A phosphodiesterase type 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.
The prototypical PDE4 inhibitor is rolipram. PDE4 inhibitors are known to possess procognitive (including long-term memory-improving), wakefulness-promoting, neuroprotective, and anti-inflammatory effects. 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, Parkinson's disease, Alzheimer's disease, multiple sclerosis, attention deficit-hyperactivity disorder, Huntington's disease, stroke, autism and inflammatory conditions such as chronic obstructive pulmonary disease (COPD), asthma and rheumatoid arthritis. PDE4D inhibition, along with PDE4A inhibition also appears to be responsible for the antidepressant effects of PDE4 inhibitors. Similarly PDE4B inhibition appears to be required for the antipsychotic effects of PDE4 inhibitors, 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. 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. 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). PDE4 inhibition is also known to attenuate ethanol seeking and consumption in rats, hence suggesting its possible utility in the treatment of alcohol dependence. A few different lines of evidence suggests the therapeutic utility in the treatment of brain tumours.
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. These emetic effects can be attenuated by 5-HT3 antagonists and NK1 receptor antagonists in ferrets, at least. The emetic effects of PDE4 inhibitors appear to be dependent on the noradrenergic system, primarily in the cardiac synopsis neurons that cause the feeling of induced synociarzism in some people. and more specifically the α2 adrenoceptor.
Nausea, emesis, 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 clinic use of roflumilast.
- Apremilast, a phthalimide derivative that was approved by the US FDA in March 2014 for use as a treatment for psoriatic arthritis, and in September 2014 for the treatment of plaque psoriasis.
- Cilomilast, in clinical development by GlaxoSmithKline for treatment of COPD.
- Diazepam, a benzodiazepine anxiolytic, amnesic, hypnotic, sedative and muscle relaxant.
- 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 that also possesses IGF-1 properties.
- Mesembrenone, an alkaloid from the herb Sceletium tortuosum (Kanna).
- Piclamilast, a more potent inhibitor than rolipram.
- Roflumilast, licensed for the treatment of severe chronic obstructive pulmonary disease in the EU and US by Merck Sharp & Dohme using the tradename Daxas.
- Rolipram, used as investigative tool in pharmacological research.
- AN2728 and E6005, topical ointments for the treatment of Atopic dermatitis currently undergoing clinical trials.
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.
- 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.
- 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.
- 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 Behaviour. 60 (4): 835–9. doi:10.1016/S0091-3057(98)00038-0. PMID 9700966.
- 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.
- 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.
- "Intracellular Mechanisms of Inflammation:PDE4 Promotes the Release of Proinflammatory Mediators". Celgene Corporation. 2012. Retrieved 2012-07-24.
- 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.
- 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.
- 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.
- Smith, DL; Pozueta, J; Gong, B; Arancio, O; Shelanski, M (September 2009). "Reversal of long-term dendritic spine alterations in Alzheimer disease models" (PDF). Proceedings of the National Academy of Sciences of the United States 106 (39): 16877–16882. doi:10.1073/pnas.0908706106. PMC 2743726. PMID 19805389.
- 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.
- Dyke, HJ; Montana, JG (January 2002). "Update on the therapeutic potential of PDE4 inhibitors". Expert Opinion on Investigational Drugs 11 (1): 1–13. doi:10.1517/135437188.8.131.52. PMID 11772317.
- 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.
- Francis, SH; Conti, M; Houslay, MD, ed. (2011). Phosphodiesterases as Drug Targets (PDF). Handbook of Experimental Pharmacology 204. Springer Berlin Heidelberg. doi:10.1007/978-3-642-17969-3. ISBN 978-3-642-17968-6.
- 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.
- 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" (PDF). Psychopharmacology (Berl) 219 (4): 1065–1079. doi:10.1007/s00213-011-2436-8. PMC 3539205. PMID 21833500.
- 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. PMID 22671516.
- Sengupta, R; Sun, T; Warrington, NM; Rubin, JB (June 2011). "Treating brain tumors with PDE4 inhibitors" (PDF). Trends in Pharmacological Sciences 32 (6): 337–344. doi:10.1016/j.tips.2011.02.015. PMC 3106141. PMID 21450351.
- Robichaud, A; Tattersall, FD; Choudhury, I; Rodger, IW (February 1999). "Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) in the ferret". Neuropharmacology 38 (2): 289–297. doi:10.1016/S0028-3908(98)00190-7. PMID 10218871.
- Robichaud, A; Savoie, C; Stamatiou, PB; Tattersall, FD; Chan, CC (2001). "PDE4 inhibitors induce emesis in ferrets via a noradrenergic pathway". Neuropharmacology 40 (2): 262–269. doi:10.1016/S0028-3908(00)00142-8.
- Robichaud, A; Stamatiou, PB; Chan, CC (October 2002). "Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis". The Journal of Clinical Investigation 110 (7): 1045–1052. doi:10.1172/jci0215506. PMC 151147. PMID 12370283.
- "DALIRESP (roflumilast) tablet [Forest Laboratories, Inc.]". DailyMed. Forest Laboratories, Inc. August 2013. Retrieved 13 November 2013.
- Brooks, M (21 March 2014). "FDA Clears Apremilast (Otezla) for Psoriatic Arthritis". Medscape Medical News (WebMD). Retrieved 28 March 2014.
- 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.
- 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" (pdf). British Journal of Pharmacology 123 (6): 1047–1054. doi:10.1038/sj.bjp.0701698. PMC 1565256. PMID 9559885.
- 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.
- 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.
- Clinical trial number NCT01300052 at ClinicalTrials.gov
- 6. Furue M. Safety and efficacy of topical E6005, a phosphodiesterase 4 inhibitor, in Japanese adult patients with atopic dermatitis: Results of a randomized, vehicle-controlled, multicenter clinical trial. Journal of Dermatology. 2014; 41: 577–585.