PROSTAGLANDINS AND ITS TYPES

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About Authors:
S. Ramya Silpa
Department of Pharmacology,
Balaji College of Pharmacy, Anantapur, AP, India.
shilpasankarapu@gmail.com

Abstract:
Prostaglandins are potent bioactive lipid messengers synthesized from arachidonic acid mediated by enzyme COX. Prostaglandins (PGs) play a key role in the initiation of the inflammatory response. Their biosynthesis is significantly increased in inflamed tissue, and they contribute to the development of the cardinal signs of acute inflammation. Although the proinflammatory properties of individual PGs during the acute inflammatory response are well established, their role in the resolution of inflammation is more controversial.

REFERENCE ID: PHARMATUTOR-ART-2152

PharmaTutor (ISSN: 2347 - 7881)

Volume 2, Issue 5

Received On: 15/12/2013; Accepted On: 10/03/2014; Published On: 01/05/2014

How to cite this article: SR Silpa; Prostaglandins and its Types; PharmaTutor; 2014; 2(5); 31-37

Introduction:
Prostaglandins are potent bioactive lipid messengers synthesized from arachidonic acid mediated by enzyme COX.[1,2,3] Arachidonic acid is derived from membrane phospholipids catalyzed by PLA2.[4] They play a very prominent role in reproductive biology like ovulation, endometrial physiology, proliferation of endometrial glands and menstruation and pathological conditions like dysmenorrhoea, carcinoma, endometriosis, menorrhagia.[5] There are different types of prostaglandins like PGD2, PGE2, PGF2, PGI2.[6,7]

COX:
COX is an enzyme that is responsible for formation of different forms of prostaglandins. It is also referred as prostaglandin synthase, prostaglandin endoperoxidase or prostaglandin G/H synthase. (PGS, PGTS, PGHS).[7]

COX is involved in two pathways or two catalytic activities. 1. Cyclooxygenation 2.peroxidation.

Cyclooxygenase activity is responsible for bisoxygenation of arachidonic acid to PGG2.i.e., COX cyclizes and adds 2 molecules of oxygen to AA for formation of cyclo hydroperoxide PGG2.

Peroxidase activity is involved in reduction of PGG2 to PGH2.[8] The COXs exist in two isoforms, a constitutive form (COX-1) and an inducible form (COX-2), and a COX-1 splice variant termed as COX-3 has been reported.[9] COXs catalyze the conversion of AA to PGs and thromboxanes, which trigger as autocrine and paracrine chemical messengers in many physiological and pathophysiological responses.[10]  COX-1 and -2 share the same substrates, produce the same products, and catalyze the same reaction using identical catalytic mechanisms.[11,12]

COX-1:
The primary structure of COX-1 was first characterized in sheep and subsequently in a number of species (Merlie et al., 1988; DeWitt and Smith, 1988; Smith et al., 2000).[7] The COX-1 gene is ,22 kilobases (kb) in length, contains 11 exons, maps to human chromosome 9q32-q33.3, and is transcribed as a 2.8 kb mRNA.[8,13] It is involved in several physiological functions like maintainance of homeostasis (gastric and renal integrity) and normal production of PG.[14,15,16]

It is involved in several carcinomas.[17,18,19,20]

COX-2:
The COX-2 gene is about 8 kb long with 10 exons and it is transcribed as 4.6, 4.0 and 2.8 kb mRNAs variants.8,13 It is involved in several inflammatory and pathological conditions.[5,7,21]

COX-2 is found in brain, kidney and endothelial cells. COX-2 expression can be induced in response to growth factors, cytokines, proinflammatory stimuli, carcinogens, tumor promoting phorbol esters.[14,15,16]

COX-3:

A third COX isoform, named COX-3, has recently been characterized in dogs.[22] The enzyme is sensitive to acetaminophen and highly expressed in the central nervous system, suggesting that inhibiting COX-3 may represent an important mechanism for controlling the synthesis of prostanoids mediating pain and fever.[23]

PGE2:
One of the most abundant PG produced in humans is PGE2. It is formed by all cell types of the body like epithelia, fibroblasts, infiltrating inflammatory cells.[24] PGE2 binds to different EP receptors like EP1, EP2, EP3, EP4 that regulate function of macrophages and dendritic cells.[25,26]

Degradation of PGE2:
The rate of PGE2 degradation is controlled by 15-PGDH.[27,28,29,30,31]

Receptors:
PGE2 acts by autocrine-paracrine signaling on four different types of receptors on target cells. Interaction of PGE2 with the EP1 receptor mobilizes intracellular calcium and inositol trisphosphate (IP3) via Gαq.[5]

EP1 and EP2 usually act at higher concentrations and slow effective signaling. EP3 and EP4 show high affinity for PGE2. EP2 and EP4 are G-protein coupled receptors and are mediated by AC-triggered cAMP/PKA/CREB pathway.[32,33]

Physiological role:
It plays a pivotal mediator in several biological functions like regulation of immune responses, bp, gastrointestinal integrity, fertility.[26] PGE2 signalling suppresses colitis symptoms and mucosal damage by protecting the integrity of epithelial intestinal wall, presumably through the enhancement of epithelial survival and regeneration.[34]

Pathological role:
An alterations in PGE2 synthesis or degradation leads to pathological conditions like inflammation, chronic infections,[26] colorectal and different types of cancer,[35] Stem cell differentiation,[36] arthritis,[37] Inflammatory bowel disease (IBD).[38]

The 15-PGDH activity is suppressed in some forms of cancer.[31] PGE2 is found to be key mediator in inflammatory process. IT includes redness, swelling, pain. Redness and edema result from increased blood flow into inflamed tissue through PGE2- mediated augmentation of arterial dilation and increased microvascular permeability. Pain results from the action of PGE2 on peripheral sensory neurons and on central sites within spinal cord and brain.[39]

Immunosuppresssion:
It is also involved in immunosuppression. In cancer patients, PGE2 inhibit B and T-cell proliferation and then allowing defective cells to proliferate undetected by immune system.[5] PGE2 also inhibits IL-2 and IFN production from T-lymphocytes and IL-1 and TNF release from macrophages. [40]

Fever:
When infected organisms enter the body, bacterial LPS or circulating IL-1 stimulate COX and PGE synthase, results in formation of PGE2. The PGE2 formed diffuses out of endothelial cellsinto OVLT regulation of hypothalamus that is responsible for controlling fever.[2] Pyrogens, including cytokines released during bacterial infection also potentiate synthesis of PGE2  in hypothalamus, that resets the thermostat to cause fever.[41]

Metabolism:
PGE2 are lipolytic, exert an insulin-like effect  on carbohydrate metabolism and mobilize ca2+ from bone: may mediate hypercalcemia due to bony metastasis.[41]

GIT:
PGE2 acts directly on intestinal mucosa and increases water, electrolyte and mucus secretion.[42]

It acts on EP3 receptor and decreases gastric acid secretion, histamine stimulated acid secretion. It also stimulates EP1 receptor, causes contraction of smooth muscle.[2]

Bronchial muscle:
They act on bronchial smooth muscle and cause vasodilation.[42]

Kidney:
PGE2 increase water, Na+ and K+ excretion and have diuretic effect. It also antagonize ADH action and this adds to diuretic effect.[42]

PGE2 have vasodilator actions in the kidney, and intrarenal infusions of these PGs increase renal blood flow. PGs are also natriuretic, inhibiting tubular sodium reabsorption, and in the thick ascending limb of the loop of Henle, they reduce chloride transport. PGE2  synthesized in cortex is an important stimulator of renin.[2]

Endocrine system:
PGE2 facilitates release of anterior pituitary hormones – growth hormone, prolactin, ACTH, FSH, LH as well as that of insulin and adrenal steroids. It has TSH like effect on thyroid.[41]

Alzeimer disease:
In patients with AD, PGE2 concentration is elevated in CSF than age matched control subjects.[43]

Blood vessels:
PGE2 causes vasodilation of blood vessels, there by resulting in decreased bp.

Intestine:
PGE2 has the tendency of contracting longitudinal muscles and relax circular muscles thereby increasing peristalsis.[44]

PGI2:
PGIis synthesized in the presence of COX and PGIs from PGH2. PGIS colocalizes with COX in endoplasmic reticulum, plasma membrane, nuclear membrane.[7] PGI2 is released by healthy endothelial cells.[45] Vascular cells including endothelial cells, VSMCs and endothelial progenitor cells are major source of PGI2.[46] It is antimitogenic and inhibits DNA synthesis in VSMC.[16] It is involved in edema, pain and inflammation. These levels found to be elevated in synovial fluid of human arthritic patients.[47] PGI2 is an essential vasodilator and is involved in leukocyte adhesion and VSMC proliferation.[48]

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