The brain histamine H3 receptor as a novel therapeutic target for vigilance & sleep disorders
J.S. Lin
Integrative Physiology of the Brain Arousal Systems Lyon Neuroscience Research Center, INSERM U1028-CNRS5292, Université Claude Bernard , Lyon, France
http://sommeil.univ-lyon1.fr/u628.html
U1028 umr5292 The brain histamine H3 receptor as a novel therapeutic target for vigilance & sleep disorders
… the most difficult task has been to fight against sleepiness and to stay awake …
Charles Lindbergh
U1028 umr5292 Sleepiness & sedation induced by classical antihistaminics (H1-receptor antagonists)
“In therapeutic doses, all H1 brokers elicit side effects, the side effect with the highest incidence, and the one common to all drugs in this group, is sedation.”
---- W.W. Douglas “The Pharmacological Basis of Therapeutics” 1985 Histaminergic neurons, a wake promoting system
Cortex
Colliculus Olfactory Hippocampus bulb
Thalamus Mesopontin e Tegmentum Basal forebrain Hypothalamus Medulla TM, Histamine Sleep-wake discharge in identified histamine & orexin neurons in mice
K Takahashi Takahashi et al., 2006; 2008; 2009; 2010 juxtacellular K Sakai recording & labeling Wake-specific low aW/qW Histamine • Tonic cortical EEG activation
• High vigilance
Wake-active high aW/qW • Movement Orexin Locomotion
• Behavioral arousal
In large brain target cells, increased HA neuronal activity produces postsynaptic excitatory & facilitatory action
Examples on BF and MPT cholinergic neurons: ● direct depolarization
● enhancing the discharge rate
Histamine cells increase their activity during W and activate or facilitate large brain areas, contributing, therefore, to cortical activation.
Khateb et al., 1995; Haas et al., 2008 Effects of systemic administration of mepyramine (H1-receptor antagonist) on the cortical EEG & sleep- wake cycle in the cat Effects of systemic administration of ranitidine (H2-receptor antagonist) on the sleep-wake cycle in cats
Decresesing waking & increasing SWS in a slow & progressive manner Sleep can be modulated via H3-receptors Their ligands therapeutic use Histaminergic transmission & cellular mechanisms of arousal Target cell
+ H1 K Wake Histidine Induction
ATP HDC A C + K Histamine cAMP Na+ Wake Facilitation + K H2 Histaminergic H3 ending
Postsynaptic H1, H2, Responsible for histamine’s waking action H3 autoreceptor Negative feedback on histamine’s release & synthesis Lin, 2000; Lin et al., 2011 Brain neural network involved in histaminergic arousal
A ascending activating system, distinct from those classically defined Brain neural network involved in histaminergic arousal
What happens in the case of a deficiency of the HA system, any pathological involvement? Brain neural network involved in histaminergic arousal
What happens in the case of a deficiency of the HA system, any pathological involvement of the system? Somnolent phenotypes in histamine-deficient mice
Wake deficit at lights-off Reduced EEG ratio SWS/W
50 °°°° HDC+/+
160 45 150
140 °°
°°°°
40 HDC-/-
°°° °°
130 °°°°
35 120 110
30 ° Deficit of EEG power during W
100
25 5% 0.2%
Hourly Hourly amounts (min.) 4% HDC+/+ 20 HDC-/- 0.1% 3% HDC-/- HDC+/+ 15 2% 0,0% Light Dark 0,0 0,8 1,6 2,4 10 1% 7 a.m. 7 p.m. 7 a.m. 0% Parmentier et al., 2002; Lin et al., 2011 0 6 12 18 24 30 36 42 48 54 60Hz60 Mice lacking histamine: unable to maintain awake in a new environment
TM (histamine)
Absence of histamine
Parmentier et al., 2002 Mice lacking histamine: impairment of motivated waking
Palatable food
Wild type HDC -/-
Gondart et al., 2013 Guo et al., in prep. H3-receptor KO mice which have a permanent enhancement of histamine EEG ө ↗ during waking turnover show exaggerated waking facing a motivation test Gondard et al., 2013
Test of motivation
H3R +/+
H3R -/- Mice lacking histamine: deficit of anticipatory wakefulness
HDC -/- Wild type
Predictable meal time Histamine deficiency & sleepiness
Permanent sleepiness Parmentier et al. 2002; 2007; Anaclet et al. 2009
Histamine deficient mice
Sleepiness & histaminergic transmission Nishino et al. 2001 Narcoleptic dogs
Sleepiness & Nishino et al. 2009 CSF histamine Bassetti et al. 2010
Croyal et al. 2011 Narcoleptic patients ~
A deficient histamine system constitutes the major cause of sleepiness encountered in narcolepsy & other sleep disorders Histaminergic transmission & cellular mechanisms of arousal
Target cell
tonic discharge Wake H1 glycogenolysis Induction Histidine
ATP HDC A C Histamine cAMP discharge Wake facilitation H2 Histaminergic H3 ending
H3-receptor, a brain therapeutic target for vigilance & sleep disorders ?
Lin et al., 2000; 2011 Awakening properties of H3-receptor inverse agonists, with reference to current psychostimulants & modafinil
• What is their awakening potency? • Do they improve waking quantitatively & qualitatively? • Is their W-promoting effect followed by a sleep rebound? • Are their brain targets & mechanisms of action clearly distinct from those of psychostimulants? • Are they clinically suitable & can be used in sleep disorders, such as narcolepsy & sleepiness? Awakening properties of H3-receptor inverse agonists, compared with modafinil & psychostimulants in mice Parmentier et al., 2007; Lin et al., 2011
Thioperamide 0 – 10 – 30 – 100 mg/kg
Ciproxifan 0 – 1 – 3 – 10 mg/kg
Prompt awakening effect enhance daytime waking followed by normal nocturnal sleep Awakening properties of H3-receptor inverse agonists, compared with modafinil & psychostimulants in mice Parmentier et al., 2007; Lin et al., 2011
Only H3 receptor antagonists increase cortical fast rhythms Effects of ciproxifan on the cortical EEG & sleep-wake cycle in the cat Lin, 2000, 2011 Ciproxyfan 2 mg/kg
Because the occurrence of cortical fast rhythms is closely associated with the so-called high mental activities, e.g. attention, alertness & learning, these results suggest that the histamine system plays a role not only in waking, the basis for all other high brain functions, but also in some cognitive functions. Awakening properties of H3-receptor inverse agonists, compared with modafinil & psychostimulants in mice
Parmentier et al., 2007; Lin et al., 2011
** Thioperamide 10 – 30 – 100 mg/kg
**
*
**
*
**
**
**
** **
Ciproxifan 1 – 3 – 10 mg/kg
*
*
**
**
**
** **
Lack of sleep rebound
with modafinil & H3R-antagonists
**
** absence of undesirable increase in sleep pressure after waking effect Are the waking effects of amphetamine, modafinil & ciproxifan mediated by histamine ?
Characterization of the wake-promoting agents using KO mouse models :
HDC KO Amphetamine has the same wake-promoting effect in WT & histamine deficient mice
Amphetamine 1 mg/kg HDC +/+ W for 4h EEG
19-60 Hz
0,8-5 Hz
EMG PS SWS W HDC -/-
EEG
19-60 Hz
0,8-5 Hz
EMG PS SWS W
0 1 2 3 4 h Modafinil has the same wake-promoting effect in WT & histamine deficient mice Modafinil 32 mg/kg W for 4h 180
90
0
180
90
0 Ciproxifan elicits waking in WT but not in histamine deficient mice W for 4h 180
90
0
180
90
0
Sleep-wake effects of ciproxifan, but not those of amphetamine or modafinil, depend on HA-mediated transmission. Absence of wake-promoting effect of ciproxifan in H3-receptor KO mice
Gondard et al., 2013 Only ciproxifan, but not modafinil or amphetamine, elicits cortical activation & c-fos expression in histamine neurons in brain transectioned cats Lin et al., 2000, 2011 Ciproxifan 0.5 mg/kg A clinically suitable H3-receptor inverse agonist improves wakefulness in narcolepsy, Lin et al., 2008; Guo et al. 2009
Suppress SOREM Orexin-/- mouse
Pitolisant Pitolisant improves in teenagers:
● significantly excessive daytime sleepiness
Epworth Score 14 ± 1 to 9 ± 3 alone or 7 ± 3 + another psychostimulant
● slightly the severity & frequency of cataplexy Pitolisant, an alternative for the treatment of refractory sleepiness in teenagers with narcolepsy Histamine neurons:
● contain all dopamine receptor subtypes: D1 to D5.
● are able to uptake l-dopa, to convert it into dopamine for finally release dopamine from histamine terminals in the striatum
a brain target for l-dopa therapy
important interactions between the DA & HA systems with possible synergy between l-dopa & pitolisant Pitolisant
● significantly improves excessive daytime sleepiness in Parkinsonian patients
● allows them to reduce their daily dose of l-dopa The waking action of some neuropetides & neuroactive constituents is mediated by histamine Summary Cortex
Th MPT ● The HA system constitutes a brain RD BF activating system distinct from those classically defined.
● Its deficiency causes sleepiness. I’m feeling like myself again Somnolence Somnolence + cataplexy
● 2 classes of wake-promoting agents: HA dependent & HA independent.
● H3-receptor inverse agonists have several advantageous characteristics :
A well-defined brain target & mechanisms of action A more specified treatment for sleepiness Simultaneous cognitive improvement Probably a unique approach against narcolepsy U1028 umr5292
Anatomical organization of the histaminergic system
Thalamus (Glu) PF MPT (Orexin) (Ach, NA)
TM SI PAH (Histamine) (Ach) (Gaba)
TM (Histamine)
From Lin et al., 1986,2000 Parmentier et al., 2002 & in preparation Conclusion
Histaminergic transmission mediated via H3-receptors
The H3-receptor constitutes a brain therapeutic target for sleep disorders Absence of wake-promoting effect of ciproxifan in H1-receptor KO mice
PS SWS W
h Parmentier et al., 2007 H3-receptor agonist imetit increases sleep in mice (Parmentier et al., 2007)
H3-receptor inverse agonists promote waking, improve vigilance & can go to clinics
Do H3-receptor agonists induce or facilitate sleep ? Effects of BP2-94 (H3-receptor agonist) on the neocortical EEG in the cat Lin, 2000 Imetit antagonizes ciproxifan’s waking effect (Parmentier et al., 2007)
H3R agonists – promising non-benzodiazepine compounds, developed for insomnia associated with stress & anxiety.