Phosphodiesterase-4 inhibitor

Rolipram, the prototypical PDE4 inhibitor

A phosphodiesterase-4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.[1]

Therapeutic utility

The prototypical PDE4 inhibitor is rolipram. PDE4 inhibitors are known to possess procognitive (including long term memory-improving),[2] wakefulness-promoting,[3] neuroprotective,[4][5] and anti-inflammatory effects.[6] Consequently, PDE4 inhibitors have been investigated as treatments for a diverse group of different diseases, including central nervous system disorders such as major depressive disorder (clinical depression), anxiety disorders, schizophrenia,[7][8] Parkinson's disease,[9] Alzheimer's disease,[10] multiple sclerosis,[11] attention deficit-hyperactivity disorder, Huntington's disease, stroke, autism and inflammatory conditions such as chronic obstructive pulmonary disease (COPD), asthma and rheumatoid arthritis.[12][13][14]

PDE4D inhibition, along with PDE4A inhibition also appears to be responsible for the antidepressant effects of PDE4 inhibitors.[14] Similarly PDE4B inhibition appears to be required for the antipsychotic effects of PDE4 inhibitors,[13] in line with this view PDE4B polymorphisms and altered gene expression in the central nervous system have been associated with schizophrenia and bipolar disorder in a postmortem study.[15] PDE4 also regulates the D1/PKA/DARPP-32 signalling cascade in the frontal cortex, which may contribute to the antipsychotic and procognitive effects of PDE4 inhibitors.[16] Whereas PDE4C is expressed primarily in the periphery and hence may be partly responsible for the peripheral effects of PDE4 inhibitors (e.g. their anti-inflammatory effects).[14] PDE4 inhibition is also known to attenuate ethanol seeking and consumption in rats,[17] hence suggesting its possible utility in the treatment of alcohol dependence. Indeed, one experiment has found that intake of a PDE4 oral medication for psoriasis has significantly reduced alcohol consumption in serious human drinkers compared with those taking the placebo.[18] A few different lines of evidence suggests the therapeutic utility in the treatment of brain tumours.[19]

The clinical development of PDE4 inhibitors has been hampered by their potent emetic effects, which appear to be related to their inhibition of PDE4D which is expressed in the area postrema.[14]

Adverse reactions

Nausea, vomiting, and related general gastrointestinal side effects are the most commonly implicated side effects of PDE4 inhibitors. Other possible side effects include respiratory and urinary tract infections, which have been discovered from the clinical use of roflumilast.[20]

Examples

  • Apremilast, a phthalimide derivative that was approved by the U.S. FDA in March 2014 for use as a treatment for psoriatic arthritis,[21] and in September 2014 for the treatment of plaque psoriasis under the brand name Otezla.[22]
  • Cilomilast, in clinical development by GlaxoSmithKline for treatment of COPD.[23]
  • Crisaborole (AN2728), a boron-containing drug for the topical treatment of psoriasis and atopic dermatitis.[24][25][26] It was approved by the FDA on December 14, 2016 under the brand name Eucrisa for the treatment of mild-to-moderate atopic dermatitis (eczema) in patients 2 years of age and older.[27]
  • Diazepam, a benzodiazepine anxiolytic, amnesic, hypnotic, sedative and muscle relaxant.[28]
  • Ibudilast, a neuroprotective and bronchodilator drug used mainly in the treatment of asthma and stroke. It inhibits PDE4 to the greatest extent, but also shows significant inhibition of other PDE subtypes, and so acts as a selective PDE4 inhibitor or a non-selective phosphodiesterase inhibitor, depending on the dose.
  • Luteolin, supplement extracted from peanuts and other plants that also possesses IGF-1 properties.[29]
  • Mesembrenone, an alkaloid from the herb Sceletium tortuosum (Kanna).
  • Piclamilast, a more potent inhibitor than rolipram.[30]
  • Roflumilast, licensed for the treatment of severe chronic obstructive pulmonary disease in the EU, Russia and U.S. by Merck & Co. under the trade names Daxas[20] and Daliresp.
  • Rolipram, used as investigative tool in pharmacological research.

Mode of action

PDE4 hydrolyzes cyclic adenosine monophosphate (cAMP) to inactive adenosine monophosphate (AMP). Inhibition of PDE4 blocks hydrolysis of cAMP, thereby increasing levels of cAMP within cells.

See also

References

  1. ↑ Spina, D (2008). "PDE4 inhibitors: current status". British Journal of Pharmacology. 155 (3): 308–315. doi:10.1038/bjp.2008.307. PMC 2567892. PMID 18660825.
  2. ↑ Barad M, Bourtchouladze R, Winder DG, Golan H, Kandel E (1998). "Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory". Proceedings of the National Academy of Sciences of the United States of America. 95 (25): 15020–5. doi:10.1073/pnas.95.25.15020. PMC 24568. PMID 9844008.
  3. ↑ Lelkes Z, Alföldi P, Erdos A, Benedek G (1998). "Rolipram, an antidepressant that increases the availability of cAMP, transiently enhances wakefulness in rats". Pharmacology Biochemistry and Behavior. 60 (4): 835–9. doi:10.1016/S0091-3057(98)00038-0. PMID 9700966. S2CID 37020086.
  4. ↑ Block F, Schmidt W, Nolden-Koch M, Schwarz M (2001). "Rolipram reduces excitotoxic neuronal damage". NeuroReport. 12 (7): 1507–11. doi:10.1097/00001756-200105250-00041. PMID 11388438. S2CID 2768440.
  5. ↑ Chen RW, Williams AJ, Liao Z, Yao C, Tortella FC, Dave JR (2007). "Broad spectrum neuroprotection profile of phosphodiesterase inhibitors as related to modulation of cell-cycle elements and caspase-3 activation". Neuroscience Letters. 418 (2): 165–9. doi:10.1016/j.neulet.2007.03.033. PMID 17398001. S2CID 25453633.
  6. ↑ "Intracellular Mechanisms of Inflammation:PDE4 Promotes the Release of Proinflammatory Mediators". Celgene Corporation. 2012. Retrieved 2012-07-24.
  7. ↑ Maxwell CR, Kanes SJ, Abel T, Siegel SJ (2004). "Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications". Neuroscience. 129 (1): 101–7. doi:10.1016/j.neuroscience.2004.07.038. PMID 15489033. S2CID 19578277.
  8. ↑ Kanes SJ, Tokarczyk J, Siegel SJ, Bilker W, Abel T, Kelly MP (2006). "Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity". Neuroscience. 144 (1): 239–246. doi:10.1016/j.neuroscience.2006.09.026. PMC 3313447. PMID 17081698.
  9. ↑ Beal, MF; Cleren, C; Calingasan, NY; Yang, L; Klivenyi, P; Lorenzl, S (2005). "Oxidative Damage in Parkinson's Disease". U.S. Army Medical Research and Material Command Fort Detrick, Maryland 21702-5012.
  10. ↑ Smith, DL; Pozueta, J; Gong, B; Arancio, O; Shelanski, M (September 2009). "Reversal of long-term dendritic spine alterations in Alzheimer disease models". Proceedings of the National Academy of Sciences of the United States of America. 106 (39): 16877–16882. doi:10.1073/pnas.0908706106. PMC 2743726. PMID 19805389.
  11. ↑ Dinter, H (February 2000). "Phosphodiesterase type 4 inhibitors: potential in the treatment of multiple sclerosis?". BioDrugs. 13 (2): 87–94. doi:10.2165/00063030-200013020-00002. PMID 18034515. S2CID 23444101.
  12. ↑ Dyke, HJ; Montana, JG (January 2002). "Update on the therapeutic potential of PDE4 inhibitors". Expert Opinion on Investigational Drugs. 11 (1): 1–13. doi:10.1517/13543784.11.1.1. PMID 11772317. S2CID 22623399.
  13. 1 2 Halene, TB; Siegel, SJ (October 2007). "PDE inhibitors in psychiatry – future options for dementia, depression and schizophrenia?". Drug Discovery Today. 12 (19–20): 870–878. doi:10.1016/j.drudis.2007.07.023. PMID 17933689.
  14. 1 2 3 4 Francis, SH; Conti, M; Houslay, MD, eds. (2011). Phosphodiesterases as Drug Targets (PDF). Handbook of Experimental Pharmacology. Vol. 204. Springer Berlin Heidelberg. doi:10.1007/978-3-642-17969-3. ISBN 978-3-642-17968-6.
  15. ↑ Fatemi, SH; King, DP; Reutiman, TJ; Folsom, TD; Laurence, JA; Lee, S; Fan, YT; Paciga, SA; Conti, M; Menniti, FS (April 2008). "PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia". Schizophrenia Research. 101 (1–3): 36–49. doi:10.1016/j.schres.2008.01.029. PMID 18394866. S2CID 32661995.
  16. ↑ Kuroiwa, M; Snyder, GL; Shuto, T; Fukuda, A; Yanagawa, Y; Benavides, DR; Nairn, AC; Bibb, JA; Greengard, P; Nishi, A (February 2012). "Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex". Psychopharmacology. 219 (4): 1065–1079. doi:10.1007/s00213-011-2436-8. PMC 3539205. PMID 21833500.
  17. ↑ Wen, RT; Zhang, M; Qin, WJ; Liu, Q; Wang, WP; Lawrence, AJ; Zhang, HT; Liang, JH (December 2012). "The Phosphodiesterase-4 (PDE4) Inhibitor Rolipram Decreases Ethanol Seeking and Consumption in Alcohol-Preferring Fawn-Hooded Rats". Alcoholism: Clinical and Experimental Research. 36 (12): 2157–2167. doi:10.1111/j.1530-0277.2012.01845.x. PMC 4335658. PMID 22671516.
  18. ↑ Wilson, C. (2021). Psoriasis drug may cut alcohol misuse. New Scientist, 250(3340), p.16
  19. ↑ Sengupta, R; Sun, T; Warrington, NM; Rubin, JB (June 2011). "Treating brain tumors with PDE4 inhibitors". Trends in Pharmacological Sciences. 32 (6): 337–344. doi:10.1016/j.tips.2011.02.015. PMC 3106141. PMID 21450351.
  20. 1 2 "DALIRESP (roflumilast) tablet [Forest Laboratories, Inc.]". DailyMed. Forest Laboratories, Inc. August 2013. Retrieved 13 November 2013.
  21. ↑ Brooks, M (21 March 2014). "FDA Clears Apremilast (Otezla) for Psoriatic Arthritis". Medscape Medical News. WebMD. Retrieved 28 March 2014.
  22. ↑ Lowes, R (23 September 2014). "FDA Approves Apremilast (Otezla) for Plaque Psoriasis". Medscape Medical News. WebMD. Retrieved 13 October 2014.
  23. ↑ Rennard, S; Knobil, K; Rabe, KF; Morris, A; Schachter, N; Locantore, N; Canonica, WG; Zhu, Y; Barnhart, F (2008). "The efficacy and safety of cilomilast in COPD". Drugs. 68 (Suppl 2): 3–57. doi:10.2165/0003495-200868002-00002. PMID 19105585. S2CID 2216800.
  24. ↑ Anacor AN2728 at Anacor website Page accessed May 15, 2015
  25. ↑ Nazarian, R; Weinberg, JM (November 2009). "AN-2728, a PDE4 Inhibitor for the Potential Topical Treatment of Psoriasis and Atopic Dermatitis". Current Opinion in Investigational Drugs. 10 (11): 1236–42. PMID 19876791.
  26. ↑ Moustafa, F; Feldman, SR (16 May 2014). "A Review of Phosphodiesterase-Inhibition and the Potential Role for Phosphodiesterase 4-Inhibitors in Clinical Dermatology" (PDF). Dermatology Online Journal. 20 (5): 22608. doi:10.5070/D3205022608. PMID 24852768.
  27. ↑ "FDA Approves Eucrisa for Eczema". U.S. Food and Drug Administration. 14 December 2016.
  28. ↑ Collado, M. C.; Beleta, J.; Martinez, E.; Miralpeix, M.; Domènech, T.; Palacios, J. M.; Hernández, J. (1998). "Functional and biochemical evidence for diazepam as a cyclic nucleotide phosphodiesterase type 4 inhibitor". British Journal of Pharmacology. 123 (6): 1047–1054. doi:10.1038/sj.bjp.0701698. PMC 1565256. PMID 9559885.
  29. ↑ Yu, M. C.; Chen, J. H.; Lai, C. Y.; Han, C. Y.; Ko, W. C. (2009). "Luteolin, a non-selective competitive inhibitor of phosphodiesterases 1-5, displaced [(3)H]-rolipram from high-affinity rolipram binding sites and reversed xylazine/ketamine-induced anesthesia". European Journal of Pharmacology. 627 (1–3): 269–275. doi:10.1016/j.ejphar.2009.10.031. PMID 19853596.
  30. ↑ de Visser, Y. P.; Walther, F. J.; Laghmani E. H.; van Wijngaarden, S.; Nieuwland, K.; Wagenaar, G. T. (2008). "Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury". European Respiratory Journal. 31 (3): 633–644. doi:10.1183/09031936.00071307. PMID 18094015.
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