serotonergic receptors: the new targets in the treatment
TRANSCRIPT
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Serotonergic receptors: the new targets in Serotonergic receptors: the new targets in the treatment of Alzheimerthe treatment of Alzheimer’’s diseases disease
Dorotea MDorotea Müückck--ŠŠeler eler R.BoR.Bošškovikovićć
Institut, Zagreb, Croatia (HR)Institut, Zagreb, Croatia (HR)[email protected]@irb.hr
Malta 24.10.2013.
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Alzheimer’s diseaseSymptoms and risk factors
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Pathological mechanisms in Alzheimer’s disease
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Neurotransmitters in AD
memory
Acethylcholine
memory
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Serotonin
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95%hormone
5%neurotransmitter
peristalticvomitingplatelet aggregation and homeostasismediator of inflammationtonus of blood vessels
BBB
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moodappetite (feeding)
body weightpainsleep
circadian rhythm termoregulation
SEROTONIN neurotransmitter in CNS
regulates:
Altered function in neuropsychiatric disorders
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“It is possible that the serotonin in our brain plays an essential part in keeping us sane.....”
Sir John Gaddum, 1954
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serotonin
MemorycognitionReduced 5‐HT neurotransmission
impairs
learning and memory functions
Increased 5‐HT neurotransmission
is
associated with improved memory and
cognitive performance
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Transmission of serotonin descending from
the rostral
raphe
nuclei to the
limbic
cortex and temporal lobe is decreased
in
Alzheimer’s disease compared with
normal. The other major pathways for
serotonin transmission, which project to
the cerebellum and frontal lobe and
descend the spinal cord, remain
unchanged.
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Progressive accumulation of neurofibrilar tangles in neurons
and senile plaques in the region of serotonergic cell bodies
Reduced number of neurons
Decreased serotonin levels in cortex,
hippocampus, striatum (30%)
Decreased platelet 5‐HT
levels
Plat
elet
5-H
T co
ncen
trat
ions
(nm
ol/m
g p)
0 ,0
0 ,2
0 ,4
0 ,6
0 ,8
1 ,0
1 ,2
1 ,4
1 ,6
H e a lth y P a t ie n ts w ith A D in C o n tr o ls E a r ly M id d le L a te P h a s e (4 9 ) (2 3 ) (2 5 ) ( 2 8 )
* * * * * *
Mück Šeler et al., 2009.
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Appears in 70-90% of patients
Influence the progress of AD
Stress for patients and caregivers
Interaction of several factors (psychological, biological, genetical...)
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Agitation: repeat movement, aimless wandering
Agression: verbal, physical
Depression: tearfulness, anxiety, guilt
Apathy: loss of interest
Psychosis: delusion, halucination
Changes in appetite and sleep
Treatment with antidepressants and
antipsychotics
serotonin
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Multiple receptor subtypes
Receptor regulate complex
signal transduction pathways
Serotonergic receptors as targets
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5-HT 3
5-HT2
5-HT1 5-HT 4 -
7
Serotonergic receptors
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Distribution of serotonergicreceptors
Dementia ‐
Affected areas
5‐HT1A5‐HT1B5‐HT25‐HT35‐HT4
5‐HT1A 5‐HT65‐HT1B 5‐HT75‐HT25‐HT35‐HT4
5‐HT1A5‐HT1B5‐HT25‐HT4
5‐HT1A5‐HT1B
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Among the most abundant and widely distributed 5‐HT receptors
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Distribution of 5-HT1A receptors
On the neuron:Presynaptic (autoreceptors)
Postsynaptic (heteroreceptors)
In the brain regions:
HippocampusPrefrontal cortex
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Associated with inhibitory G‐protein
(Gi)
Inhibits adenylate cyclase
Decrease production of cyclic AMP
(cAMP)
Inactivates protein kinase A (PKA)
Critical role in the regulating the activity of the entire serotonin systemOver‐expression implicated in reducing 5‐HT neurotransmission
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Possible explanations for the discrepant findings include differences
in specificity and
sensitivity of the neurocognitive
test
procedures used, methodological differences and
potential variation
in the samples due to ethnic background.
Borg (2008)
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A decrease of MPPF binding to 5‐HT1A receptors in the
hippocampus and in the parahippocampus in mild AD (PET study)
Truchot et al., 2008
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22mild to moderate AD
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control
AD
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24Lai et al 2003
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In vitro
Ki= 2.3 μM
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Lecozotan (SRA‐333)
5‐HT1A receptor antagonist (Ki = 1.6 nM)
enhances the potassium‐stimulated release of acethylcoline and glutamate4‐Cyano‐N‐[(2R)‐2‐[4‐(2,3‐dihydro‐1,4‐benzodioxin‐5‐yl)‐1‐piperazinyl]propyl]
‐N‐2‐pyridinylbenzamide hydrochloride
Aged rhesus monkeys
Performance in a Delayed Matching to Sample Task (DMTS)
Lecozotan
IR was safe and well tolerated after administration of multiple oral
doses up to 5mg
q12h in young and elderly subjects. These results support the
development of lecozotan
in patients
with Alzheimer’s disease.(Parks et al., 2008)
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PutamenVentral striatumOccipital cortex
Varnas et al ., 2011
Autoreceptors: nerve terminals Heteroreceptors: postsynaptic neuron)
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30Garcia Alloza et al., 2004
frontal cortex temporal cortex
Activation of 5‐HT1B receptors in AD associated with poorer memory
5‐HT1B decrease acethylcholine releases
Anti‐dementia compunds unknown
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5‐HT2 receptors
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5-HT2 receptors in CNS
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20 years 66 years 67 years
Meltzer et al., 1999
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(Salmon , J Neural Transm 114:1179, 2007)
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Healthy control AD
Lorke et al., 2006
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37Hasselbach 2008
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improves working
memory function
in young and aged monkeys, (Terry et al., 2005)
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5‐HT3 receptors
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A cation-selective ligand-gated ion channelIncreases intracellular cations such as Ca2+, Na+ and K+
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Antagonists of 5-HT3 have antiemetic properties
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Ban i Seong 2005
5‐HT3 receptor antagonists induce cognitive enhancing effects
PB = 1‐phenylbiguanide
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ondansetron
Pro-cognitive effects
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The high-affinity 5-HT3 receptor antagonist with potent acetylcholinesterase (AChE) inhibitory activity
for 5‐HT3 receptors Ki = 5.6 ± 0.02 nMfor human AChE = IC50
= 4.1 ± 0.60 nM
Fakhfouri et al., Drug Discovery Today, 17:741, 2012
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Inhibit glutamate releaseIncrease acethylcholine release
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5‐HT4 receptors
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Frontal cortexHippocampusSubstania nigra
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A decline with age of 1% per decade only in striatum
Women have lower 5‐HT4 receptor binding 13% in limbic system19% in amygdala
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5‐HT4‐receptor agonists
have the potential to modify the
pathogenesis of Alzheimer’s
disease.
(Lezoualc’h, 2007)
•In vivo:•facilitate ACh
release in rat
frontal cortex and
hippocampus
•modulate memory performance
in behavioural
experiments
In vitro:•increase the extracellular
release of sAPPα•decrease amyloid
β‐peptide
secretion in primary neurons.
•memory‐enhancing effects
neuroprotective
and
neurotrophic
properties
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Tesseur
et al.,: Chronic 5‐HT4 receptor activation decreases Aß
production
and deposition in
hAPP/PS1 mice. Neurobiology of Aging 2013; 34: 1779
some evidence that 5‐HT4 receptor
agonist treatment can decrease Aß
pathology
in a murine
model of
Alzheimer’s disease.
The
results suggest that the 5‐HT4
receptor agonist SSP‐002392 might modify Aß
levels in the brain
during the early stages of disease.
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52No specific and selective comounds
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5‐HT6 receptors
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learningmemoryfeeding
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Garcia Alloza et al., 2004
Lorke et al., 2006
frontal cortex temporal cortex
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•
Antagonism of 5‐HT6 receptors leads
to an increase in the release of Ach
• Stimulate glutamatergic cholinergic transmission
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Double‐blind, controlled phase II study of a 5‐HT6 receptor antagonist, SB‐742457, in Alzheimer's disease
.
(Maher‐Edwards et al., 2010)
Conclusion: SB‐742457 was generally safe and well tolerated and may be
efficacious in AD
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2‐(6‐fluoro‐1H‐indol‐3‐yl)‐N‐(3‐(2,2,3,3,3‐pentafluoropropoxy)benzyl)ethanamine
Phase III clinical trials3 000 patients with mild‐to moderate
ADIn a dose of 10‐60 mg in combination with donepezil 10 mg/day
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5‐HT7 receptors
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cognitive functionsleepdiurnal rhythmpainmood
ThalamusHippocampusHypothalamus
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?Are the changes in the 5‐HT markers (receptors)
in the AD
primary
orsecondary
(retrograde)
due to the loss of
target (postsynaptic)
neurons in regions of the nerve endings
?
Do they directly
or indirectly
contributing to the physiological
and pharmacological basis of memory and its pathogenesis or
they represent protective
or adaptable
mechanisms
(at least in initial stages)
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Mainly 5‐HT projections are showed in brain areas important for memory. 5‐HT receptors acting as heteroreceptors modulate release of other
neurotransmitters.
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•Serotonergic system could be involved in the etiology and
treatment of AD; neuroprotective effects of serotonin?
•5‐HT1A, 5‐HT4 and 5‐HT6 receptors
are densely expressed in
brain regions innervated by
serotonergic
projections from the
raphe
nuclei and are
associated with learning and memory.
•It has been hypothesized that 5‐HT1A
(lecozotan), 5‐HT3
and 5‐
HT6
antagonists
and 5‐HT4 agonists
might function as the
effective treatment of the
cognitive deficits associated with AD, as
they have been shown
to improve cognitive performance in
multiple animal models of
learning and memory.
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Thank you for your attention....
Malta 24. 10. 2013.