Lecture 74: Melatonin and Eicosanoids

major role of melatonin is

regulation of sleep and wakefulness

melatonin is produced by

pineal gland - located behind 3rd ventricle

melatonin is synthesized from

tryptophan, with serotonin as an intermediate

how does blue light suppress melatonin

photic information from retina transmitted to hypothalamus and SNS via the supra-chiasmatic nucleus, then to pineal gland

secretion of melatonin is regulated by

light

melatonin is stimulated by

darkness

how is melatonin stimulated by darkness

• retinal photoreceptors release norepinephrine, which activates beta-adrenergic receptors in the pineal gland

• serotonin converted to melatonin

melatonin is inhibited by

light

how is melatonin inhibited by light

• retinal photoreceptor cells become hyperpolarized, which inhibits the release of norepinephrine

• blind can still have light-induced suppression of melatonin

melatonin increases until

1-3 years old, then declines

circadian rhythm of melatonin secretion is controlled by

endogenous pacemaker in the supra-chiasmatic nucleus

what can alter the timing of circadian rhythm

environmental lighting

what can modify circadian rhythm

day-night cycles

what suppresses melatonin

brief pulses of light

secretion of melatonin usually begins at

dusk and peaks around 2-4 am

shifts of melatonin secretion occur

after flights across time zones and in night-shift workers

melatonin activates

MT1 AND MT2 receptors

melatonin regulates/affects

• sleep

• circadian rhythm

• mood

• sexual maturation and reproduction

• may have anti-inflammatory effects on immune system

• may have beneficial effects on cancer

• aging

melatonin affects the speed of

falling asleep and duration/quality of sleep

how does melatonin affect mood

• abnormal circadian rhythms implicated in mood disorders

• depression

• seasonal affective disorders

• bright-light therapy can decrease depression and help sad

how does melatonin affect sexual maturation and reproduction

• hours of darkness/season linked to reproductive activity

• decreases in melatonin at puberty

• may affect sex steroid hormone synthesis and modulate ovarian function

how do hours of darkness link to reproductive activity

• mare estrous cycles

• melatonin increases during long winter nights

• in spring, melatonin decreases, GnRH starts to increase

a decrease in melatonin at puberty activates

pituitary-gonadal axis

how does melatonin affect sex steroid hormone synthesis

• receptors for melatonin on ovaries

• stimulates progesterone synthesis

how can melatonin treat alopecia in dogs

may decrease GnRH, which decreases LH/FSH effects on adrenal androgen precursors

does melatonin increase or decrease anxiety and seizure activity?

decrease

short-term side effects of melatonin

sedation and incoordination

eicosanoids are a group of signaling molecules synthesized by

oxidation of 20-carbon essential fatty acids (EFA)

omega-3 EFAs yield

eicosapentenoic acid - less inflammatory

omega-6 EFAs yield

arachidonic acid - pro-inflammatory

eicosapentaenoic acid

• 5 double bonds

• prostanoids with 3 double bonds

• leukotrienes with 5 double bonds

arachidonic acid

• 4 double bonds

• prostanoids with 2 double bonds

• leukotrienes with 4 double bonds

2 letter abbreviation for eicosanoids

PG

one ABC sequence letter for eicosanoids

PGE

subscript indicating number of double bonds for eicosanoids

PGE2

PGAs are

alpha, beta-unsaturated ketones

PGEs are

beta-hydroxyl ketones

PGFs are

1,3-diols

eicosapentenoic acid cascade

• formed from omega-3 EFAs

• form mostly prostanoids

• major function is to dampen inflammatory effects of arachidonic acid prostanoids

arachidonic acid cascade

• prostanoids

• leukotrienes

• lipoxins

arachidonic acid cascade prostanoids

• prostaglandins

• prostacyclins

• thromboxanes

• major effects - inflammatory responses

overall effects of arachidonic acid cascade

• stimulate inflammatory responses

• modulate pain and fever

• reproductive functions

• inhibit gastric secretion

• blood pressure regulation

• platelet activation/inhibition

dietary precursors of arachidonic acid

• linoleic acid (18 C EFA)

• gamma linoleic acid

why can’t cats convert linoleic acid to arachidonic acid?

they have low delta 6-desaturase enzyme

what releases arachidonic acid from phospholipids in cell membrane?

phospholipase A2

arachidonic acid will be oxygenated by

• cyclooxygenase (COX1 and COX2) to make prostanoids

• lipooxygenase (5LOX) to make leukotrienes

major actions of prostanoids derived from arachidonic acid

• local hormones with autocrine or paracrine action

• short half-life (seconds to minutes)

• mediated by specific receptors

• mediate inflammation (except for lipoxins)

PGE2 actions

smooth muscle contraction, bronchoconstriction, pain, heat, fever

PGI2 actions

vasodilation, inhibits platelet aggregation

TXA2 actions

vasoconstriction, stimulates platelet aggregation

what decreases inflammation, redness, swelling, pain, and heat?

NSAIDs

NSAIDs that inhibit COX1 and COX2

• aspirin

• carprofen, flunixin, phenylbutazone, ibuprofen, naproxen

NSAIDs that inhibit only COX2

• less side effects

• firocoxib, deracoxib

• meloxicam, piroxicam, celecoxib