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MELATONINE ET VIEILLISSEMENT

MELATONINE : UNE THERAPEUTIQUE ?

1 BACKGROUND

2 LA MOLECULE

3 LES ORIGINES

4 LA PHYSIOLOGIE

5 LES "AUTRES FONCTIONS" PHYSIOLOGIQUES

6 LA PHARMACOLOGIE

7 CONCLUSIONS

8 QUELQUES REFERENCES RECENTES



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

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2 LA MOLECULE :


Dérive assez directement d’un acide aminé, en 2 étapes :

TRYPTOPHANE
I
SEROTONINE (5OH-Tryptamine)
I
MELATONINE



Décarboxylation et hydroxylation du tryptophane
Acétylation et méthoxylation de la sérotonine

Sérotonine - Mélatonine : 2 molécules très voisines

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3 LES ORIGINES :

La glande Pinéale (Epiphyse)

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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)

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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

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6 LA PHARMACOLOGIE :

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

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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.


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