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Pineal gland

Pineal gland. Described for the first time in the third century Later, was called the "third eye" 17 th century, French philosopher Descartes called it the seat of the human soul. History. 1958: Aaron B. Lerner isolated the hormone produced by the pineal and named it melatonin

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Pineal gland

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  1. Pineal gland • Described for the first time in the third century • Later, was called the "third eye" • 17th century, French philosopher Descartes called it the seat of the human soul

  2. History • 1958: Aaron B. Lerner isolated the hormone produced by the pineal and named it melatonin • 1961: Virginia Fiske showed that light affects pineal weight in rats; these lighting changes affect their sexual desire • 1965: Axelrod and Wurtman proposed "melatonin hypothesis”

  3. Pineal gland Photoneuroendocrine transducer

  4. Background • Pineal gland = epiphysis • Shaped like a pine cone (hence its name) • Unpaired cerebral structure • Varies in size among species • Its blood flow is second only to the kidney

  5. Pineal gland

  6. Background • Large in children, but shrinks at puberty • Has no blood-brain barrier • Composed of "pinealocytes" and glial cells

  7. Pinealocytes • Like neurons • Star shaped and arranged in clusters • Have numerous microtubules, extensive smooth-surfaced endoplasmic reticulum, and a few small granules • Produce melatonin and other hormones

  8. Glial cells • Elongated and run between nests of pinealocytes • Dense nuclei • Rich vascular supply

  9. Pineal gland • In reptiles and birds, pineal is close to skin and needs no interaction with the eye to register day/night cycle • Pineal gland = master clock • Contains magnetic material in birds - a center for navigation

  10. In mammals, pineal gland is subordinate to the eye - SCN system

  11. Melatonin Major pineal hormone

  12. Synthesis of melatonin

  13. Melatonin Synthesis and secretion is dramatically affected by light exposure to the eyes

  14. Melatonin circadian rhythm

  15. Melatonin receptors • Mel1A, Mel1B, Mel 1C (MT1, MT2, MT3) • MT3 in mammal-controversial • G protein-coupled receptors • Highest density of receptors in the SCN, anterior pituitary (predominantly pars tuberalis), and the retina

  16. Melatonin receptor Melatonin enhances GABAA receptor function in SCN (Brown et al.) May be responsible for the regulatory effects of melatonin on mammalian circadian time-keeping and melatonin's sleep-inducing effects?

  17. Melatonin receptor • Melatonin decreases GABAA receptor current amplitude in CA1 neurons in hippocampal slices (Brown et al.) Different receptor subtypes?

  18. Melatonin receptors Differentially expressed in different tissues • Mel1a in SCN • Mel1b in hippocampus • Found Mel1a in cerebellum, medulla, midbrain, neocortex, hypothalamus • Physiological significance of melatonin receptors in those several brain regions is still not known Brown et al.

  19. Effects on reproduction • A hamster without a pineal gland or with a lesion that prevents the pineal from receiving photo-information is not able to prepare for the breeding season • Sheep that normally breed only once per year can be induced to have two breeding seasons by treatment with melatonin

  20. Effects on reproduction • Human reproduction is also under melatonin’s influence • Inuit women stop menstruating when the dark winter months of the North greatly raise their melatonin • Return of daylight in spring lowers their melatonin, allowing the menstrual cycle to begin again and fertility to return

  21. How? Melatonin inhibits the GnRH-induced secretion of the LH from the anterior pituitary Vanecek et al.

  22. Effects on sleep • Since the early 1970s melatonin was reported to exerts sleep promoting effects • In most studies melatonin (0.3 to 5 mg) improved sleep parameters in patients suffering from insomnia • Melatonin is also used to relieve jet-lag

  23. Other actions of melatonin • Free radical scavenger • Protects against abnormal phosphorylation of cytoskeletal proteins • Controls cancer cell proliferation

  24. Melatonin - .OH scavenger • MPP+ induces .OH production • Salicyclic acid traps .OH to form 2,3 DHBA (2,3-dihydroxybenzoic acid) Melatonin attenuated MPP+ -induced 2,3-DHBA formation Thomas et al., 2004

  25. Melatonin-oxidative stress Melatonin scavenges: -Nitric oxide (NO.) (Noda et al.) -ONOO- (Blanchard et al.) -H2O2 (Tan et al.) (H2O2 metabolizes to .OH)

  26. Possible mechanism Reiter et al., 2000

  27. Melatonin-oxidative stress • Enhances GRd activity (GRd important for GSH recycling) (Pablos et al.) • Enhances GRx activity (GRx important for GSH synthesis) (Pablos et al.) • Inhibits NOS (NOS generates NO.) (Pozo et al.) • Enhances SOD (superoxide dismutase) activity (Thomas et al.)

  28. SN=substantia nigra • NCP=nucles caudatus putamen Melatonin blocked MPTP-induced GSH depletion in SN & NCP Thomas et al., 2004

  29. Conclusion Melatonin protects against oxidative stress by: -scavenging free radicals -stimulating the synthesis of antioxidative enzymes & antioxidative molecules -inhibiting activity of free radical generating enzymes

  30. Melatonin-Alzheimer • TNP=0: no neuritic plaques • TNP=1: plaques were present • TNFT=0: no neurofibrillary tangles • TNFT = 1: tangles were present Melatonin seems to have neuroprotective effect Zhou et al., 2003

  31. Human neuroblastoma SH-SY5Y cells Okadaic acid (OA) = potent protein phosphatase inhibitor NF-H/M = neurofilament H/M subunits SMI31 = antibody recognizes phoshorylated (p)-NF-H/M SMI32 = antibody recognizes non-phosphorylated (np)-NF-H/M DM1A = antibody recognizes tubulin Wang et al. 2004

  32. Wang et al. 2004

  33. Conclusion • Melatonin prevents abnormal phosphorylation of NF • Melatonin attenuates OA-induced disruption of microtubule  Melatonin has protective functions against pathological lesions in AD Mechanism?

  34. Melatonin - cancer Karasek et al.

  35. Melatonin - cancer • Chromium compounds = carcinogens • Cr(III) induces DNA strand breaks, DNA-protein cross-links, and oxidative DNA base modifications (eg:8-hydroxydeoxyguanosin = 8-OH-dG) Qi et al.

  36. Melatonin inhibited Cr(III)-induced formation of 8-OH-dG in a dose-dependent manner Qi et al.

  37. Trolox = vitamin E Melatonin was more effective in reducing oxidative damage to DNA Qi et al., 2000

  38. Melatonin - cancer Hepatoma 7288CTC in rats Melatonin suppresses tumor growth Blask et al., 2002

  39. Possible mechanism-no melatonin -LA= linoleic acid -FATP=fatty acid transport protein -13-HODE=13-hydroxyoctadecadienoic acid Blask et al., 2002

  40. Possible mechanism LA= linoleic acid FATP=fatty acid transport protein 13-HODE=13-hydroxyoctadecadienoic acid

  41. Conclusion Melatonin • Protects nuclear DNA from oxidative damage • Inhibits tumor growth

  42. Blindness may reduce cancer • Studies from Sweden and Finland showed lower breast cancer risk in totally blinded women (Feychting et al. & Verkasalo et al.) • Study from US indicated that women with bilateral blindness have ½ the risk of developing breast cancer (Hahn) • Study from Norway indicated that totally blind women are at decreased risk of breast cancer, especially if they became blind before age 65 (Kliukiene et al.)

  43. Circadian profile of melatonin Arendt et al. 1995

  44. Melatonin = ‘rejuvenating’ agent ? • Melatonin is not yet approved by the FDA • Long term effects of melatonin is not known

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