第十四章 松果体激素-第四节

1、Pineal gland hormone and itssecretion regulationPoints:1. The key enzymes of melatonin synthesis and the impact of light on melatonin.2. The conception of Circadian rhythm、lunar rhythm and Seasonal rhythm.3. Characteristics of circadian rhythm4. Neural regulation pathway of melatoninsecretion.一、Intr

2、oduction of pineal glandPineal gland in different species of animal aredifferente in number, anatomy, morphology and cell function。1、The morphology of the pineal gland 1）Anatomy2）Development process 3）Histological features 4）Functional characteristics2、the cognition process of Pineal gland function3

3、1. The morphology of the pineal gland1) Anatomical characteristics of the pineal gland animals：间脑顶端后背部，即缰连合与后连合之间的正中线上。human：位于中脑上丘之上，通过一条细柄与第三脑室相连，其形似松果，长5-9mm，宽3-5 mm，重120-200 mg。42）Development process of Pineal glandNeural ectoderm ependymal cells of the thirdventriclethe first 2 months after the

4、 embryonic development/emergence processesSaccateFollicularCell proliferationSubstantive endocrine organsPineal cells stop proliferationAfter birthCells continue to increase, support cells incre7 ased83）Histological features of the pineal glandPineal glandconsists of: Pineal cells Glial cellsMesench

5、ymal cells4）Functional characteristics of the pineal glandPhotographic features:Lower vertebratesPineal gland cells can be stimulated directly by the light - light sensitivity cells-photoreceptor cellSecretion:MammalComplete loss of photoreceptor cells in the pineal gland and only as neurosecretory

6、cells.92. Cognition of Pineal function1.2.Pineal organ was considered to be a degradation1896 Otto Heuber found:A 3 year old boy suffering Pineal tumors had sexual precocity, and speculated that tumor in the pineal gland might inhibite the release of hormone which delay the sexual maturity, that is

7、found in the regulatory function of pineal gland inpuberty.In 1959 Lerner extracted hormone from bovine pineal gland. Frog skin could fade with the material, and was named melatonin (MLT), the pineal gland renewed attention.3.104. Currently considered1) The pineal gland is an important neuroendocrin

8、e transducerPeripheral nerve fibers move into the pineal gland, and accept the incoming of optical signal of retinal nerve impulses, through the NE effect, so that the pineal gland releases melatonin.2) secretion of a variety of biologically active substancesIn addition to MLT but also have: GnRH, T

9、RH, OT, ADH, AVT (arginine oxytocin), LH, CA (catecholamine), GABA (r-aminobutyric acid), etc.Up to MLT secretion3) the regulation of body functionsSuch as: biological rhythms, reproductive system, immune system, CNS, cardiovascular system, endocrine system, respiratory system, digestive system, uri

10、nary system.12light stimulation retinal superior cervical ganglion of noradrenergic fibers pineal melatonin and other bioactive substances褪黑素（melatonin, MLT)(A) MLT synthesis, metabolism(B) mechanism of(C) MLT rhythm(D) MLT regulationMLT secretion(E) MLT physiological function14（一）MLT synthesis 1.ML

11、T structure：5 - methoxy-N- acetyl serotonin2.MLT synthesis: TPHNAT HIOMT15MLT metabolismMLTLiver mitochondriahydroxylase6 - hydroxy melatonin+Sulfuric acid or glucuronic acidUrine(6 - hydroxy melatonin in urine may reflect the level of blood MLT)16（二）MLT的分泌1.MLT Source: pineal gland Mammals, human b

12、eings:Main: pineal glandSmall: intestinal chromaffin cells,retina, Deputy lacrimalgland(副泪腺) and salivary glandsCold-blooded animal: eyes, brain, skin (frog),and stomach Intestinal172. MLT secretion pathway：1) The pineal gland blood circulationRat and rabbit:confluens sinusMLT in plasma concentratio

13、n of sinus / peripheral blood and cerebrospinal fluid concentration = 2 to 82) The pineal glandCSFCloven-hoofed animals (sheep, cattle): MLT concentration in CSF / in plasma= 2.6- 18.4193. MLT release mechanism of basal secretion1) passive diffusion:2) vesicles form, active batch release:MLT first s

14、tored in vesicles, under the control of the corresponding signal, then release in the pulse form.20The main regulator of MLT secretion is NEwhich released by postganglionic fibre of the superior cervical ganglia (SCG).MLT by pulsed release is different indifferent animal species, rat and rabbit sinu

15、s melatonin concentration fluctuation in the exchange rate is 3 to 5 times per hour, the frequency is higher than young people and adults, but lower than the frequency of thesheep.214.MLT distribution in body fluids and changes in rhythm1) Blood:MLT in the blood was day and night cycle, the concentr

16、ation reached a peak at night, while daytime levels are low, This change of MLT is the result of secretion of pineal rhythms.2) Urine:Urinary 6 - hydroxy MLT excretion rate also showed circadian rhythm, the same as the time phase of blood, it can reflect the concentration and metabolic changes of ML

17、T in blood.224.MLT distribution in body fluids and changes in rhythm3) CSF:Concentration of MLT in cerebrospinal fluid is low in rat, rabbit, rhesus monkey, human, but it is high in cloven-hoofed animalscerebrospinal fluid. MLT level was diurnal periodic variation, the highest concentrations at nigh

18、t, daytime was almost undetectable.4) Saliva:MLT in saliva is source of blood, saliva MLT / blood MLT = 0.3-0.5, consistent with the change of its period.23（三）The rhythm of MLT1.Circadian rhythmLunar rhythmSeasonal or annual rhythm241. Circadian rhythmCircadian rhythm（近日节律）:Synthesis and secretion o

19、f melatonin was 24 hours of cyclical changes, the peak in the night.褪黑素合成和分泌呈24小时周期性变化，其高峰值在 夜晚。Features:1. The circadian rhythm of MLT is synchronized with the light cycle2. MLTs circadian rhythm is endogenous3. Supraoptic nucleus is the initiator of circadian rhythm25Circadian rhythm of melatonin1

20、. The circadian rhythm of MLT is synchronized with the light cycleLight stimulation retinal hypothalamic tract supraoptic nucleus the rhythm of supraoptic nucleusis synchronized with the light1) the role of light in tune occurs slowly2) NAT, HIOMT, tryptophan hydroxylase, 5 - hydroxy tryptophan deca

21、rboxylase and N-acetyl serotonin -5 are circadian rhythm27Schematic Model of the Components of a Circadian SystemThe Circadian Rhythm of Metabolic Activity of the SCN2. circadian rhythm of MLT is endogenous1) light / dark cycle is not the real reason of circadian rhythm.Circadian rhythm:in non-alter

22、nating day and night lighting effects - free runningA light change alternating day and night - light/ dark - Cycle Synchronization2) circadian rhythm is the endogenous rhythm.303. Supraoptic nucleus is the initiator of circadian rhythmLight stimulation retinal hypothalamic tract supraoptic nucleus t

23、he rhythm of SCN is synchronization with lightA.retina hypothalamic tract is almost completecessation in the supraoptic nucleus.B. If there is transection under the optic chiasm(damage pupil reflection and eye muscle movement), while retaining the retinal hypothalamic tract, the activities of SCN re

24、main unchanged.31C. cut off contact between the SCN and the retina,the circadian rhythm becomes free running rhythm.D. damage the adult rodent SCN, disappearance of many processes in the circadian rhythm. To destroy the SCN during the three weeks after birth, the majority of circadian rhythm can not

25、 be formed.322. Lunar rhythmLunra rhythm: Fluctuations of melatonin in the blood of women is synchronization with menstrual cycle.女性血液中褪黑素波动与月经周期同步。menstrual cycleMLTNELHestrogenPreovulatoryminimumpeakThe eve of menstrual crampsReasonsEffect the release of NE of sympatheticInhibition the synthesis o

26、f MLTEstrogen(Preovulatory)Directly on the pineal gland cellsRole of MLT:MLT levelreduced the inhibition of gonadalsexhormonesFurther increase in sex hormonelevelscause ovulation343. Seasonal or annual rhythmSeasonal breeding animals: many species of animal,only a limited period of one year females

27、showed ovarian cycle activity, and male animals only in the same period of development, sexual maturation.Seasonal animals generally associated with day length, it will be divided into:Short-day breeder: the days get shorter the animalsenter the breeding season: sheep Long-day breeder: The days get

28、longer animals enterthe breeding season: hamster35Seasonal or annual rhythm:The breeding of animals is related with the seasons, stationary phase of their reproductive peak 、 the pituitary and gonadal system alternating. This phenomenon is due to periodic changes in sunlight, affect the reproductive

29、 system by the pineal gland, MLT is the intermediary .与季节繁殖有关的动物，其生殖高峰与垂体、系统的静止期交替出现。这一现象是由于日照周期变化，通过松果体影响生殖系统而实现的，MLT是这一变化的中介。3637IV. The regulation of MLT secretion1.Neural Regulation2.Light influence the synthesis and secretionof mammal MLT3.Other factors381. Neural RegulationNeuromodulation path

30、way of MLT secretion : Retina - Pineal Pathway:light stimulationretinalretinalhypothalamic tractsupraoptic nucleushypothalamic medial forebrain bundlemidbraintegmentalthoracic spinal cordpreganglionicadrenergicrelease offibers terminate in the bilateral SCGpostganglionic fiberspineal glandNEenter th

31、e pineal cell1 adrenergicreceptorMLTstimulation synthesis and secretion of39Neural regulatory pathway of secreted MLTEvidence of Retina - pineal pathway:1. out of the eye - MLT secretion and light / dark, out of sync2. Removal of SCG - MLT secretion was significantly affectedHuman, mouse: retinal -

32、pineal gland pathway is the main channel of MLT secretion.Birds and other lower animals: light directly affects the synthesis and secretion of MLT, the retina - the pineal gland pathway is secondary.412. Light on synthesis and secretion of mammal MLTNE is an important intermediary:light stimulationr

33、etinalneural pathwaysadrenergic postganglionic fiberspineal glandrelease NEenter the pineal gland cells1adrenergic receptorsecretion of MLTeffect the synthesis andNE NAT , HIOMT , TPH 42Light on the impact of MLT synthase1.NATlight NE NATin the early darkness NE receptor NE release 2.HIOMTlong-term

34、light HIOMT activity night HIOMT activityNATwhen the N-acetyl -5-HT accumulate largely, HIOMTplay the role of limiting enzyme.43Light on the impact of MLT synthase3. TPHDark: TPHBright light: Inhibition the activity of TPH MLTNE: TPH4. amino acid decarboxylaseNE: amino acid decarboxylaseBright light

35、 : activity increased 2-fold higher than in continuous darkThe lightNEamino acid decarboxylase443. Other factors influence the synthesis of MLT1)2)tryptophan in food 5-HT MLT NE pineal taurine -adrenergic receptor NAT activity stress sympathetic nerve MLT estradiol: low concentration HIOMTactivity H

36、igh concentration HIOMTactivity 3)4)45（五）Physiological function of MLT1.2.3.4.5.Reproductive systemImmune system Central nervous system cardiovascular systemother systems46MLT on the regulation of reproductive systemRegulating puberty, delayed sexual maturity age animalsControl the reproductive cycl

37、e, especially for seasonal breeding animals.Inhibition of hypothalamic GnRH release, control gonadotropin synthesis and secretion.1.2.3.4.5.Reduce the ovulation response induced by gonadotropinBlocking ovulation and uterine proliferation induced bythe human chorionic gonadotropin, and reduce the pro

38、gesterone content.The atrophy of gonads, prostate gland organ.476.short photoperiod effectsthereproductive system of hamsterMale hamsters: testicular atrophy, stopspermatogenic, with gonadal atrophy, GnRH , LH , testosteroneFemale hamsters: estrous cycle arrest,infantileuterus, follicle numbers lute

39、al PRL 48MLT involved in light regulation of the reproductive system in hamstersMLT is an important intermediary in the process of the short photoperiod induced gonadal atrophy, only in higher concentrations and / or short photoperiod to play.Such as: evening administrationsuperposition ofendogenous

40、 and exogenousDamage to the SCNdisrupt the endogenous rhythm49 There are MLT receptors on Pineal gland, so pineal gland also is the target organ for the MLT. MLT has a positive feedback effect on the pineal gland. In NAT, HIOMT is high, the positive feedback effect is more evident. The sensitivity o

41、f the MLT receptors havecircadian fluctuations, showing the diurnal variation. Continuing release of MLT reduce the number of MLT receptors, so receptors lose sensitivity to dark or lightdeprivation.50MLT in the short effects of light on the role of the reproductivesystem:MLT is the effect of short

42、photoperiod on the sexual organs of the IntermediaryTest :Normal hamster light (blinding) testicular atrophyThat: short illumination inhibited sexual organsHamster pineal gland resection light (blinding) changedlittle sex organsShow: the impact of photoperiod on the sexual organs and the pineal glan

43、d on hamster SCG removed blinding light, little change in sexualorgansThat: the pineal gland depends on the sex organs of the sympathetic role.51Mechanisms of MLT1.MLT effects the gonadal cells directlychanges the morphology of testcular cell and hormone secretion capacity;reduce the reactivity of g

44、onadotropinThe enhanced role of the pituitary gland reduce the sensitivity of the pituitary to the GnRHMLT effects the hypothalamic GnRH neurons,inhibiting the release of LH and FSH2.3.52Short day and melatonin can increase the pituitarygonadal steroid hormones on negative feedback sensitivity.Short

45、 day + ovariectomized hamsters Trace exogenous testosterone LH and FSHlong-day+ castrated hamsters increasing doses of exogenous testosterone,LH and FSHCastrated hamsters injected with melatonin Hamsters in the darktestosterone sensitivity of the same53MLT regulate the immune systemImmune enhancemen

46、t1.Stimulating proliferation of immune cells 2.Increase the red blood cell antibodyresponse in primary and secondary3. Cytotoxic T cell response 4. IL-2 production5. Helper T cell activity 6.NK cell activity 7.antibody-dependent cytotoxicity 54MLT-mediated immune regulation pathway1.2.3.4.Opioid receptor networkEndocrine systemDirect role in lymphoid tissue Antioxidant55alamicThe role of MLT in the central nervo