PROSTAGLANDINS AND ITS TYPES
IP receptor is present in spinal cord and has been involved in spinal cord transmission. This receptor is present in kidney, liver, platelets, heart and aorta. So, IP antagonists helps in reducing pain in several models like acetic acid–induced abdominal constriction, mechanical hyperalgesia produced by carrageenan, and pain associated with models of osteoarthritis and inflammatory arthritis.
Mode of action:
PGI2 acts through paracrine signaling. Its action commences by acting on GPCR on near platelets and endothelial cells.
Platelets:- As this receptor gets activated, GPCR signals AC to synthesize cAMP. cAMP cAMP goes on to inhibit any undue platelet activation (in order to promote circulation) and also counteracts any increase in cytosolic calcium levels that would result from thromboxane A2 (TXA2) binding (leading to platelet activation and subsequent coagulation).
Endothelial cells:- This receptor is also involved in elevating cAMP levels in cytosol. This cAMP then goes on to activate protein kinase A (PKA). PKA then continues the cascade by phosphorylating and inhibiting myosin light-chain kinase, which leads tosmooth muscle relaxation and vasodilation.
It is a potent inhibitor of platelet aggregation. It prevents formation of platelet plug involved in primary hemostasis ( a part of blood clot formation).
It is main lipid mediator synthesized from arachidonic acid via the catalytic activities of cyclooxygenases (COX) and PGD2 synthases (PGDS) in mast cells, macrophages, and other cellular sources.
Synthesis and metabolism:
The peroxidase activity of COX-1,2 enzymes transforms PGG2 to PGH2. PGH2 is unstable intermediate endoperoxidase that is immediately converted to PGD2 by PGDS. PGD2 is metabolized non-enzymatically to 15-deoxy-Δ12,14- PGJ2 (15dPGJ2) or Δ12-PGJ2 depending on the presence of serum albumin.
There are two types of PGDS. Hematopoietic PGDS (H-PGDS) is present in mast cells, macrophages, and dendritic cells, Hematopoietic PGD synthase is widely distributed in the peripheral tissues and localized in the antigen-presenting cells, mast cells, and megakaryocytes.
H-PGDS-producing inflammatory cells that are chemotactically compelled to permeate the vasculature.
Lipocalin-type PGD synthase is localized in the central nervous system and male genital organs of various mammals and the human heart and is secreted into cerebrospinal fluid, seminal plasma, and plasma, respectively. while lipocalin-type PGDS (L-PGDS) is mostly expressed in the central nervous system. L-PGDS expression is induced by laminar sheer stress in vascular endothelial cells and is actively expressed in synthetic smooth muscle cells of atherosclerotic intima and coronary plaques of arteries with severe stenosis.47,51,52
It acts on 2 types of receptors. So, PGD2 action is mediated by both DP1 and DP2/CRTH2 receptors. D prostanoid receptor (DP) is a classic PGD2 receptor also known as PTGDR or DP112,13; the second is chemoattractant receptor-homologous molecule expressed on Th2 (CRTH2), also known as DP2. These receptors are GPCR. DP1 is coupled to Gs protein, that elevates the levels of cAMP. DP2 is coupled to Gi protein, that increase concentration of calcium and decrease in cAMP. Both receptors binding to PGD2 have high affinity.
PGD2 is major eicosanoid that is synthesized in CNS and peripheral tissues.
CNS:- It plays an important role in regulation of sleep. In peripheral tissues, it is produced mainly by mast cells and leukocytes, resulting in activating many signaling pathways leaving to different effects. It is also resulting in atherosclerosis. It results in modulating physiology of airways by causing bronchoconstriction, vasodilation, increased capillary permeability and mucous production. PGD2 and its metabolites play crucial role in leukocyte biology, acting via several different signaling mechanisms to play pro and anti inflammatory role.PGD2 can influence multiple stages in the life of the mature eosinophil, from causing its release from the bone marrow to inducing its recruitment and activation and, ultimately, regulating its apoptosis.
Abnormal PG production or disrupted signaling cascade leading to PG release by the epithelium has been recognized as one of the important causes underlying many disease processes with smooth muscle disorders, such as asthma, overactive bladder, dyspepsia, and dysmenorrhea. Other disease processes are irritable bowel syndrome or inflammatory bowel disease and infertility.
Treatment strategies are aimed to provide exogenous source of prostaglandins or to suppress endogenous PG production.
Prostaglandins are potent bioactive lipid messengers synthesized from arachidonic acid mediated by enzyme COX.Arachidonic acid is derived from membreane phospholipids catalyzed by PLA2.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. Several types of prostaglandins like PGD2, PGE2, PGF2, PGI2 are present. Abnormal PG production or disrupted signaling cascade leading to PG release by the epithelium has been recognized as one of the important causes underlying many disease processes with smooth muscle disorders, such as asthma, overactive bladder, dyspepsia, and dysmenorrhea. Other disease processes are irritable bowel syndrome or inflammatory bowel disease and infertility.
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