Pineal gland and Melatonin Lecture NO:2nd MBBS Dr Muhammad Ramzan

Pineal gland – Location and role Pineal gland is a small organ, shaped like a Pine cone. is located at the midline of the brain at the roof of 3rd ventricle Pineal body is present in human as well as in animals It secretes a hormone – the Melatonin that informs the body parts about environmental light

Pineal gland – its location

Melatonin (Mell.) – the definition 3rd eye A protein hormone produced by the Pineal gland in the brain Communicates information about environmental light to : The different parts of the body through Retina – 3rd eye Is best known for helping to regulate the body's circadian sleep-wake cycle in human

Melatonin – the background the light of night Mell is the naturally occurring protein found in animals including mammals; plants Insects and microbes Is a derivative of essential AA Tryptophan Its production is influenced through the detection of light and darkness by the Retina of the eye Mell synthesis is inhibited by light and stimulated in the absence of light – the hormone of darkness ↑ Melatonin is present in Tomatoes; Bananas, Spinach and almonds

Foods high in Mell

Melatonin – the Photoperiod length of the day vs. night It is the daily exposure of an animal to light and has important effects on its : Growth, development and breading/reproductive season Can be described as length of the Day Versus Night and is different in Winter and Summer

Melatonin secretion and age no secretion at < 3 months Very little melatonin is secreted by the children < 3 months Its secretion ↑es, becomes circadian as the infant grows and is highest at the age of 1- 3 years Mell production starts falling after puberty and virtually disappears in the elderly A phenomenon which could help to explain why sleep disturbances are more prevalent among old age

Mell – Target tissues with GPRC Hypothalamic nuclei, GIT and retina Target tissues are the ones that express Mell receptors Mel.1 and Mel.11 (Mell A or Mell B) - GPCR Major target tissues for the Mell are : CNS – Supra Chiasmic and PVN nuclei and ant. Pituitary Retina; GIT; Ovary and blood vessels Total Mell GIT secretion is 400 times than from Pineal gland

Melatonin synthesis – from Tryptophan Hydroxylation and Methylation Tryptophan, an amino acid is taken up by the Cells of the Pineal gland from the circulation Undergoes Hydroxylation to 5 - Hydroxy Tryptophan 5- Hydroxy Tryptophan is Decarboxilated to the Serotonin Serotonin is Methylated to the Melatonin ( an Indole) Melatonin is rapidly metabolized in liver by Hydroxylation and Conjugation and then excreted in urine

Melatonin – the biosynthesis

Summary for the pathway of Mell synthesis Photo receptor cells of the retina perceives the light status Produce and send signals to the hypothalamic nucleic which include: Suprachiasmatic,PVN and then to the Superior Cervical ganglion via spinal inter mediolateral cell column that sends : Sympathetic nerve fibers to the cells of Pineal gland to ↑ Mell synthesis at night Mell production induces sleep by ↓ body temp. and respiratory rate Melopsin is a photosensitive retinal pigment – a member of retinal proteins Opsin

Melatonin synthesis – the pathway Melopsin is a photosensive

Mell synthesis – signal pathway eye to Pineal gland

Mell synthesis and mechanism of action Release of NE (nor epinephrine)

Regulation of Mell by Nor epinephrine nor epinephrine(NE) is released at night Photoreceptor retinal cells are activated in the night and sends signals across the pathway for Mell. synthesis Mell production is regulated by the nor epinephrine, which is released from the Sympathetic nerve fibers These fibers are conveyed to the Pineal gland by the Superior Cervical ganglion Activation of these fibers releases the nor epinephrine

SCN regulates Mell synthesis during the day SCN prevents release of NE Nor epinephrine binds to the β – adrenergic receptors on the Pineal cells and activates Adenylate Cyclase : that converts ATP to cAMP (2nd messenger) that stimulates the Mell synthesis from Tryptophan During the day, SCN inhibits the release of Nor epinephrine and Mell synthesis SCN nucleus regulates Circadian oscillation in brain

Melatonin – The mechanism of action GPCR and 2nd messenger Melatonin is a protein hormone and acts as such Melatonin acts through Receptors in mammals : Mell A and Mell B (Mel.1 and Mel 2) - GPCR GPCR are expressed on the cells membranes of the: Target tissues : Retina; GIT, ovary, blood vessels,SCN, PVN and ant. Pituitary gland

Melatonin – The mechanism of action cont. Mell binds to the extracellular domain of the GPCR Produces conformation changes in the G- protein Exchanges GDP for α GTP and activates membranous enzyme Adenylate Cyclase which converts : ATP to CAMP – the 2nd messenger cAMP, Phosphorylates various intracellular proteins and enzymes to carry out Melatonin action

Mell – the mechanism of action

Biological effects of Melatonin Mell maintains the body Circadian Sleep- wake cycle and promotes the sleep via SCN 1 Regulates the secretion of hypothalamic and ant. Pituitary hormones like GH, FSH and LH 2 Manipulates the breeding season in animals like sheep 3 Regulates the distribution of Melanin pigments in lower species like amphibians, tadpole/frog and birds 4

Circadian Rhythm

Mell – Biological effects

Mell – Biological effects It is an antioxidant and Improves the function of the lymphoid tissues of the immune system Provides protection against the malignancies- GIT; ovary Liver, Pancreas and breast

Mell uses - Sleep Disorders and alteration in breeding season Melatonin is used in certain sleep disorders when there is disturbance in sleep- wake cycle This happens in Shift workers, International business travelers and Jet lag Used for sleep disturbances in old age Melatonin is used to manipulate breeding season to have 2/year instead of one especially in sheep

Melatonin for sleep disorders. Remeltion(FDA approved) Tablets 3/5mg Melatonin for sleep disorders.Remeltion(FDA approved) Tablets 3/5mg. capsules, liquid and skin spray

Biological effects of Mell