Sunday, 14 July 2013

PDE4 inhibitors and their potential applications in the treatment of a variety of conditions

Note: Terms that are not explained in the body are explained in a Glossary near the end (before the references) of the post.

The enzyme phosphodiesterase 4 (PDE4) is an emerging drug target in the management of psychiatric, neurologic, immune and inflammatory disorders such as major depressive disorder1 (MDD), schizophrenia1, Alzheimer’s disease1 (AD), chronic obstructive pulmonary disease2 (COPD) and multiple sclerosis (MS). The drugs being developed to target PDE4 all inhibit the aforementioned enzyme – that is they reduce the activity of the PDE4 and this is how they elicit their therapeutic effects. These drugs are called the PDE4 inhibitors. In order to explain just how PDE4 inhibition leaves these drugs open to being used in the management of the aforementioned conditions I need to first explain the role of PDE4 in cells.

PDE4 belongs to a group of enzymes called the cyclic nucleotide phosphodiesterases which catalyse (or help) the reactions involved in the breakdown of cyclic nucleotides, which includes two chemical messengers that are of particular biologic significance – cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). These messengers are also referred to as second messengers. This is because when some G protein-coupled receptors (GPCRs; which are usually expressed on a cell’s surface) are activated these second messengers relay their respective signals to the inner components of the cell. Hence drugs that inhibit cyclic nucleotide phosphodiesterases are able to produce many of the same effects as drugs that directly interact with these G protein-coupled receptors on the cell surface. Not all GPCRs transmit their signals by increasing intracellular (inside the cell) concentrations of cyclic nucleotides, some, upon activation, decrease intracellular cyclic nucleotide concentrations and these receptors include, among numerous others, the dopamine, D2, family of receptors (D2, D3, D4).1

The different phosphodiesterases, however, do have different respective affinities towards the different cyclic nucleotides and hence the cyclic nucleotide(s) that PDE4 prefers to (or has a higher affinity to) degrade is relevant and is cAMP. Hence PDE4 inhibitors increase intracellular cAMP levels and since PDE4 is found in virtually every organ system of the body it increases intracellular cAMP levels throughout the body.1

The interesting thing about PDE4 inhibitors is that they also elicit very potent anti-inflammatory effects and they also elicit antidepressant effects, which would appear to be in agreement with the inflammatory hypothesis of depression. Although this could very easily a coincidence seeing how cAMP is a very common second messenger throughout the body and it is well known that serotonin is heavily involved in mood regulation, as is glutamate (I know this one is a lesser known neurotransmitter as far as its role in depression but ketamine, the anaesthetic turned rapid-acting and robust antidepressant acts on the glutamate receptors to elicit its effects and hence this is also a popular theory for the cause of depression) and norepinephrine (noradrenaline) and a few of the receptors for all three of these neurotransmitters use cAMP as their second messengers and hence by inhibiting PDE4 and raising cAMP levels it is entirely possible that it mimics the effects of those these neurotransmitters in the central nervous system (CNS).

Another thing that PDE4 inhibitors do that they share with all other antidepressants is that they promote neurogenesis and exert neuroprotective effects – that is, they induce the formation of new neurons and have protective effects on existing neurons, respectively. They also seem to induce long-term potentiation, the process by which the signalling between two neurons is enhanced in a long-lasting fashion.

PDE4 inhibitors also possess antipsychotic activity which may be related to the fact that the D2 family of receptors – which thing all antipsychotics in clinical use block – are G­i/o protein-coupled and hence inhibit the formation of cAMP. Hence by blocking them antipsychotics increase cAMP synthesis in cells that express the D2 family of receptors. Plus they also appear to interact with the metabotropic glutamate receptors which regulate the release of the neurotransmitter glutamate, which also appears to play a key role in schizophrenia. In fact until mid-last year it appeared that soon a drug that directly acted on two types of metabotropic glutamate receptor (mGluR 2 and 3) would soon be FDA approved for the treatment of schizophrenia as it showed promise in early clinical testing in the treatment of this indication. The serotonin 5-HT1A receptor has also been found to be involved in the antipsychotic action of some TGA and FDA approved antipsychotics and it also couples to a Gi/o protein.5-6

Currently there is only one PDE4 inhibitor that has received FDA and TGA approval – Roflumilast. It received TGA approval in November 2011 (see http://www.tga.gov.au/pdf/auspar/auspar-daxas.pdf for details) for the treatment of severe COPD, specifically chronic bronchitis. Roflumilast is, from what I have read on Micromedex, a rather well-tolerated drug, that is, its side effects are rather mild and rare, for the most part at least (it has been found to cause suicidal ideation – thinking about suicide – which is its only particularly worrying side effect). According to Micromedex aside from suicidal ideation it has the following side effects:7
  • weight decreased (7% to 20% ) 
  • Decrease in appetite (2.1% ) 
  • Diarrhoea (9.5% ) 
  • Nausea (4.7% ) 
  • Influenza (2.8% ) 
  • Backache (3.2% ) 
  • Dizziness (2.1% ) 
  • Headache (4.4% ) 
  • Insomnia (2.4% )
(with their respective incidence in brackets)
The side effect of influenza is particularly worrying to me, considering the fact that patients with COPD are particularly vulnerable to respiratory infections like influenza. It is also interesting because PDE4 inhibitors have also been found to reduce innate immunity – the first line of the body’s immune defences where the second-line is the more specific (to the microbe, that is) line of immunity, which also recognises prior bugs encountered by the body’s defenses8-10 which would explain an increased susceptibility of PDE4 inhibitor-treated individuals to common infections such as the flu.

Most of the original PDE4 inhibitors to be developed, such as rolipram, had one side effect in particular that limited their clinical utility – severe emesis. Despite this side effect it turns out that some South African individuals have been using a PDE4 inhibitor-containing plant for its antidepressant effects for centuries – the kanna plant. This plant contains mesembrenone, among other alkaloids which display PDE4 inhibitory effects.

Glossary

Central Nervous System (CNS) – the brain and spinal cord.
Chronic Obstructive Pulmonary Disease (COPD) – a collection of progressive, disabling, incurable and often, with time, fatal lung diseases that cause a progressive deterioration in lung function. They include emphysema, chronic bronchitis and even some cases of asthma. They are normally associated with smoking.  
Emesis – nausea and vomiting.
Endogenous Ligand – a ligand for a particular receptor
Enzyme – an enzyme is a chemical catalyst in reactions, that is, they serve to increase the rate of a chemical reaction despite not being directly involved in the reaction. By directly it is meant that the enzyme is not transformed by the chemical reaction, or used up by the reaction.
Extracellular – outside cells.
Intracellular – inside cells.
Ligand – a compound that binds to its respective receptor (for which it is a ligand). Agonists are a type of ligand that activate the receptor whereas antagonists do not activate the receptor but rather prevent agonists from activating the receptor.
Neuron – electrically-signalling cells of the brain, spinal cord and nerves.
Receptor – receptors are proteins that, upon the binding of an agonist, cause the modulation of cellular functions. G protein-coupled receptors (GPCR) are receptors that are bound to G proteins, which in turn, upon binding by an agonist to the receptor, set off a series of chemical reactions that alter the functioning of a cell. The Gi/o protein is a G protein that when the receptor it is coupled with is activated (and hence it is too as this is the purpose of coupling between receptor and G proteins) it inhibits adenylate cyclase – the enzyme responsible for the formation of cAMP, from the energy source of cells, adenosine triphosphate (ATP). Likewise the Gs protein is a G protein that enhances adenylate cyclase activity upon its activation.

Reference List

  1. Halene TB, Siegel SJ. PDE inhibitors in psychiatry – future options for dementia, depression and schizophrenia? Drug Discovery Today [Internet]. 2007 Oct [cited 2013 Jul 12];12(19–20):870–8. Available from: http://www.sciencedirect.com/science/article/pii/S1359644607003066
  2. Spina D. PDE4 inhibitors: current status. Br J Pharmacol [Internet]. 2008 Oct [cited 2013 Jul 12];155(3):308–15. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567892/
  3. Boswell-Smith V, Spina D, Page CP. Phosphodiesterase inhibitors. Br J Pharmacol [Internet]. 2006 Jan [cited 2013 Jul 12];147(Suppl 1):S252–S257. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760738/
  4. Barad M, Bourtchouladze R, Winder DG, Golan H, Kandel E. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proc Natl Acad Sci U S A [Internet]. 1998 Dec 8 [cited 2013 Jul 12];95(25):15020–5. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC24568/
  5. Bantick RA, Deakin JFW, Grasby PM. The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics? J Psychopharmacol [Internet]. 2001 Jan 1 [cited 2013 Jul 14];15(1):37–46. Available from: http://jop.sagepub.com/content/15/1/37
  6. Ohno Y. Therapeutic Role of 5-HT1A Receptors in The Treatment of Schizophrenia and Parkinson’s Disease. CNS Neuroscience & Therapeutics [Internet]. 2011 [cited 2013 Jul 14];17(1):58–65. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1755-5949.2010.00211.x/abstract
  7. Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Jul 14]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  8. Koo M-S, Manca C, Yang G, O’Brien P, Sung N, Tsenova L, et al. Phosphodiesterase 4 Inhibition Reduces Innate Immunity and Improves Isoniazid Clearance of Mycobacterium tuberculosis in the Lungs of Infected Mice. PLoS ONE [Internet]. 2011 Feb 25 [cited 2013 Jul 14];6(2):e17091. Available from: http://dx.doi.org/10.1371/journal.pone.0017091
  9. Sadrai Z, Stevenson W, Okanobo A, Chen Y, Dohlman TH, Hua J, et al. PDE4 Inhibition Suppresses IL-17–Associated Immunity in Dry Eye Disease. IOVS [Internet]. 2012 Jun 1 [cited 2013 Jul 14];53(7):3584–91. Available from: http://www.iovs.org/content/53/7/3584
  10. Serezani CH, Ballinger MN, Aronoff DM, Peters-Golden M. Cyclic AMP. Am J Respir Cell Mol Biol [Internet]. 2008 Aug [cited 2013 Jul 14];39(2):127–32. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720142/

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