Brain histamine and schizophrenia: Potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649

Ligneau, Xavier; Landais, Laurent; Perrin, David; Piriou, Johanne; Uguen, Marilyne; Denis, Emmanuel; Robert, Philippe; Parmentier, Régis; Anaclet, Christelle; Lin, Jian‐Sheng; Burban, Aude; Arrang, Jean‐Michel; Schwartz, Jean‐Charles

doi:10.1016/j.bcp.2007.01.023

Cited by 103 publications

(111 citation statements)

References 28 publications

(31 reference statements)

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“…Both tiprolisant and modafinil enhanced wakefulness during the lights-off (active) period in orexin-/-mice, as is observed in WT rodents (Scammell et al,2000;Parmentier et al,2007;Ligneau et al,2007b) and cats (Lin et al,1992;Ligneau et al,1998Ligneau et al, ,2007a.…”

Section: Discussionmentioning

confidence: 68%

“…It may reflect the procognitive efficacy of these drugs on higher functions such as attention or learning (Ligneau et al,1998,2007aand b, Parmentier et al,2007, a property of potential therapeutic interest since narcoleptic patients often complain of deficits in attention and memory (Dauvilliers et al,2007).…”

Section: Discussionmentioning

confidence: 99%

“…We examined this hypothesis, first using a reliable animal model of narcolepsy, the orexin-/-mouse, which displays DREMs, a characteristic symptom of the disease (Chemelli et al, 1999;Mignot, 2005;Fujiki, et al, 2006), then in narcoleptic patients, by testing the effects of tiprolisant (BF2.649), a potent and selective inverse agonist of the H3 receptors (Ligneau et al, 2007a and2007b) in both proof-of-concept studies. This class of agents is known to promote wakefulness by inhibiting the constitutively active H3-autoreceptor, thereby enhancing histaminergic neuron activity and histamine (HA) release (Schwartz et al, 1991;Lin, 2000;Morisset et al, 2000;Vanni-Mercier et al, 2003;Parmentier et al, 2002Parmentier et al, , 2007.…”

Section: Introductionmentioning

confidence: 99%

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An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin−/− mice and patients

Lin

Dauvilliers

Arnulf

et al. 2008

Neurobiology of Disease

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247

178

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Abbreviations AbstractNarcolepsy is characterized by excessive daytime sleepiness(EDS), cataplexy, direct onsets of rapid eye movement(REM) sleep from wakefulness(DREMs) and deficiency of orexins, neuropeptides that promote wakefulness largely via activation of histamine (HA) pathways. The hypothesis that the orexin defect can be circumvented by enhancing HA release was explored in narcoleptic mice and patients using tiprolisant, an inverse H3-receptor agonist. In narcoleptic orexin-/-mice, tiprolisant enhanced HA and noradrenaline neuronal activity, promoted wakefulness and decreased abnormal DREMs, all effects being amplified by co-administration of modafinil, a currently prescribed wake-promoting drug. In a pilot single-blind trial on 22 patients receiving a placebo followed by tiprolisant, both for one week, the Epworth Sleepiness Scale(ESS) score was reduced from a baseline value of 17.6 by 1.0 with the placebo(p>0.05) and 5.9 with tiprolisant(p<0.001). Excessive daytime sleep, unaffected under placebo, was nearly suppressed on the last days of tiprolisant-dosing. H3-receptor inverse agonists could constitute a novel effective treatment of EDS, particularly when associated with modafinil.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin−/− mice and patients

Lin

Dauvilliers

Arnulf

et al. 2008

Neurobiology of Disease

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178

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“…These data thus distinguish two classes of wake-improving agents: one acting through histamine, the other via nonhistaminergic mechanisms. Whereas the wake-promoting property of H 3 receptor inverse agonists most likely depends on H 3 autoreceptor-mediated modulation of histaminergic neurotransmission, their procognitive activity seems to involve not only the histaminergic but also other neurotransmitter systems that are controlled by H 3 heteroreceptors and play important roles in cognition such as the cholinergic neurons (Khateb et al, 1995;Lin et al, 1996b;Passani et al, 2004;Jones, 2005;Bonaventure et al, 2007;Ligneau et al, 2007a;Parmentier et al, 2007;Haas et al, 2008).…”

Section: H 3 Receptors: Targets For Arousal Control and Treatment Of mentioning

confidence: 99%

Histamine H₃ Receptors and Sleep-Wake Regulation

Lin

Sergeeva²,

Haas³

2010

J Pharmacol Exp Ther

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119

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The histaminergic system fulfills a major role in the maintenance of waking. Histaminergic neurons are located exclusively in the posterior hypothalamus from where they project to most areas of the central nervous system. The histamine H 3 receptors are autoreceptors damping histamine synthesis, the firing frequency of histamine neurons, and the release of histamine from axonal varicosities. It is noteworthy that this action also extends to heteroreceptors on the axons of most other neurotransmitter systems, allowing a powerful control over multiple homeostatic functions. The particular properties and locations of histamine H 3 receptors provide quite favorable attributes to make this a most promising target for pharmacological interventions of sleep and waking disorders associated with narcolepsy, Parkinson's disease, and other neuropsychiatric indications. Sleep and WakingWakefulness and consciousness depend on perturbation of intrinsic cortical activity that is achieved through ascending activating systems taking a ventral route, the ascending reticular activating system of Moruzzi and Magoun, and a dorsal route whose main station is the hypothalamus. Both pathways send direct projections to the cortex and indirect ones through the thalamus, the door to perception of sensory input. Both waking and paradoxical sleep (REM) are conscious states and need activation by subcortical structures, although in different ways.Cholinergic neurons of the brainstem and the basal forebrain discharge tonically during both wakefulness and paradoxical sleep, can directly excite cortical neurons, and facilitate the thalamo-cortical transmission by inhibiting the thalamic reticular sleep-onset generator. Brainstem and basal forebrain cholinergic neurons are excited by glutamatergic, noradrenergic, and histaminergic neurons; they are particularly important in cortical electroencephalogram arousal, but do not seem to be essential for the waking state (Szymusiak and McGinty, 1986;Lin, 2000).Monoaminergic ascending projections containing catecholamines and serotonin are involved in sleep-waking regulation and the pathophysiology of major psychiatric disorders, schizophrenia, and depression, all of which include disturbance in sleep-waking. Inhibition of catecholamine synthesis decreases waking, and psychostimulants, such as amphetamine, increase waking through accumulation of catecholamines. A lesion of the serotonergic dorsal raphe causes insomnia. These aminergic systems mediate different behavioral expressions during waking, activate immediate early genes, and facilitate locomotion, perception, and cognition (reviewed in Jones, 2005).

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“…ABT-239, GSK189254, JNJ-10181457, and tiprolisant) enhanced acetylcholine levels by application of H 3 R antagonists restore impaired cognitive functions. 18,159,163,238) A direct correlation between histaminergic neurotransmission and cognitive impairment is controversially discussed due to different findings regarding histamine levels in brain compartments of AD patients. This might be related to the extent of neuronal apoptosis and course of disease.…”

Section: )mentioning

confidence: 99%

Histamine H3 Receptor Antagonists Go to Clinics

Sander

Kottke

Stark

2008

Biological & Pharmaceutical Bulletin

184

118

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INTRODUCTIONThe biogenic amine histamine, 2-(1H-imidazol-4-yl)-ethanamine, is produced by decarboxylation of L-histidine and is implicated in a wide range of physiological and pathophysiological functions. It is metabolised by histamine N tmethyltransferase (HMT) and mono-or diaminoxidase. Histamine is mainly acting via four distinct metabotropic histamine receptor subtypes (H 1 R-H 4 R), which have meanwhile all been cloned. Whereas antagonists for H 1 R and H 2 R subtypes have been blockbusters in therapy of allergy and ulcer, respectively, antagonists for H 3 R and H 4 R subtypes are not on the market. The recently described H 4 R seems to be involved in inflammatory and immunomodulatory processes. H 3 Rs play a central role in neurotransmission of histamine and in control of many other neurotransmitters. Several antagonists are in preclinical and some in clinical stage of development. PHARMACOLOGICAL BACKGROUND Auto-and HeteroreceptorThe H 3 R was first described in 1983 as a presynaptic autoreceptor, which mediates synthesis of histamine and inhibition of its release from histaminergic neurons in slices of rat cerebral cortex. 1) Localisation studies in rodents show a predominance in distinct regions of the central nervous system (CNS) as the H 3 R is mainly located in cerebral cortex, hippocampus, amygdala, nucleus accumbens, globus pallidus, striatum, and hypothalamus 2-5) ( Fig. 1). In addition, it is expressed in the peripheral nervous system, e.g. in gastrointestinal tract, airways and cardiovascular system. 6) Molecular aspects of the receptor, [7][8][9][10] structure-activity relationships (SAR) of ligands, [11][12][13][14][15][16][17][18][19] and pharmacology [20][21][22][23][24][25][26] have recently been resumed in many excellent reviews. This contribution focuses on the development of clinical candidates and the multifaceted potential indications targeted.In mammalian brain histaminergic neurons originate in the tuberomammillary nucleus (TMN) spreading into above mentioned brain regions, where they control histamine levels by regulation of synthesis and liberation rates 27) and modulate different neuronal systems. 28) H 3 R expression is not solely restricted to histaminergic neurons: due to its function as a heteroreceptor it can be found on colocalised neurons, and H 3 R activation modulates the release of various important neurotransmitters, i.e. dopamine, [29][30][31][32][33] acetylcholine, [34][35][36][37] norepinephrine, 38,39) serotonin, 40,41) GABA, [42][43][44] glutamate, 45) and substance P. [46][47][48] Therefore, histaminergic neurons and the cross-linkage between major neurotransmitter systems are involved in many (patho)physiological brain functions, including vigilance, memory processes, feeding behaviour and locomotor activity (Fig. 2). Interneuron cross-talk and adaptive processes seem to be important factors in H 3 Rmediated signalling. Molecular AspectsThe human histamine H 3 receptor (hH 3 R) cDNA firstly described 1999 encodes a 445 amino acid protein and belongs to the his...

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Brain histamine and schizophrenia: Potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649

Cited by 103 publications

References 28 publications

An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin−/− mice and patients

An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin−/− mice and patients

Histamine H₃ Receptors and Sleep-Wake Regulation

Histamine H3 Receptor Antagonists Go to Clinics

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Brain histamine and schizophrenia: Potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649

Cited by 103 publications

References 28 publications

An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin−/− mice and patients

An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin−/− mice and patients

Histamine H3 Receptors and Sleep-Wake Regulation

Histamine H3 Receptor Antagonists Go to Clinics

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Histamine H₃ Receptors and Sleep-Wake Regulation