or protrypti- REUPTAKE BLOCKERS
line, together with amphetamines or methylphenidate are still too The current success of modafinil, with its recently extended often used as first line treatments.13 These therapies are effective indications to shift work sleep disorder and residual sleepiness in Novel Narcolepsy Therapies—Mignot and Nishino Table 2—Future Potential Narcolepsy Treatments and Their Pharmacologic Properties
Treatment Types
Advantages and Limitations
Non-hypocretin–based therapiesNovel monoaminergic Inhibitors of DA reuptake likely to be mild stimulants; inhibitors of adrenergic reuptake likely to be anticataplectic reuptake inhibitors agents. Possibly targeting multiple reuptake sites; may be developed in the context of depression, wake-promotion, attention-deficit/hyperactivity disorder treatments or as therapies for cocaine or stimulant abuse The efficacy of sodium oxybate (GHB) suggests that other hypnotics with SWS effect could have similar effects; pos- sible agents in this class could include novel GABA-B ago nists, GABA-A subtype specific compounds such as gabox- adol, longer-acting GBH analogues, and GABA reuptake inhibitors such as tiagabine or others. Autoreceptor of histaminergic neurons; will stimulate histaminergic transmission; effective on sleepiness and cataplexy in animals models; Effects in humans still uncertain, but multiple compounds available preclinically or in early human Typically peptide analogues; effective in animal models but very high dose required; some compounds failed human trials on depression; limited activity for this area in the pharmaceutical industry Hypocretin-Based TherapyHypocretin-1 itself Disappointing effects after intravenous, intracisternal, and intranasal administration to date, but extremely high doses could still be effective; would likely be effective if could be delivered intracerebroventricularly.
Similarly to TRH analogues, could be effective at very high dose. Hypocretin is a larger peptide, and derivatives are unlikely to cross the blood-brain barrier sufficiently and will probably be unstable in vivo.
Best possible hope, especially if targeting the hcrtr2 receptor; with central penetration; impossible to predict success to date; peptide receptor agonists are often difficult if not impossible to make.
May one day provide a cure; results to date in other diseases are disappointing because of potential graft rejection, low survival rate of implant, and lack of supply for graft availability. This last problem could be solved on a long-term basis through stem cell technology, likely to be more than 10 years away.
Promising in the future but need appropriate vector; potentially dangerous side effects; could be combined with cell- Ineffective in 1 human and 1 canine case; unlikely to be useful.
May be effective in decreasing symptoms but only if used before a year or so after onset; reported effects are still subjective and not confirmed through placebo-controlled trials; gener ally safe but occasionally life-threatening side Similar to IV Ig but less available data; more invasive than IVIg.
DA refers to dopamine; SWS, slow-wave sleep; NE, norepinephrine, 5-HT, serotonin; H3, histamine receptor 3; TRH, thyrotropin-releasing hor-mone; IVIg, intravenous immunoglobulins.
sleep apnea,13 together with the expanding use of stimulants for at- A traditional problem with dopaminergic stimulants is their tention-deficit/hyperactivity disorders and the continued need for addiction potential. Cocaine, amphetamine, and methylphenidate novel treatments for resistant depression, have fueled the growth have addiction potential, and all modulate DA release (amphet- of new products in this area. R-(-)-modafinil, the longer acting amine) and/or reuptake (methylphenidate, cocaine).9,11 Interest- isomer of the currently available racemic modafinil mixture28 is ingly however, not all DA reuptake inhibitors have a similar ad- currently being evaluated in narcolepsy and sleep apnea. The half- diction potential.11 Mazindol, a high-affinity DAT inhibitor, for life of R-(-)-modafinil is approximately 3 times longer than that example, is only moderately addictive. Current hypotheses for of S-(+)-modafinil in humans. This variation will slightly increase explaining these differences involve a combination of factors the half-life of the product, facilitating a potential once-per-day rather than a single property. These include pharmacokinetic dif- administration. A number of companies have also developed im- ferences (rapid brain penetration and onset of action, high po- proved delivery formulations and single isomer preparations for tency, and solubility allowing the possibility of intravenous recre- typical stimulants such as methylphenidate and amphetamines ational use) and possibly combined effects on other monoamines (for example, 5-HT plus DA effects may change addiction po- Novel Narcolepsy Therapies—Mignot and Nishino tential).11,29 Differential effects on DA transmission (VMAT plus be critical to its addictive potential. Novel GABA-B agonists or DAT inhibition for amphetamine; differential effects on basal ver- modulators may also be of interest (development is limited by sus stimulated DA release with some drugs) and distinct binding epileptogenic properties at high doses), but longer-acting GABA- sites on the DAT protein itself may also be involved.11,29,30 In this B agonists, such as baclofen, are already available but have not direction, federal agencies and companies have been engaged in been systematically evaluated in human narcolepsy.
the identification of DAT inhibitors that may not have strong (or At the pharmacologic level, GHB is unique as a strong hypnot- any) addiction potential. These would be used to reduce exposure ic because of its ability to increase slow-wave sleep (SWS).25 We to more dangerous stimulants, a strategy akin to that taken by the have hypothesized that a core abnormality in hypocretin deficien- methadone program for opiate abusers. In this direction, DA reup- cy is the inability of patients to counteract even small amounts of take inhibitors with known stimulant effects, such as GBR12909 sleep debt.38 Whether the SWS-enhancing property of GHB, and (vanoxerine), amineptine, or NS2359 (combined monoamine the resulting decrease in homeostatic sleep debt, is needed for the reuptake blocker), have been explored as a preventive treatment beneficial effect of the compound on the various symptoms of for cocaine abusers31,32 or in the treatment of amphetamine with- narcolepsy is tantalizing.22 This question will only be answered drawal33 and may become available for other indications (Table when other compounds with similar SWS-enhancing profiles, but 2). A difficulty in this area remains the determination of what is distinct molecular modes of action, will be available. Currently abuse (eg, drug seeking and withdrawal symptoms) or misuse studied or available GABAergic hypnotics with SWS-enhancing (eg, occasional use to counteract recreational sleep deprivation properties include gaboxadol, a GABAergic modulator with pref- or to increase productivity). Other DA reuptake inhibitors such erential effects on extrasynaptic GABAergic receptors contain- as amineptine (DAT inhibitor) and nomifensine (a dual DAT and ing the delta and alpha-4/5 subunits,39 and tiagabine, a GABA adrenergic reuptake inhibitor) have been available in the past in reuptake inhibitor.40 The existence of numerous other potential Europe, only to be eventually withdrawn because of misuse or receptors antagonists, H autoreceptor agonists, and ion channel A similar trend is also being seen in the area of antidepressant blockers, together with the renewed interest of the pharmacologic therapies where novel single, dual (duloxetine, milnacipram),34 sector in hypnotic therapies may also be beneficial to narcoleptic and even triple (DA, 5-HT, and adrenergic eg, DOV 216,303, patients (see reference 41). Of note, ritanserin, a 5-HT receptor NS 2359)35 monoaminergic reuptake inhibitors are being studied. antagonist, has been reported to have beneficial effects on dis- These compounds may be of interest as modulators of both cata- turbed nocturnal sleep in narcoleptic patients.42 plexy and sleepiness but are not novel in terms of mode of action (Table 2). Many may never be finally developed due to side ef- HISTAMINE AGONISTS AND ANTAGONISTS
fects, abuse potential, or other considerations. It is also likely that Like adrenergic and serotonergic cells, histaminergic cells sig- combination therapies with monoamine-selective inhibitors will nificantly decrease activity during non-rapid eye movement and often remain easier to titrate to control sleepiness and cataplexy rapid eye movement sleep.43 The sedative effects of H -receptor antagonists illustrate the importance of histamine in sleep regula-tion. The pioneering work of Lin and colleagues on the tuber- NOVEL HYPNOTICS WITH POTENTIAL ENHANCING EFFECTS ON
omammillary nucleus also indicate a major role for this system.44 SLOW-WAVE SLEEP
Hypocretin neurons have strong projections and excitatory Another area of potential interest may be the use of novel seda- effects on histamine transmission, an effect mediated by hcrtr2, tive hypnotics in narcolepsy-cataplexy (table 2). Disturbed noc- the receptor mutated in canine narcolepsy.2 The effects of hypo- turnal sleep is a common and disabling symptom in narcolepsy. In cretin on alertness after intracerebroventricular (ICV) injections the past, insomnia was treated using benzodiazepine-based hyp- are diminished or abolished when histaminergic transmission is notics or other sedatives. These compounds are typically effective blocked,45 suggesting the importance of the downstream effects for insomnia but have little, if any, effects on daytime symptoms of hypocretin on this neurotransmitter system in mediating wake of narcolepsy. In contrast, GHB has proven to be remarkably ef- promotion. We and others have also found that human narcolepsy, ficacious in the treatment of multiple symptoms of narcolepsy: and possibly idiopathic hypersomnia, is associated with decreased sleepiness, cataplexy, and disturbed nocturnal sleep.22-25 As dis- histamine in cerebrospinal fluid (CSF).46,47 The rationale for in- cussed above, the mode of action of GHB is debated but likely creasing histaminergic tone to treat narcolepsy and hypersomnia involves effects on GABA-B and possibly effects on less well- is thus strong from the pathophysiologic perspective.
characterized GHB receptors.22,26,27 A problem in its current for- The use of H -receptor agonists, though logically plausible, mulation is the short half-life of the compound. The development is made impossible by the lack of available centrally penetrat- of longer-acting GHB formulations or derivatives is ongoing. ing compounds and intolerable peripheral side effects. Current The short half-life is indeed an inconvenience but may improve pharmaceutical industry interest is therefore mostly focused on safety and could be advantageous in avoiding residual sedation. the H receptor (Table 2), a receptor known to be, among other It is also possible that the short half-life is important in prevent- actions, an autoreceptor located on brain histaminergic cell bod- ing the development of tolerance and addiction. GHB addiction ies.48 Stimulation of this receptor is sedating, while antagonism is not a problem in narcolepsy, and withdrawal symptoms are promotes wakefulness (or reduces SWS) in rodents and dogs.49,50 not observed upon abrupt cessation.36 In contrast, GHB abusers Experiments in narcoleptic canines have found anticataplectic and experience withdrawal symptoms when stopping but are typi- wake-promoting effects for some H antagonists and inverse ago- cally round-the-clock, high-dose GHB users, often also abusing nists.49 Preliminary results in orexin/ataxin-3 narcoleptic mice, in multiple drugs.37 Twenty-four–hour exposure to GHB may thus which hypocretin-producing neurons are ablated,5 indicate that Novel Narcolepsy Therapies—Mignot and Nishino these mice are more sensitive to an H antagonist in promoting ined by John et al66 and Fujiki et al.67 In 2002, John et al found wakefulness.51 A significant number of pharmaceutical compa- that hypocretin-1, when injected at the low dose of 3 µg/kg IV, nies are currently developing or clinically exploring the use of was wake-promoting and able to reverse cataplexy in hrctr-2 H antagonists or H inverse agonists to promote wakefulness and mutated Dobermans, while the IV administration of 4 µg/kg sig- cognition for various indications. Whether the promising results nificantly worsened cataplexy.66 This result was surprising from in animal models will also extend to humans, and whether these a pathophysiologic point of view, and, indeed, we found that, in compounds will have enough efficacy, remains to be established.
our narcoleptic hcrtr2-mutated canines, a similar dose was inef-fective in producing wakefulness, even when bolus ICV injec- THYROTROPIN-RELEASING HORMONE AGONISTS AND OTHER
tions were employed.67 Similar IV-injected doses per kilogram were also barely wake-promoting in normal dogs with functional receptors.67 Significantly higher doses were later injected through The use of thyrotropin-releasing hormone (TRH) direct or indi- both IV (for cataplexy and sleep) and ICV (for cataplexy) routes rect agonists may also be potentially interesting (Table 2).52 TRH without significant effect (up to 24 µg/kg IV or 120 nmoles ICV) is a small peptide of 3 amino acids, which penetrates the blood- in hcrtr2-mutated dogs,67 in disagreement with John’s study. brain barrier at very high doses. Small peptide derivatives with A better model to assess the effects of hypocretin on narcolep- agonistic properties and increased blood-brain barrier penetration sy may be to use hypocretin-deficient animals (rather than hcrtr2- (eg, CG3703, CG3509, or TA0910) have been developed,52,53 a mutated animals). In orexin/ataxin-3 narcoleptic mice, ICV hypo- success facilitated by the small nature of the parent TRH pep- cretin-1 (3 nmoles) can almost completely suppress episodes of tide. TRH (at the high dose of several mg/kg) and TRH agonists behavioral arrests (cataplexy-like episodes) and reverse sleep increase alertness and have been shown to be wake promoting fragmentation and sleep-onset rapid eye movement sleep periods and anticataplectic in the narcoleptic canine model.52 TRH has in this model.68 These experiments strongly suggest that if deliv- excitatory effects on motoneurons54 and enhances both DA and ered to the right location, hypocretin-1 may prove to be a viable adrenergic neurotransmission,55,56 properties that could contribute treatment in narcolepsy. In 2 hypocretin ligand-deficient canines to its wake-promoting and anticataplectic effects. Interestingly, (a close model of human narcolepsy), we administered high doses recent studies suggest that TRH may promote wakefulness by of IV hypocretin-1 (96-384 µg/kg) and found limited effects on directly interacting with thalamocortical networks. Indeed, TRH cataplexy:67,69 indeed, at best, we found that the 196- to 384-µg/kg itself and TRH receptor type 2 are abundant in the reticular tha- doses decreased cataplexy, but for less than 15 minutes.47 Whether lamic nucleus,57 and local thalamic application of TRH abolishes this transient effect is a reflection of side effects rather than genu- spindle wave activity.58 In slices, TRH depolarizes thalamocorti- ine therapeutic relief due to centrally penetrating hypocretin-1 is cal and reticular/perigeniculate neurons by inhibiting a leak K+ unknown. We also examined blood and CSF hypocretin-1 levels conductance.58 Unfortunately, however, human clinical studies at after IV administration and found extremely high concentrations low doses in depression have shown limited efficacy and only in the blood (up to 10 million pg/mL in blood after 384 µg/kg moderate subjective alerting effects;53,59,60 whether better com- IV) with minimal and variable increases in CSF hypocretin-1 lev- pounds can or will be developed is unknown. Other possibly in- els (plus 400 pg/mL after 384 µg/kg IV; with exclusion of CSF teresting development directions could involve inhibitors of the samples containing blood).67 These results indicate that the blood- TRH-degrading enzyme, a relatively specific metallopeptidase.61 brain barrier is, in fact, quite impermeable to hypocretin-1 (unless Other experimental targets for wake promotion could also it is locally broken, for example with the insertion of a dialysis involve novel neuropeptide systems and protein targets such as probe). Peripherally administered hypocretins are thus not likely circadian clock proteins or kinases, novel ion channels, proki- to be effective in the treatment of narcolepsy, unless administered neticin,62 or the recently described wake-promoting neuropeptide at much higher doses. The effects of even higher doses, similar to those found to be active for TRH (500 µg/kg to several mg/kg) in the canine model,65 however, still need to be tested, as no signifi- HYPOCRETIN PEPTIDE SUPPLEMENTATION: INTRAVENOUS, IN-
cant peripheral side effects have been noted. TRANASAL, INTRACISTERNAL, AND ICV EFFECTS
Another possible path towards delivering hypocretin-1 to the The gold standard for narcolepsy treatment will one day like- brain may be intranasal delivery.70,71 Some investigators have re- ly be hypocretin replacement therapy. This could be achieved ported CNS penetration for selected peptides and increased CSF through the delivery of hypocretin peptides themselves, the use levels in humans after intranasal administration, suggesting direct of prodrugs or agonists, or the use of genetic engineering or cell- penetration from the nose to the brain.71 In mice, we found that af- replacement therapies (Table 2). Unlike the very small TRH mol- ter intranasal 125I-hypocretin-1 administration (5 nmol), high lev- ecule, hypocretin-1 and hypocretin-2 are peptides of medium size, els of putative labeled hypocretin-1 (10-1000 nmol) were found in multiple brain regions.70 In addition to delivery to the brain, in- Early experiments using radio-labeled hypocretin peptides tranasal hypocretin-1 also resulted in delivery to the spinal cord, have suggested that the peptide may cross the blood-brain bar- with a decreasing gradient from cervical (96 nmol) to lumbar (3 rier by passive diffusion.64 Hypocretin-1 has been found to be nmol) regions. However, a preliminary observation did not allow more stable than hypocretin-2 in both the blood and the CSF,64,65 us to observe significant changes in locomotion in either control a property that likely explains why hypocretin-1 is more active or narcoleptic mice after intranasal administration (J. Zeitzer, than hypocretin-2 after ICV injection. Subsequent pharmacologic Ph.D., personal oral communication). Experiments in humans are experiments have therefore generally employed hypocretin-1. needed to further test this hypothesis.
The effects of intravenous (IV) and ICV administration of The finding that ICV administration was efficacious in rodents hypocretin-1 in hcrtr2-mutated canine narcolepsy has been exam- led us to implant a Medtronic pump in a 3 year-old hypocretin Novel Narcolepsy Therapies—Mignot and Nishino deficient Weimaraner with a connection to the cisterna magna.69 DA neurons of fetal mesencephalon grafts is only 5% to 10%.79 These pumps are commonly used to continuously administer This low survival rate suggests that it may be impossible to gath- analgesic (eg, opioids for pain) or spasmolytic (eg, baclofen for er enough material from cadaver donors to achieve the required spasticity) compounds, and timing of the administration can be number of functioning cells. To solve the problem of supply, ef- controlled remotely. It was our hope that hypocretin-1 would ficient cell-sorting or selection methods for hypocretin-contain- backflow through the foramina of Luschka into the ICV system, ing cells may need to be developed. A similar problem has also and that, if successful, a similar device could be implemented in been encountered in the field of type I diabetes, where intraportal humans through catheterization of the lumbar sac. Unfortunately, islet-cell transplantation has been found to be effective, but donor these experiments were not successful, even when up to 1200 material is scarce, and long-term benefits are still unclear.80,81 nmol of hypocretin-1 (150 µg/kg) were injected, suggesting the The possibility of immune reactions to the grafted hypocretin impracticality of this approach. A possibility may be that hypo- cells may be another concern, particularly if an autoimmune pro- cretin receptors are downregulated after long periods of hypocre- cess indeed causes hypocretin deficiency in humans. A similar tin deficiency and therefore could not stimulated by the perfused problem is emerging in the area of islet-cell transplantation.80,81 hypocretin-1. This is however less likely, since neither hcrtr1 nor The long-term solution for these problems may therefore be the hcrtr2 mRNA have been found to be significantly decreased in genetic engineering of cells delivering hypocretins, either using hypocretin-deficient human brains (M. Honda, unpublished re- stem-cell technology or genetically modified transplanted cells. sults using human cDNA arrays in postmortem human narcolepsy In this area, like in others, narcolepsy is likely to benefit from brains). We are planning to pursue this experimental approach parallel advances in other areas of medicine.
with the direct lateral ventricle infusion of hypocretin-1 in hypo-cretin-deficient dogs.
HYPOCRETIN PEPTIDE ANALOGUES
An obvious solution considering the lack of central nervous HYPOCRETIN GENE THERAPY AND HYPOCRETIN CELL TRANS-
system penetration of exogenous hypocretin peptides may be to PLANTATION
develop centrally acting hypocretin agonists. The molecular size Another possible experimental approach involves induction and innate water solubility of compounds are some of the impor- of endogenous hypocretins, which could involve gene therapy tant issues to consider when attempting to deliver peptides effec- or hypocretin cell replacement therapy. Meieda et al, using mice tively into the brain parenchyma.82 The fact that most of the nar- nonspecifically overexpressing the hypocretin gene in the cen- colepsy phenotype is recapitulated by hcrtr2-deficient animals2,19 tral nervous system (with a beta-actin/cytomegalovirus hybrid suggests that hcrtr2- rather than hcrtr1-targeted agonists may be promoter), found that crossing these mice with orexin/ataxin-3 most appropriate. Hypocretin-2, a peptide with higher hcrtr2 ver- narcoleptic mice could rescue the phenotype of narcolepsy (both sus hcrtr1 affinity, may be a useful starting point, but it has a very sleep abnormalities and behavioral arrests).68 It is therefore theo- short biologic half-live;64,65 more-stable molecular entities will be retically possible that viral delivery of a transgene (or indirect de- livery via cells carrying such a transgene but entering the central The modification of the native peptide or the design of pre- nervous system) resulting in the expression of hypocretin could cursor molecules (ie, prodrug) may potentially overcome these be effective (despite the lack of proper anatomic distribution or hurdles.83 Substitution scans, truncated peptide analysis, and cross-species comparisons indicate that the C-terminal amide Closer on the horizon may be the use of cell transplantation. portion of both hypocretin peptides, most notably the last 8 amino Transplanted cells are likely to keep their regulatory mechanisms acids (a region of high homology between hypocretin-1 and 2) intact. Transplantation of fetal hypothalamic tissue has, for exam- is most critical.84,85 Selected identified peptide substitutions have ple, been shown to rescue circadian abnormalities in suprachias- also been found to have increased selectivity toward hcrtr1 and matic nuclei-lesioned or clock-mutated animals.72,73 In Parkinson hcrtr2.84,85 Unfortunately, none of the provided structures is small disease, a large number of animal studies have indicated feasibility enough to be a likely viable drug. However, further study of these of cell transplantation, while clinical studies have shown variable modified peptides at very high doses, together with further struc- effects (see reference 74). In a preliminary study, Arias-Carrión et tural improvement to increase stability and central penetration, al75 recently found that the transplantation of neonatal rat hypo- thalami into the brainstem of adult rats might result in the devel-opment of stable grafts containing hypocretin neurons. Survival HYPOCRETIN-RECEPTOR AGONISTS
of the grafts was poor, however, and whether these grafts will Direct agonists with adequate pharmacokinetic properties restore function and project to their normal targets is unknown. would be ideal therapies. For most G-protein coupled receptor Additional work is needed to further validate this approach in ani- (GPCR) systems, it is however typically more difficult to identify agonists than antagonists. Indeed, agonists must not only bind the In humans, it is estimated that about 70,000 hypocretin neurons receptor, but must also interact tightly at the molecular level to exist in the brain and that narcolepsy is associated with a 85% to stimulate secondary messenger systems. This may be even more 100% loss.76,77 Although the number of restored neurons needed dificult for peptide-receptor systems, considering the size of the to rescue the narcolepsy phenotype is unknown, narcolepsy typi- ligand and the potential complexity of the associated molecular cally presents when CSF hypocretin-1 levels are below 30% of interactions. In spite of these difficulties, a dozen nonpeptide control values.78 It is thus likely that a minimum of 10% of the agonists for GPCR peptide receptors, including the urotensin-II normal cell population may be required to have a clinical effect. receptor (GPR14),86 opioid receptor-like (ORL1) receptor,87 and In models of Parkison disease, however, the survival rate of galanin receptor88 are currently under development. Novel Narcolepsy Therapies—Mignot and Nishino Several companies have succeeded in identifying small mo- study98 indicated persistence of low CSF hypocretin-1 levels, al- lecular hypocretin-receptor antagonists,89-92 with both hcrtr1 and though in 1 case a possible small increase (from undetectable to hcrtr2 selectivity. These molecules are active in vitro and in vivo, 79 pg/mL) was noted. Whether a small improvement in hypocre- but it is still too early to predict whether some of these compounds tin deficiency, without increasing CSF hypocretin-1 levels above have the appropriate characteristics to become viable drugs. It is the limit of detection was present, will have to be addressed by also unclear if these drugs will have acceptable side-effect profiles improving sensitivity of the reported measurements. Similarly, and whether a proper indication will be found within or outside reports by Zuberi99 indicated more improvement in subjective the sleep disorder market. Whether nonpeptide hypocretin-recep- sleepiness than in cataplexy. Finally, while Multiple Sleep La- tor agonists can or will be identified and successfully developed tency Test and Maintenance Wakefulness Test evaluations in the Dauvillier’s study indicated a nonstatistically significant im-provement in sleep latency in 2 cases, the phenotype persisted.98 IMMUNOMODULATION AS A PREVENTIVE TREATMENT FOR NAR-
Indeed, sleep-onset rapid eye movement periods were still ob- served in all situations. To confirm these results, proper double-blind, placebo-controlled trials will be needed. This will require The combined observation of hypocretin cell loss76,77 and HLA close coordination of research and clinical resources in our field, association93 suggests an autoimmune basis for narcolepsy. If this as reports of narcolepsy within a few months of disease onset are, is the case, it is likely that the process is only reversible prior to at present, extremely rare. It may also be interesting to explore the near complete ablation of cells. Studies in young children near the effect of other immunomodulatory treatments, for example those abrupt onset of symptoms and presumed disease onset (typically 3 months to 1 year) indicate that, in most cases, CSF hypocretin- The mode of action of IVIg on these symptoms will also need 1 levels are undetectable or very low at the time of presentation, to be studied further. IVIg therapy is believed to act by clearing even when the subject does not have cataplexy.78,94,95 This unfor- autoantibodies, yet most attempts at detecting such pathogenic tunately suggests that symptoms only appear after the majority of antibodies in human narcolepsy have failed.100,101 A notable ex- the cell population is destroyed. Indeed, rat studies indicate that a ception may be the recent report of Smith et al,102 who found that 70% cell loss only results in a 50% decrease in CSF hypocretin-1, passive transfer of immunoglobulin from a patient with narcolep- suggesting compensation in cases of partial cell loss.96 However, sy into mice may result in secondary M3 cholinergic hypersen- it is also possible that the loss of CSF hypocretin-1 is a reflection sitivity (central cholinergic hypersensitivity is one of most well- of decreased cell function without actual cell death and that the documented characteristics of canine narcolepsy)103,104 in bladder destruction can still be partially reversed at this early stage with However, the IVIg mixture is complex, and modulation of oth- To address this issue, we first attempted to reverse narcolepsy er arms of the immune system is possible. It remains possible that using prednisone in an 8-year-old child with an abrupt onset 3 the mode of action of immune-modulatory drugs is symptomatic, months prior to diagnosis.94 The child had already undetectable as experiments at the University of California Los Angeles, in CSF hypocretin-1 (normal CSF protein, CSF cell count and fluid- hcrtr2-mutated canines (presumably without autoimmune ab- attenuated inversion recovery magnetic resonance imaging), no normalities) also suggest a paradoxical preventive effects on the cataplexy, and a positive Multiple Sleep Latency Test. Prednisone development of cataplexy.105 To address this issue, studying the was selected as a broad cell-mediated and antibody-mediated im- effect of plasmapheresis, another treatment for antibody-medi- munosuppressant. Repeat Multiple Sleep Latency Test and CSF ated diseases, may provide further answers. We recently reported evaluation were performed after 3 weeks, but no clinical improve- a case in which plasmapheresis had some temporary efficacy in ment was noted. This child now has developed cataplexy that is an adult with hypocretin deficiency, unusually severe cataplexy, controlled by venlafaxine and modafinil. A similar prednisone and late onset at age 60.106 Whether immune modulation close to trial was also performed in a hypocretin-deficient narcoleptic dog the onset and associated preventive measures, such as the moni- (Weimaraner) diagnosed 2 weeks after an abrupt onset, with simi- toring of children at risk (eg, family members with the disease HLA haplotype), as performed in with type I diabetes107 in Scan- In a patient with recent-onset cataplexy, combining IV immu- dinavia, will one day prove feasible, remains to be seen.
noglobulins (IVIg) and prednisone reduced cataplexy and sleepi-ness subjectively, but the patient was unable to continue treat- CONCLUSION
ment.97 Dauvilliers et al98 and Zuberi et al99 studied 4 additional patients each with IVIg alone; 6 with recent onset, 2 with more- In conclusion, the treatment of human narcolepsy is rapidly distant disease onset. Four monthly treatments using 2 g/kg over evolving. Much progress has recently been made through the im- 2 days were typically performed. Subjective effects on sleepiness provement of currently available symptomatic therapies that en- and/or cataplexy were observed in recent-onset cases but not in hance monoaminergic signaling. Novel stimulants and hypnotics established narcolepsy cases (defined as onset of more than a few are being developed and may further benefit narcoleptic patients. years). Side effects were mild and included short-lasting fever in More exciting, however, may be the hypocretin-based therapies some cases. Most notably, in the Dauvilliers study,98 cataplexy that are being designed. The most promising avenues include was significantly reduced and anticataplectic drugs were no lon- hypocretin agonists and hypocretin cell transplantation therapies, ger needed 9 months after ending the IVIg treatment, suggesting but these modalities are most likely decades away. Recent results using IVIg, although preliminary, also suggest the possibility of Problematically, however, all the reported effects were subjec- early intervention to limit disease progression, if associated with tive. Repeat CSF hypocretin-1 measurements in the Dauvilliers Novel Narcolepsy Therapies—Mignot and Nishino ACKNOWLEDGMENT
syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory pro- This work was supported by NIH NS 23724, NS33797 to E. Mignot. All our thanks to Dr. Wynne Chen and Mali Einen for 20. Nishino S, Arrigoni J, Shelton J, Dement WC, Mignot E. Desmeth- yl metabolites of serotonergic uptake inhibitors are more potent for suppressing canine cataplexy than their parent compounds. Sleep REFERENCES
21. Nishino S. Anticataplectic medications. In: Bassetti C, Billiard M, Nishino S, Mignot E. Pharmacological aspects of human and Mignot E eds. Narcolepsy and Hypersomnia. New York: Marcel canine narcolepsy. Prog Neurobiol 1997;52:27-78.
Lin L, Faraco J, Li R, Kadotani H, et al. The sleep disorder canine 22. Arnulf I, Mignot E. Sodium oxybate for excessive daytime sleepi- narcolepsy is caused by a mutation in the hypocretin (orexin) ness in narcolepsy-cataplexy. Sleep 2004;27:1242-3.
receptor 2 gene. Cell 1999;98:365-76.
23. Broughton R, Mamelak M. The treatment of narcolepsy-cata- Ripley B, Fujiki N, Okura M, Mignot E, Nishino S. Hypocretin plexy with nocturnal gamma-hydroxybutyrate. Can J Neurol Sci levels in sporadic and familial cases of canine narcolepsy. Neuro- 24. Scrima L, Hartman PG, Johnson FH, Hiller FC. Efficacy of Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin gamma-hydroxybutyrate versus placebo in treating narcolepsy- knockout mice: molecular genetics of sleep regulation. Cell 1999 cataplexy: double-blind subjective measures. Biol Psychiatry Hara J, Beuckmann CT, Nambu T, et al. Genetic ablation of orexin 25. Mamelak M, Black J, Montplaisir J, Ristanovic R. A pilot study on neurons in mice results in narcolepsy, hypophagia, and obesity. the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep 2004;27:1327-34.
Nishino S, Mao J, Sampathkumaran R, Shelton J, Mignot E. In- 26. Maitre M. The gamma-hydroxybutyrate signalling system in creased Dopaminergic transmission mediates the wake promoting brain: organization and functional implications. Prog Neurobiol effects of CNS stimulants. Sleep Res On line; 1:49-61.
Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM. 27. Itzhak Y, Ali SF. Repeated administration of gamma-hydroxybu- Dopaminergic role in stimulant-induced wakefulness. J Neurosci tyric acid (GHB) to mice: assessment of the sedative and reward- ing effects of GHB. Ann N Y Acad Sci. 2002;965:451-60.
Nishino S, Mignot, E. CNS stimulants in sleep medicine: basic 28. Donovan JL, Malcolm RJ, Markowitz JS, DeVane CL. Chiral mechanisms and pharmacology. In: Kryger MH, Roth T, Dement analysis of d- and l-modafinil in human serum: application to hu- WC eds. Principles and Practice of Sleep Medicine. Philadelphia: man pharmacokinetic studies. Ther Drug Monit 2003;25:197-202.
29. Lile JA, Wang Z, Woolverton WL, France JE, Gregg TC, Davies Russell V, de Villiers A, Sagvolden T, Lamm M, Taljaard J. Differ- HM, Nader MA. The reinforcing efficacy of psychostimulants in ences between electrically-, ritalin- and D-amphetamine-stimulated rhesus monkeys: the role of pharmacokinetics and pharmacody- release of [3H]dopamine from brain slices suggest impaired ve- namics. J Pharmacol Exp Ther 2003;307:356-66.
sicular storage of dopamine in an animal model of attention-deficit 30. Johnson RA, Eshleman AJ, Meyers T, Neve KA, Janowsky A. hyperactivity disorder. Behav Brain Res 1998;94:163-71.
[3H]substrate- and cell-specific effects of uptake inhibitors on hu- 10. Fukui R, Svenningsson P, Matsuishi T, Higashi H, Nairn AC, man dopamine and serotonin transporter-mediated efflux. Synapse Greengard P, Nishi A. Effect of methylphenidate on dopamine/ DARPP signaling in adult, but not young, mice. J Neurochem 31. Preti A. Vanoxerine National Institute on Drug Abuse. Curr Opin 11. Volkow ND, Fowler JS, Wang GJ, Ding YS, Gatley SJ. Role of 32. Gorelick DA, Gardner EL, Xi ZX. Agents in development for the dopamine in the therapeutic and reinforcing effects of methylphe- management of cocaine abuse. Drugs 2004;64:1547-73.
nidate in humans: results from imaging studies. Eur Neuropsycho- 33. Srisurapanont M, Jarusuraisin N, Jittiwutikan J. Amphetamine withdrawal: II. A placebo-controlled, randomised, double-blind 12. Mignot E, Renaud A, Nishino S, Arrigoni J, Guilleminault C, study of amineptine treatment. Aust N Z J Psychiatry 1999;33:94- Dement WC. Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective 34. Kent JM. SNaRIs, NaSSAs, and NaRIs: new agents for the treat- uptake inhibitors and release enhancers. Psychopharmacology ment of depression. Lancet 2000;355:911-8.
35. Beer B, Stark J, Krieter P, Czobor P, Beer G, Lippa A, Skolnick P. 13. Mignot E. An update on the pharmacotherapy of excessive daytime DOV 216,303, a “triple” reuptake inhibitor: safety, tolerability, and sleepiness and cataplexy. Sleep Med Rev. 2004;8:333-8.
pharmacokinetic profile. J Clin Pharmacol 2004;44:1360-7.
14. US Modafinil. Randomized trial of modafinil as a treatment for 36. The abrupt cessation of therapeutically administered sodium oxy- the excessive daytime somnolence of narcolepsy: US Modafinil in bate (GHB) does not cause withdrawal symptoms. J Toxicol Clin Narcolepsy Multicenter Study Group. Neurology 2000;54:1166-75.
15. Shelton J, Nishino S, Vaught J, Dement WC, Mignot E. Compara- 37. Tarabar AF, Nelson LS. The gamma-hydroxybutyrate withdrawal tive effects of modafinil and amphetamine on daytime sleepiness and cataplexy of narcoleptic dogs. Sleep 1995;18:817-26.
38. Zeitzer JM, E. M. In: Bassetti C, Billiard M, Mignot E eds. Nar- 16. Willie JT, Renthal W, Chemelli RM, et al. Modafinil more effec- colepsy and Hypersomnia. New York: Marcel Dekker; 2005: In tively induces wakefulness in orexin-null mice than in wild-type littermates. Neuroscience 2005;130:983-95.
39. Krogsgaard-Larsen P, Frolund B, Liljefors T, Ebert B. GABA(A) 17. Mignot E. Mignot E, Nishino S, Guilleminault C, Dement WC. agonists and partial agonists: THIP (Gaboxadol) as a non-opi- Modafinil binds to the dopamine uptake carrier site with low affin- oid analgesic and a novel type of hypnotic. Biochem Pharmacol 18. Saper CB, Scammell TE. Modafinil: A drug in search of a mecha- 40. Mathias S, Wetter TC, Steiger A, Lancel M. The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly 19. Willie JT, Chemelli RM, Sinton CM, et al. Distinct narcolepsy subjects. Neurobiol Aging 2001;22:247-53.
Novel Narcolepsy Therapies—Mignot and Nishino 41. Mignot E, Taheri S, Nishino S. Sleeping with the hypothalamus: 62. Cheng MY, Bullock CM, Li C, Lee AG, Bermak JC, Belluzzi J, emerging therapeutic targets for sleep disorders. Nat Neurosci Weaver DR, Leslie FM, Zhou QY. Prokineticin 2 transmits the be- havioural circadian rhythm of the suprachiasmatic nucleus. Nature 42. Mayer G. Ritanserin improves sleep quality in narcolepsy. Pharma- 63. Xu YL, Reinscheid RK, Huitron-Resendiz S, et al. Neuropeptide 43. Steininger TL, Alam MN, Gong H, Szymusiak R, McGinty D. S: a neuropeptide promoting arousal and anxiolytic-like effects. Sleep-waking discharge of neurons in the posterior lateral hypo- thalamus of the albino rat. Brain Res 1999;840:138-47.
64. Kastin AJ, Akerstrom V. Orexin A but not orexin B rapidly enters 44. Lin JS. Brain structures and mechanisms involved in the control brain from blood by simple diffusion. JPET 1999;289:219-23.
of cortical activation and wakefulness, with emphasis on the 65. Yoshida Y, Fujiki N, Maki RA, Schwarz D, Nishino S. Differential posterior hypothalamus and histaminergic neurons. Sleep Med Rev kinetics of hypocretins in the cerebrospinal fluid after intracerebro- ventricular administration in rats. Neurosci Lett 2003;346:182-6.
45. Huang ZL, Qu WM, Li WD, Mochizuki T, Eguchi N, Watanabe 66. John J, Wu MF, Siegel JM. Systemic administration of hypocretin- T, Urade Y, Hayaishi O. Arousal effect of orexin A depends on 1 reduces cataplexy and normalizes sleep and waking durations in activation of the histaminergic system. Proc Natl Acad Sci U S A narcoleptic dogs. Sleep Res Online 2000;3:23-8.
67. Fujiki N, Ripley B, Yoshida Y, Mignot E, Nishino S. Effects of IV 46. Kanbayashi T, Kodama T, Hondo H, et al. CSF histamine and nor- and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene adrenaline contents in narcolepsy and other sleep disorders. Sleep mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin ligand deficient narcoleptic dog. Sleep 2003;6:953- 47. Nishino S, Sakurai E, Nevisimalova S, et al CSF histamine content is decreased in hypocretin-deficient human narcolepsy. Sleep 68. Mieda M, Willie JT, Hara J, Sinton CM, Sakurai T, Yanagisawa M. Orexin peptides prevent cataplexy and improve wakefulness in 48. Chen J, Liu C, Lovenberg TW. Molecular and pharmacological an orexin neuron-ablated model of narcolepsy in mice. Proc Natl characterization of the mouse histamine H3 receptor. Eur J Phar- 69. Schatzberg SJ, Barrett J, Cutter Kl, Ling L, Mignot E. Case study: 49. Tedford CE, Edgar DM, Seidel WF, Mignot E, Nishino S, Paw- Effect of hypocretin replacement therapy in a 3-year-old Weimara- lowski GP, Yates SL. Effects of a novel, selective, and potent his- ner with narcolepsy. J Vet Internal Med 2004;18:586-8.
tamine H3 receptor antagonist, GT-2332, on rat sleep/wakefulness 70. Hanson LR, Martinez PM, Taheri S, Kamsheh L, Mignot E, Frey and canine cataplexy. Neuroscience 1999;25:abstract 1134.
II WH. Intranasal administration of hypocretin 1 (Orexin A) 50. Barbier AJ, Berridge C, Dugovic C, et al. Acute wake-promoting bypasses the blood-brain barrier & targets the brain: a new strategy actions of JNJ-5207852, a novel, diamine-based H3 antagonist. Br for the treatment of narcolepsy. Drug Delivery Technol 2004;4:66- 51. Shiba T, Fujiki N, Wisor J, Edgar D, Sakurai T, Nishino S. Wake 71. Hallschmid M, Benedict C, Born J, Fehm HL, Kern W. Manipulat- promoting effects of thioperamide, a histamine H3 antagonist in ing central nervous mechanisms of food intake and body weight orexin/ataxin-3 narcoleptic mice. Sleep 2004;:A241-2.
regulation by intranasal administration of neuropeptides in man. 52. Nishino S, Arrigoni J, Shelton J, et al. Effects of thyrotropin-releas- ing hormone and its analogs on daytime sleepiness and cataplexy 72. DeCoursey PJ, Buggy J. Circadian rhythmicity after neural in canine narcolepsy. J Neurosci 1997;17:6401-8.
transplant to hamster third ventricle: specificity of suprachiasmatic 53. Griffiths EC, Bennett GW. Clinical applications of thyrotropin-re- leasing hormone. Clin Sci 1987;73:449-57.
73. Vogelbaum MA, Galef J, Menaker M. Factors determining the 54. Nicoll RA. Excitatory action of TRH on spinal motoneurons. Na- restoration of circadian behavior by hypothalamic transplants. J Neural Transplant Plast 1993;4:239-56.
55. Sharp T, Bennett GW, Marsden CA. Thyrotropin-releasing hor- 74. Roitberg B, Urbaniak K, Emborg M. Cell transplantation for mone analogues increase dopamine release from slices of rat brain. Parkinson’s disease. Neurol Res 2004;26:355-62.
75. Arias-Carrion O, Murillo-Rodriguez E, Xu M, Blanco-Centurion 56. Keller HH, Bartholini G, Pletscher A. Enhancement of cerebral C, Drucker-Colin R, Shiromani PJ. Transplant of hypocretin neu- noradrenaline turnover by thyrotropin-releasing hormone. Nature. rons into the pontine reticular formation: preliminary results. Sleep 57. Heuer H, Schafer MK, O’Donnell D, Walker P, Bauer K. Expres- 76. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early sion of thyrotropin-releasing hormone receptor 2 (TRH-R2) in the onset narcolepsy and a generalized absence of hypocretin peptides central nervous system of rats. J Comp Neurol 2000;428:319-36.
in human narcoleptic brains. Nat Med. 2000;6:991-7.
58 Broberger C. Neurotransmitters switching the thalamus between 77. Thannickal TC, Moore RY, Nienhuis R, , et al. Reduced number of sleep and arousal: functional effects and cellular mechanism. hypocretin neurons in human narcolepsy. Neuron 2000;27:469-74.
Presented at Showa University International Symposium for Life 78. Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal Science. 1st Annual Meeting New Frontiers in Neuroscience Re- fluid hypocretin measurement in the diagnosis of narcolepsy and search. Showa University Kamijo Hall (Tokyo), August 31, 2004.
other hypersomnias. Arch Neurol 2002;59:1553-62.
59. Vogel HP, Benkert O, Illig R, Muller-Oerlinghausen B, Poppen- 79. Bjorklund A. Neurobiology. Better cells for brain repair. Nature berg A. Psychoendocrinological and therapeutic effects of TRH in depression. Acta Psychiatr Scand 1977;56:223-32.
80. Couzin J. Diabetes. Islet transplants face test of time. Science 60. Bunevicius R, Matulevicius V. Short-lasting behavioural effects of thyrotropin-releasing hormone in depressed women: results of 81. Naftanel MA, Harlan DM. Pancreatic Islet Transplantation. PLoS placebo-controlled study. Psychoneuroendocrinology 1993;18:445- 82. Pardridge WM. Transport of small molecules through the blood- 61. Schomburg L, Turwitt S, Prescher G, Lohmann D, Horsthemke brain barrier: biology and methodology. Adv Drug Deliv Rev B, Bauer K. Human TRH-degrading ectoenzyme cDNA cloning, functional expression, genomic structure and chromosomal assign- 83. Prokai-Tatrai K, Prokai L. Modifying peptide properties by pro- ment. Eur J Biochem 1999;265:415-22.
drug design for enhanced transport into the CNS. Prog Drug Res Novel Narcolepsy Therapies—Mignot and Nishino 105. Boehmer LN, Wu MF, John J, Siegel JM. Treatment with immu- 84. Asahi S, Egashira S, Matsuda M, et al. Development of an orexin- nosuppressive and anti-inflammatory agents delays onset of canine 2 receptor selective agonist, [Ala(11), D-Leu(15)]orexin-B. Bioorg genetic narcolepsy and reduces symptom severity. Exp Neurol 85. Darker JG, Porter RA, Eggleston DS, et al. Structure-activity 106. Chen W, Black J, Einen M, Mignot E. Therapeutic effects of plas- analysis of truncated orexin-A analogues at the orexin-1 receptor. mapheresis: a case report. Sleep 2005;(suppl):In Press.
Bioorg Med Chem Lett 2001;11:737-40.
107. Sadeharju K, Hamalainen AM, Knip M, et al. Enterovirus infec- 86. Croston GE, Olsson R, Currier EA, et al. Discovery of the first tions as a risk factor for type I diabetes: virus analyses in a dietary nonpeptide agonist of the GPR14/urotensin-II receptor: 3-(4-chlo- intervention trial. Clin Exp Immunol 2003;132:271-7.
rophenyl)-3-(2- (dimethylamino)ethyl)isochroman-1-one (AC-7954). J Med Chem 2002;45:4950-3.
87. Zaveri N. Peptide and nonpeptide ligands for the nociceptin/or- phanin FQ receptor ORL1: research tools and potential therapeutic agents. Life Sci 2003;73:663-78.
88. Saar K, Mazarati AM, Mahlapuu R, et al. Anticonvulsant activity of a nonpeptide galanin receptor agonist. Proc Natl Acad Sci U S A 2002;99:7136-41.
89. Smart D, Sabido-David C, Brough SJ, et al. SB-334867-A: the first selective orexin-1 receptor antagonist. Br J Pharmacol 2001;132:1179-82.
90. Porter RA, Chan WN, Coulton S, et al. 1,3-Biarylureas as selec- tive non-peptide antagonists of the orexin-1 receptor. Bioorg Med Chem Lett 2001;11:1907-10.
91. Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ. Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor. Br J Phar-macol 2004;141:340-6.
92. Hirose M, Egashira S, Goto Y, et al. N-acyl 6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline: the first orexin-2 receptor selective non-peptidic antagonist. Bioorg Med Chem Lett 2003;13:4497-9.
93. Mignot E, Lin L, Rogers W, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet. 2001;68:686-99.
94. Hecht M, Lin L, Kushida CA, et al. Report of a case of immuno- suppression with prednisone in an 8-year-old boy with an acute onset of hypocretin-deficiency narcolepsy. Sleep 2003;26:809-10.
95. Arii J, Kanbayashi T, Tanabe Y, et al. SF hypocretin-1 (orexin-A) levels in childhood narcolepsy and neurologic disorders. Neurol-ogy 2004; 63:2440-2.
96. Gerashchenko D, Murillo-Rodriguez E, Lin L, et al. Relationship between CSF hypocretin levels and hypocretin neuronal loss. Exp Neurol 2003;184:1010-6.
97. Lecendreux M, Maret S, Bassetti C, Mouren MC, MT. Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy. J Sleep Res 2003;12:347-8.
98. Dauvilliers Y, Carlander B, River F, Touchon J, Tafti M. IVIG treatment in narcolepsy: Report on two new cases. J Sleep Res 2004;13(Suppl1):167.
99. Zuberi SM, Mignot E, Ling L, MacArthur I. Variable response to intravenous immunoglobulin therapy in childhood narcolepsy. J Sleep Res 2004;13(Suppl1):828.
100 Black JL 3rd, Krahn LE, Pankratz VS, Silber M. Search for neuron-specific and nonneuron-specific antibodies in narcoleptic patients with and without HLA DQB1*0602. Sleep 2002;25:719-23.
101. Taheri S, Krempetz M, Jackson M, Paterno J, Mignot E. Investi- gation of the autoimmune basis of narcolepsy using Western blot analysis of lateral hypothalamus protein extract with serum and cerebrospinal fluid (CSF) Sleep 2003;26:A285.
102. Smith AJ, Jackson MW, Neufing P, McEvoy RD, Gordon TP. A functional autoantibody in narcolepsy. Lancet 2004;364:2122-4.
103. Reid MS, Tafti M, Geary J, et al. Cholinergic mechanisms in ca- nine narcolepsy: I. Modulation of cataplexy via local drug adminis-tration into pontine reticular formation. Neuroscience 1994;59:511-22.
104. Nishino S, Shelton J, Reid MS, Siegel JM, Dement WC, Mignot E. A cholinoceptive site in the basal forebrain is involved in canine narcolepsy. Soc Neurosci 1992:880.
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