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prostaglandin E2 (PGE2, dinoprostone, Prepidil, Cervidil)

Pharmacology: dinoprostone Tradenames: Prepidil, Cervidil Indications: 1) cervical gel: a) to facilitate maturation of cervix in pregnant women at or near term (cervical ripening) b) induction of labor [4] 2) suppositories: a) to terminate pregnancy from 12th through 28th week of gestation b) to evacuate uterus in cases of missed abortion or intra- uterine fetal death c) management of benign hydatidiform mole Adverse effects: 1) common (> 10%) - nausea/vomiting - diarrhea - headache 2) less common (1-10%) - fever, back pain, bradycardia, uterine hyperstimulation 3) uncommon (< 1%) - hypotension, cardiac arrhythmias, bronchospasm, vasomotor & vasovagal reactions, dizziness, syncope, flushing, hot flashes, wheezing, dyspnea, pain & tightness of chest, cough, chills, shivering Mechanism of action: 1) fever: a) PGE2 may be most important hypothalamic prostaglandin involved in eliciting fever b) naproxen may be most effective NSAID at reducing hypothalamic PGE2 formation 2) mast cell activation: - PGE2 may protect against mast cell release 3) long-term potentiation (LTP) - mediates COX-2 regulation of synaptic plasticity in hippocampal perforant path-dentate gyrus synapses [3] Comparative biology: - in brain macrophages, PGE2 levels rise with aging in mice [5]* - increase in PGE2 promotes sequestration of glucose into glycogen, reducing glucose flux & mitochondrial respiration. - leads to neuroinflammation & cognitive decline - inhibiting effect of PGE2 by either genetic or pharmacologic reverses brain dysfunction: - synaptic proteins rise, mitochondrial function improves, neuroinflammation is reduced, & spatial memory deficits are reversed [5] - PGE2 stimulates muscle stem cells & helps repair muscle damage [6]* - during aging, activity of 15-PGDH that degrades PGE2 progressively increases in muscle macrophages - inhibiting macrophage 15-PGDH activity in older mice, by either genetic or pharmacologic interventions, raises levels of PGE2 & restores aged muscle, functionally & anatomically similar to muscle of young mice [6] * contrast effects of macrophage PGE2 in aging brain vs aging muscle

Interactions

molecular events

Related

arachidonate cyclooxygenase cascade fever naproxen (Naprosyn, Aleve Anaprox) prostaglandin E2 receptor EP2 subtype; prostanoid EP2 receptor; PGE receptor, EP2 subtype (PTGER2) prostaglandin E2 receptor EP3 subtype; PGE receptor, EP3 subtype; PGE2-R; prostanoid EP3 receptor (PTGER3)

General

arachidonate; arachidonic acid [C20:4w6, ARA] prostaglandin E

Properties

SIZE: MW = 304.5 G/MOL COMPARTMENT: membrane MISC-INFO: elimination route LIVER KIDNEY pregnancy-category C

Database Correlations

PUBCHEM correlations

References

  1. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
  3. Chen C et al, J Neurophysiol 87:2851, 2002
  4. Deprecated Reference
  5. Minhas PS, Latif-Hernandez A, McReynolds MR et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature 2021 Feb; 590:122 PMID: 33473210 https://www.nature.com/articles/s41586-020-03160-0
  6. Palla AR, Ravichandran M, Wang YX et al. Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength. Science 2021 Jan 29; 371:eabc8059 PMID: 33303683 https://science.sciencemag.org/content/371/6528/eabc8059