Pineal gland

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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

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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

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Pineal gland

• Photoneuroendocrine transducer

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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

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Pineal gland
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Background

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

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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

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Glial cells

• Elongated and run between nests of pinealocytes
• Dense nuclei
• Rich vascular supply

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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

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

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Melatonin

• Major pineal hormone

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Synthesis of melatonin
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Melatonin

• Synthesis and secretion is dramatically affected
  by light exposure to the eyes

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Melatonin circadian rhythm
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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

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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?

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Melatonin receptor

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

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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.

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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

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Effects on reproduction

• Human reproduction is also under melatonins
  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

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How?

• Melatonin inhibits the GnRH-induced secretion
  of the LH from the anterior pituitary

Vanecek et al.
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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

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Other actions of melatonin

• Free radical scavenger
• Protects against abnormal phosphorylation of
  cytoskeletal proteins
• Controls cancer cell proliferation

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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
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Melatonin-oxidative stress

• Melatonin scavenges
• -Nitric oxide (NO.) (Noda et al.)
• -ONOO- (Blanchard et al.)
• -H2O2 (Tan et al.) (H2O2 metabolizes to .OH)

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Possible mechanism
Reiter et al., 2000
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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.)

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• SNsubstantia nigra
• NCPnucles caudatus putamen
• Melatonin blocked MPTP-induced GSH depletion in
  SN NCP

Thomas et al., 2004
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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

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Melatonin-Alzheimer

• TNP0 no neuritic plaques
• TNP1 plaques were present
• TNFT0 no neurofibrillary tangles
• TNFT 1 tangles were present
• Melatonin seems to have neuroprotective effect

Zhou et al., 2003
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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
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• Wang et al. 2004

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Conclusion

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

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Melatonin - cancer

• Karasek et al.

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Melatonin - cancer

• Chromium compounds carcinogens
• Cr(III) induces DNA strand breaks, DNA-protein
  cross-links, and oxidative DNA base modifications
  (eg8-hydroxydeoxyguanosin 8-OH-dG)

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

Qi et al.
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• Trolox vitamin E
• Melatonin was more effective in reducing
  oxidative damage to DNA

Qi et al., 2000
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Melatonin - cancer

• Hepatoma 7288CTC in rats
• Melatonin suppresses tumor growth

Blask et al., 2002
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Possible mechanism-no melatonin
-LA linoleic acid -FATPfatty acid transport
protein -13-HODE13-hydroxyoctadecadienoic acid
Blask et al., 2002
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Possible mechanism
LA linoleic acid FATPfatty acid transport
protein 13-HODE13-hydroxyoctadecadienoic acid
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Conclusion

• Melatonin
• Protects nuclear DNA from oxidative damage
• Inhibits tumor growth

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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.)

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Circadian profile of melatonin
Arendt et al. 1995
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Melatonin rejuvenating agent ?

• Melatonin is not yet approved by the FDA
• Long term effects of melatonin is not known