Lehnart SE, Wehrens XH, Reiken S, Warrier S, Belevych AE, Harvey RD, Richter W, Jin SL, Conti M, Marks AR. Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Cell. 2005 Oct 7;123(1):25-35. PubMed.
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Columbia University
There is clear evidence that inhibition of PDE4 by the drug rolipram can improve memory in aged mice (Barad et al., 1998) and block the development of learning and memory defects in mouse models of Alzheimer disease (Gong et al., 2004). Because rolipram induces emesis in a dose-dependent manner, it has not been tested in human AD at this point, though it is possible that the therapeutic dose might be lower than the emesis-inducing dose. There has been a concerted effort by at least two companies to develop PDE4 inhibitors that enter the brain and are free of this side effect. A range of PDE4 inhibitors that do not gain ready access to the brain are currently marketed for pulmonary disease.
PDE4 is a critical enzyme in cAMP-induced signaling via protein kinase A (PKA). PKA, in turn, is a regulator in a number of physiological processes, including the phosphorylation of CREB and the storage of memory. It is inevitable that there will be side effects or unforeseen consequences whenever a regulatory molecule that serves multiple roles in inhibited. It has been known for many years that PDE inhibition can have adverse effects in acute cardiac disease (Packer et. al., 1991).
The paper by Lehnart et al. that appeared this past week reinforces the concerns of Packer. Specifically, this paper shows that the PDE4B null mouse develops cardiomyopathy and cardiac failure associated with myocardial infarction and arrhythmias. The researchers show that this is due to defective function of the ryanodine RyR2 channels and suggest that similar malfunction can occur after long-term PDE4 inhibition if PDE4 inhibitors were to be used in AD.
This is a realistic concern, but not sufficient to make trials of such agents unwise. The Lehnart study is on null animals that completely lack PDE4B. It is not clear that partial inhibition of the enzyme would cause the same effect. The studies of Packer were in patients already in failure and it is not clear that PDE4 inhibitors at therapeutic doses have adverse effects on the normal heart. These results do underline the importance of carefully scrutinizing cardiac toxicity in studies of drugs of this class. Our studies (Gong et al., 2004) suggest that continual administration of rolipram might not be necessary and that the drug could be given episodically with “drug holidays” between periods of administration. Alterations of route or form of administration might also evade cardiotoxicity if it were to occur.
Our approach during the past year has been to concentrate on the regulation of downstream elements of the memory storage pathway in order to identify targets that might be as or more effective than the activation of PKA by cyclic AMP. Studies that are currently being completed suggest that there may be other steps in this pathway that can block memory damage by Aβ and restore dendritic structure to control levels as effectively as rolipram.
The publication online by Henning and Selkoe, 2005, gives another example of the “law of unintended consequences." It raises the possibility that angiotensin converting enzyme (ACE) inhibitors such as Captopril that are widely used in the treatment of hypertension could favor elevated levels of Aβ in the brain by inhibiting Aβ clearance as the result of cleavage of the peptide by ACE. Careful epidemiologic studies will be required to determine if these inhibitors increase the risk of AD and, if so, by how much.
Both these studies are valuable contributions to the literature. They underline the problem that we are likely to face as we try to treat the multiple diseases of our aging population.
References:
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. 1998 Dec 8;95(25):15020-5. PubMed.
Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest. 2004 Dec;114(11):1624-34. PubMed.
Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. 1991 Nov 21;325(21):1468-75. PubMed.
Hemming ML, Selkoe DJ. Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem. 2005 Nov 11;280(45):37644-50. PubMed.
Bay pines VA Health care system
In the past few years there has been increasing interest in the therapeutic use of PDE4 inhibitors in the treatment of several pathological conditions including Alzheimer disease. More than 11 different families of PDE have been described, including the brain-localized PDE 1, 2, 4, and 5. The cAMP-specific PDE4 was identified more than 20 years ago and comes in 4 isoforms, A, B, C, and D. PDE 4 inhibitors such as rolipram have proven to be effective in animal models in reducing the clinical manifestations of conditions such as experimental autoimmune encephalomyelitis (EAE) and Alzheimer disease (Gong et al, 2004).
This article by Andrew Marks, first author Stephan Lehnart, and colleagues shows that the genetic deletion of PDE4D in mouse induced progressive cardiomyopathy and cardiac arrhythmias. These effects were not caused by a global increase of cAMP levels, but instead by a dysfunction of the cardiac RYR2/calcium release channel complex required for excitation-contraction coupling in heart muscle. The dysfunction of RYR2 receptor seems to be due to the PKA-dependent hyperphosphorylation of the RYR2 channels because of a local increase of cAMP.
This finding highlights the importance of an adequate characterization of the systemic effects of the inhibition of specific PDE isoforms. Based on this knowledge, it should be possible to generate PDE inhibitors more specific for PDE isoforms that could increase the cAMP levels in the brain without inducing the known side effects of some of these drugs or provoking the appearance of pathological conditions (Ke, H, 2004).
Another aspect that also needs to be considered is the possibility that an abnormal activation of the PKA-CREB pathway may not always have positive effects, as it is feasible that the overstimulation of this signaling pathway may induce the synaptic deficits observed in Alzheimer disease (Echeverria et al. 2005).
References:
Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest. 2004 Dec;114(11):1624-34. PubMed.
Ke H. Implications of PDE4 structure on inhibitor selectivity across PDE families. Int J Impot Res. 2004 Jun;16 Suppl 1:S24-7. PubMed.
Echeverria V, Ducatenzeiler A, Chen CH, Cuello AC. Endogenous beta-amyloid peptide synthesis modulates cAMP response element-regulated gene expression in PC12 cells. Neuroscience. 2005;135(4):1193-202. PubMed.
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