MELATONINE ET
VIEILLISSEMENT
MELATONINE
: UNE THERAPEUTIQUE ?
1 BACKGROUND
1
BACKGROUND :
Apparue en 1990. Depuis, de nombreuses propriétés lui
sont attribuées :
Une aide au sommeil (le plus argumenté mais encore
controversé)
Un médicament d’aide au mal de l’air et au
décalage horaire
Un medicament “scavenger” face aux radicaux libres
Un anti-cancer
Un stimulant immunitaire
Un anti vieillissement (radicaux libres, stress et corticoïdes,
déficit immunitaire, etc)
Un régulateur de la chronobiologie chez la PA :
anti-depresseur, anti-mélancholie,
etc
Un gros enjeu commercial
Peu de travaux randomisés, validés ; pas de label FDA
ou autres garants d’expertise
2 LA MOLECULE
:
Dérive assez directement d’un acide aminé, en 2
étapes :
Décarboxylation et
hydroxylation du tryptophane
Acétylation et méthoxylation de la
sérotonine
Sérotonine - Mélatonine : 2 molécules
très voisines
3
LES ORIGINES :
La glande Pinéale (Epiphyse)
4 LA PHYSIOLOGIE
:
4-1 UN
CIRCUIT NERVEUX TRÈS COMPLEXE
Dépendance +++ de l’éclairement
(“3ème oeil” chez certaines
espèces)
Voie
rétino-hypothalamique
noyau suprachiasmatique > noyau paraventriculaire de
l’hypothalamus
Voie hypothalamo-médullaire
noyaux paraventriculaires > faisceaux olfactifs basaux >
colonne lat. moëlle
Voie Sympathique
colonne lat moëlle (tronc cérébral) > ggl ·
cervical sup > épiphyse
Une voie très complexe, difficile à cerner...
Une voie susceptible de recevoir de multiples afférences de
modulation
- autres influx sensoriels,
- voie ·, stress, corticoïdes
- hypothalamus, homéostasie, comportements
4-2 UN
SCHÉMA SUCCINT DES VOIES DE REGULATION
voir
schéma précédent
4-3 LA
SECRETION RYTHMEE DE MELATONINE
Sécrétion en
fonction de l’éclairement
Information +++ sur la
durée nuit/jour
Un rythme nycthéméral.
Avec les taux élevés de mélatonine :
- température corporelle basse
- propension au sommeil
- activité basse fréquence augmentée
- ondes lentes et théta réduites
Le phénomène est pérennisé même
avec cycle forcé (28heures)
Dijk (1997)
Czeisler et all (New England J Med, 1995)
11 aveugles sans perception de la lumière :
> 3 avec rythme de mélatonine normal
> 7 avec asynchronisme nycthéméral,
mais meilleur sommeil lorsque taux de mélatonine
élevés
4-4 UNE
ACTION ANTIGONADOTROPE
Abaisse le contenu hypophysaire en RH
Synchronise le rut pour naissance à la bonne saison
N’apparait pas sur les statistiques de naissances humaines
Influence cependant évidente sur les taux de
stéroïdes gonadiques
4-5 VARIATIONS
AVEC L’AGE
Déclin
avec l’âge
Taux diminués de 1/2 à 80 ans
à toutes les heures de la journée
à toutes les saisons
Mais accentuation +++ de la différence
saisonnière chez la PA
Taux très abaissés ches déments
âgés (Touitou - 1992)
4-6 ETIOLOGIE
DES VARIATIONS AVEC L’AGE
Calcification
de la glande pinéale
Baisse des récepteurs ß-adrénergiques sur cell.
épiphysaires
Ralentissement de la synthèse cellulaire
Désynchronisation du biorythme chez 70% des PA > 60ans
contre 20% des < 40 ans
(Touitou & Fèvre - 1984)
5 LES “AUTRES
FONCTIONS” PHYSIOLOGIQUES ?
RADICAUX
LIBRES
Plus efficace que la Glutathione pour piéger les Rx
libres
De là, envisager le bénéfice de la
mélatonine dans toutes
les pathologies où les Rx libres sont suspectés
?...
Artéromatose, maladies neuro -dégéneratives,
Alzheimer, cataracte, diabète, emphysème... etc
Par contre, la carence en mélatonine chez la PA,
particulièrement dans les DTA, est un facteur probable
d’aggravation des processus de neurodegenerescence (par
déficit de protection)
PRÉVENTION
DE L’OSTÉOPOROSE
Travaux sur animaux et rythmes circadiens
Melatonine inhibe le release de calcitonine, via l’hypophyse.
Chez l’homme ?
Difficile
d’envisager le rôle de la mélatonine dans le
traitement de l’ostéoporose face à
l’efficacité des autres thérapeutiques
AMÉLIORATION
DE L’IMMUNITÉ
Via les hormones
hypophysaire > diminution du cortisol
(en particulier rôle de la vasopressine)
Travaux sur animaux (souris)
davantage de protection virale et infectieuse
Mais travaux anciens (Pierpaoli - 1987)
Pas de travaux chez l’homme
MÉLATONINE
ET CANCER
Effet anti
prolifératif sur des cancers hormonaux dépendants.
Etudes sur culltures de cellules. Aucune preuve
in-vivo
Dollins et all (PNAS, 1994)
20 sujets à habitudes normales de vie et de sommeil
Mélatonine 5 à 10 mg/j versus placebo
Avec mélatonine :
diminution du temps d’endormissement
augmentation de la duree du sommeil
Fainstein et all : étude pilote US (Current
thérap. research - 1997)
Patients âgés avec endormissement > 30 min, > 3
réveils/nuit, etc
Sépares en : simple trouble du sommeil
trouble du sommeil + dépression
3mg mélatonine ou placebo 30 min avant heure coucher
Amélioration significative des critères de sommeil chez
77% des patients
Seulement 44% si dépression et non significatif versus
placebo
Efficacité maximum vers 9eme 10eme jour sur une période
test de 21j
Attenburrow et all (psychopharmacology - 1996)
Adultes bonne santé
Pas de différences significatives
placebo/mélatonine
sur qualité subjective du sommeil
Mais pourtant,
temps de sommeil effectif augmenté significativement
régularisation des tracés EEG
Bien d’autres publications sur Mélatonine et
Insomnie...
une littérature de plus en plus abondante
7
CONCLUSIONS
MODULATEUR DU SOMMEIL ET DES BYORYTHMES >>>
SUREMENT
INTERET DE PLUS EN PLUS PROBABLE DANS UNE AIDE À LA PRISE EN
CHARGE DES TROUBLES DU COMPORTEMENT, ET DES RYTHMES DU SOMMEIL CHEZ
LE DÉMENT :
Mais les autres actions
???
un manque évident de travaux vraiment scientifiques
La part exacte du “coup” médiatico-économique
?
UNE
CERTITUDE PRESQUE RASSURANTE : LA MÉLATONINE N’EST PAS
TOXIQUE, MÊME À 300mg/jour
8
QUELQUES REFERENCES RECENTES
Lemoine
P.
Nicolas
A.
Faivre
T.
Sleep and
aging
Presse Medicale. 30(9):417-24, 2001 Mar 10.
A COMMON DISORDER: Sleep is one of the most often altered
functions in elderly people. Obviously, insomnia is one of the main
complain, inducing benzodiazepine (BSD) abuse, but we must keep in
mind that sleep apnoea syndrome (SAS) and restless legs syndrome
(RLS) are also frequent in this group of age. After exclusion of the
various age-related conditions that could induce sleep disorders, we
must focalise on primary and secondary sleep disorders. As an
introduction, methods of sleep analysis are described and qualitative
and quantitative sleep variables are given. PHYSIOLOGICAL SLEEP:
Comparing the sleep of elderly people to the one of young adult give
us the opportunity to define the limits of the physiological sleep
aging. It seems that the main age-induced sleep disturbances are
problems to maintain sleep and chronobiological disorganisation of
the sleep-wake rhythm, both responsible for insomnia complains. It is
important to note that SAS and RLS prevalence are correlated with
age. Also crucial is the complex association between sleep,
depression and dementia. These interactions are addressed from a
diagnostic and a therapeutic point of view.
THERAPEUTIC APPROACH: Lastly,
concerning insomnia we emphasise the importance of therapeutic
alternative to BZD, responsible for addictions and cognitive
impairment, mainly behavioural and chronotherapeutic methods
(phototherapy, melatonin). For clinicians, it is recommended to
respect the individual rhythms of each elderly patient and to prefer
nonpharmacological methods
Carranza-Lira
S.
Garcia Lopez
F.
Melatonin and
climactery
Medical Science Monitor. 6(6):1209-12, 2000 Nov-Dec.
Melatonin is a hormone synthesized in the pineal gland from
tryptophan. It participates in several biological processes in the
human being, such as circadian sleep rhythm, mood, reproductive
processes and aging. Melatonin serum levels are increased in
childhood and diminish importantly in older people. Serum levels are
diminished in patients with insomnia and depressive mood.
Experimentally, the melatonin inhibits the growth of mammary tumors
in animals. With respect to
endometrial cancer and Alzheimer's disease, the information is not
conclusive. No changes have been found in melatonin levels in
climacterical women. So its use has not fundament in postmenopausal
women, however it can only be administered for short periods of time
for the treatment of some sleep disturbances.
Monti
JM.
Cardinali
DP.
A critical assessment of
the melatonin effect on sleep in
humans
Biological Signals & Receptors. 9(6):328-39, 2000 Nov-Dec.
Melatonin is synthesized and secreted during the dark period of the
light-dark cycle. The rhythmic nocturnal melatonin secretion is
directly generated by the circadian clock, located in mammals within
the suprachiasmatic nucleus (SCN), and is entrained to a 24-hour
period by the light-dark cycle. The periodic secretion of melatonin
may be used as a circadian mediator to any system that can 'read' the
message. In addition, direct effects of the hormone on the SCN could
explain some of the melatonin effects on the circadian system.
Duration of the melatonin nocturnal secretion is directly
proportional to the length of the night and it has experimentally
been demonstrated to be the critical parameter for photoperiod
integration. The sites and mechanisms of action of melatonin for
circadian and photoperiodic responses are far from being elucidated,
but action through specific membrane receptor sites starts to emerge.
A possible bicompartmental model of distribution for melatonin, the
first compartment in plasma acting on peripheral organs and the
second in the cerebrospinal fluid affecting neurally mediated
functions at a much higher concentration, has recently been proposed.
From earlier studies it was concluded that melatonin administration
to humans reduces sleep latency and induces sleepiness and fatigue.
More recently, the effect of lower pharmacologic or physiologic doses
of melatonin was examined in different laboratories. These studies
included young normal volunteers and patients with chronic insomnia,
as well as dementia patients exhibiting sundowning syndrome.
Irrespective of the method of assessment, melatonin showed effects in
insomniac patients in most studies.
With some exceptions,
melatonin administration reduced sleep latency and/or increased total
sleep time and sleep efficiency. Furthermore, melatonin was more
effective when given to elderly insomniacs, or Alzheimer disease
patients, although sleep improvement was not strictly correlated with
prior levels of the hormone.
Mishima
K.
Okawa
M.
Hozumi
S.
Hishikawa
Y.
Supplementary
administration of artificial bright light and melatonin as potent
treatment for disorganized circadian rest-activity and dysfunctional
autonomic and neuroendocrine systems in institutionalized demented
elderly persons.
Chronobiology International. 17(3):419-32, 2000 May.
Increased daytime napping, early morning awakening, frequent
nocturnal sleep interruptions, and lowered amplitude and phase
advance of the circadian sleep-wake rhythm are characteristic
features of sleep-waking and chronobiological changes associated with
aging. Especially in elderly patients with dementia, severely
fragmented sleep-waking patterns are observed frequently and are
associated with disorganized circadian rhythm of various
physiological functions. Functional and/or organic deterioration of
the suprachiasmatic nucleus (SCN), decreased exposure to time cues
such as insufficient social interaction and reduced environmental
light, lowered sensitivity of sensory organs to time cues, and
reduced ability of peripheral effector organs to express circadian
rhythms may cause these chronobiological changes. In many cases of
dementia, the usual treatments for insomnia do not work well, and the
development of an effective therapy is an important concern for
health care practitioner and researchers. Recent therapeutical trials
of supplementary administration of artificial bright light and the
pineal hormone melatonin, a potent synchronizer for mammalian
circadian rhythm, have indicated that these treatments are useful
tools for demented elderly insomniacs.
Both bright light and
melatonin simultaneously ameliorate disorganized thermoregulatory and
neuroendocrine systems associated with disrupted sleep-waking times,
suggesting a new, potent therapeutic means for insomnia in the
demented elderly. Future studies should address the most effective
therapeutic design and the most suitable types of symptoms for
treatment and investigate the use of these tools in preventive
applications in persons in early stages of
dementia.
Skaper
SD.
Floreani
M.
Ceccon
M.
Facci
L.
Giusti
P.
Excitotoxicity, oxidative
stress, and the neuroprotective potential of
melatonin.
Annals of the New York Academy of Sciences. 890:107-18, 1999.
The brain consumes large quantities of oxygen relative to its
contribution to total body mass. This, together with its paucity of
oxidative defense mechanisms, places this organ at risk for damage
mediated by reactive oxygen species. The pineal secretory product
melatonin possesses broad-spectrum free radical scavenging and
antioxidant activities, and prevents kainic acid-induced neuronal
lesions, glutathione depletion, and reactive oxygen species-mediated
apoptotic nerve cell death. Melatonin's action is thought to involve
electron donation to directly detoxify free radicals such as the
highly toxic hydroxyl radical, which is a probable end-product of the
reaction between NO. and peroxynitrite. Moreover, melatonin limits
NO.-induced lipid peroxidation, inhibits cerebellar NO. synthase,
scavenges peroxynitrite, and alters the activities of enzymes that
improve the total antioxidative defense capacity of the organism.
Melatonin function as a free radical scavenger and antioxidant is
likely facilitated by the ease with which it crosses
morphophysiological barriers, e.g., the blood-brain barrier, and
enters cells and subcellular compartments. Pinealectomy, which
eliminates the nighttime rise in circulating and tissue melatonin
levels, worsens both reactive oxygen species-mediated tissue damage
and brain damage after focal cerebral ischemia and excitotoxic
seizures. That melatonin
protects against hippocampal neurodegeneration linked to excitatory
synaptic transmission is fully consistent with the last study.
Conceivably, the decreased melatonin secretion that is documented to
accompany the aging process may be exaggerated in populations with
dementia.