835
Views
97
CrossRef citations to date
0
Altmetric
Reviews

PDE4 as a target for cognition enhancement

, , &
Pages 1011-1027 | Published online: 25 Jul 2013

Bibliography

  • Buccafusco JJ. Emerging cognitive enhancing drugs. Expert Opin Emerg Drugs 2009;14:577-89
  • Plath N, Lerdrup L, Larsen PH, et al. Can small molecules provide truly effective enhancement of cognition? Current achievements and future directions. Expert Opin Investig Drugs 2011;20:795-811
  • Blokland A, Menniti FS, Prickaerts J. PDE inhibition and cognition enhancement. Expert Opin Ther Pat 2012;22:349-54
  • Blokland A, Schreiber R, Prickaerts J. Improving memory: a role for phosphodiesterases. Curr Pharm Des 2006;12:2511-23
  • Ghavami A, Hirst WD, Novak TJ. Selective phosphodiesterase (PDE)-4 inhibitors: a novel approach to treating memory deficit? Drugs R D 2006;7:63-71
  • Kleppisch T. Phosphodiesterases in the central nervous system. Handb Exp Pharmacol 2009(191):71-92
  • Menniti FS, Faraci WS, Schmidt CJ. Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 2006;5:660-70
  • Xu Y, Zhang HT, O'Donnell JM. Phosphodiesterases in the central nervous system: implications in mood and cognitive disorders. Handb Exp Pharmacol 2011(204):447-85
  • Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 2007;76:481-511
  • Conti M, Richter W, Mehats C, et al. Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J Biol Chem 2003;278:5493-6
  • Rutten K, Prickaerts J, Hendrix M, et al. Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors. Eur J Pharmacol 2007;558:107-12
  • Davis RL, Cherry J, Dauwalder B, et al. The cyclic AMP system and Drosophila learning. Mol Cell Biochem 1995;149–150:271-8
  • Dudai Y, Jan YN, Byers D, et al. Dunce, a mutant of Drosophila deficient in learning. Proc Natl Acad Sci USA 1976;73:1684-8
  • Kauvar LM. Defective cyclic adenosine 3':5'-monophosphate phosphodiesterase in the Drosophila memory mutant dunce. J Neurosci 1982;2:1347-58
  • Wachtel H. Characteristic behavioural alterations in rats induced by rolipram and other selective adenosine cyclic 3', 5'-monophosphate phosphodiesterase inhibitors. Psychopharmacology (Berl) 1982;77:309-16
  • Wachtel H. Potential antidepressant activity of rolipram and other selective cyclic adenosine 3',5'-monophosphate phosphodiesterase inhibitors. Neuropharmacology 1983;22:267-72
  • Zeller E, Stief HJ, Pflug B, et al. Results of a phase II study of the antidepressant effect of rolipram. Pharmacopsychiatry 1984;17:188-90
  • Jin SLC, Richter W, Conti M. Insights into the physiological functions of PDE4 from knockout mice. In: Beavo J, Francis S, Houslay M, editors. Cyclic nucleotide phosphodiesterases in health and disease. CRC Press, Boca Raton; 2006. p. 323-46
  • Houslay MD. Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci 2010;35:91-100
  • Richter W, Conti M. Dimerization of the type 4 cAMP-specific phosphodiesterases is mediated by the upstream conserved regions (UCRs). J Biol Chem 2002;277:40212-21
  • Richter W, Conti M. The oligomerization state determines regulatory properties and inhibitor sensitivity of type 4 cAMP-specific phosphodiesterases. J Biol Chem 2004;279:30338-48
  • MacKenzie SJ, Baillie GS, McPhee I, et al. Long PDE4 cAMP specific phosphodiesterases are activated by protein kinase A-mediated phosphorylation of a single serine residue in Upstream Conserved Region 1 (UCR1). Br J Pharmacol 2002;136:421-33
  • Sette C, Conti M. Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase. Involvement of serine 54 in the enzyme activation. J.Biol.Chem 1996;271:16526-34
  • Bruss MD, Richter W, Horner K, et al. Critical role of PDE4D in beta2-adrenoceptor-dependent cAMP signaling in mouse embryonic fibroblasts. J Biol Chem 2008;283:22430-42
  • Sette C, Iona S, Conti M. The short-term activation of a rolipram-sensitive, cAMP-specific phosphodiesterase by thyroid-stimulating hormone in thyroid FRTL- 5 cells is mediated by a cAMP-dependent phosphorylation. J Biol.Chem 1994;269:9245-52
  • Grange M, Sette C, Cuomo M, et al. The cAMP-specific phosphodiesterase PDE4D3 is regulated by phosphatidic acid binding. Consequences for cAMP signaling pathway and characterization of a phosphatidic acid binding site. J Biol Chem 2000;275:33379-87
  • Grange M, Sette C, Prigent AF, et al. Regulation of cAMP-phosphodiesterases by phosphatidic acid binding. Lipids 1999;34(Suppl):S83
  • Baillie GS, MacKenzie SJ, McPhee I, et al. Sub-family selective actions in the ability of Erk2 MAP kinase to phosphorylate and regulate the activity of PDE4 cyclic AMP-specific phosphodiesterases. Br J Pharmacol 2000;131:811-19
  • Hoffmann R, Baillie GS, MacKenzie SJ, et al. The MAP kinase ERK2 inhibits the cyclic AMP-specific phosphodiesterase HSPDE4D3 by phosphorylating it at Ser579. Embo J 1999;18:893-903
  • Barad M, Bourtchouladze R, Winder DG, et al. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proc Natl Acad Sci USA 1998;95:15020-5
  • Burgin AB, Magnusson OT, Singh J, et al. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol 2010;28:63-70
  • Gallant M, Aspiotis R, Day S, et al. Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment. Bioorg Med Chem Lett 2010;20:6387-93
  • Huang Z, Dias R, Jones T, et al. L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition. Biochem Pharmacol 2007;73:1971-81
  • Li YF, Cheng YF, Huang Y, et al. Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. J Neurosci 2011;31:172-83
  • Rutten K, Basile JL, Prickaerts J, et al. Selective PDE inhibitors rolipram and sildenafil improve object retrieval performance in adult cynomolgus macaques. Psychopharmacology (Berl) 2008;196:643-8
  • Bruno O, Fedele E, Prickaerts J, et al. GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses. Br J Pharmacol 2011;164:2054-63
  • Egawa T, Mishima K, Matsumoto Y, et al. Rolipram and its optical isomers, phosphodiesterase 4 inhibitors, attenuated the scopolamine-induced impairments of learning and memory in rats. Jpn J Pharmacol 1997;75:275-81
  • Imanishi T, Sawa A, Ichimaru Y, et al. Ameliorating effects of rolipram on experimentally induced impairments of learning and memory in rodents. Eur J Pharmacol 1997;321:273-8
  • Zhang HT, Huang Y, Suvarna NU, et al. Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats. Psychopharmacology (Berl) 2005;179:613-19
  • Zhang HT, O'Donnell JM. Effects of rolipram on scopolamine-induced impairment of working and reference memory in the radial-arm maze tests in rats. Psychopharmacology (Berl) 2000;150:311-16
  • Zhang HT, Crissman AM, Dorairaj NR, et al. Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism. Neuropsychopharmacology 2000;23:198-204
  • Davis JA, Gould TJ. Rolipram attenuates MK-801-induced deficits in latent inhibition. Behav Neurosci 2005;119:595-602
  • Zhang HT, Zhao Y, Huang Y, et al. Inhibition of the phosphodiesterase 4 (PDE4) enzyme reverses memory deficits produced by infusion of the MEK inhibitor U0126 into the CA1 subregion of the rat hippocampus. Neuropsychopharmacology 2004;29:1432-9
  • Rutten K, Lieben C, Smits L, et al. The PDE4 inhibitor rolipram reverses object memory impairment induced by acute tryptophan depletion in the rat. Psychopharmacology (Berl) 2007;192:275-82
  • Li LX, Cheng YF, Lin HB, et al. Prevention of cerebral ischemia-induced memory deficits by inhibition of phosphodiesterase-4 in rats. Metab Brain Dis 2011;26:37-47
  • de Lima MN, Presti-Torres J, Garcia VA, et al. Amelioration of recognition memory impairment associated with iron loading or aging by the type 4-specific phosphodiesterase inhibitor rolipram in rats. Neuropharmacology 2008;55:788-92
  • Ramos BP, Birnbaum SG, Lindenmayer I, et al. Dysregulation of protein kinase a signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline. Neuron 2003;40:835-45
  • Bourtchouladze R, Lidge R, Catapano R, et al. A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4. Proc Natl Acad Sci USA 2003;100:10518-22
  • Vitolo OV, Sant'Angelo A, Costanzo V, et al. Amyloid beta -peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc Natl Acad Sci USA 2002;99:13217-21
  • Gong B, Vitolo OV, Trinchese F, et al. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest 2004;114:1624-34
  • Cheng YF, Wang C, Lin HB, et al. Inhibition of phosphodiesterase-4 reverses memory deficits produced by Abeta25-35 or Abeta1-40 peptide in rats. Psychopharmacology (Berl) 2010;212:181-91
  • Wang C, Yang XM, Zhuo YY, et al. The phosphodiesterase-4 inhibitor rolipram reverses Abeta-induced cognitive impairment and neuroinflammatory and apoptotic responses in rats. Int J Neuropsychopharmacol 2012;15:749-66
  • Sharma V, Bala A, Deshmukh R, et al. Neuroprotective effect of RO-20-1724-a phosphodiesterase4 inhibitor against intracerebroventricular streptozotocin induced cognitive deficit and oxidative stress in rats. Pharmacol Biochem Behav 2012;101:239-45
  • Li YF, Huang Y, Amsdell SL, et al. Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus. Neuropsychopharmacology 2009;34:2404-19
  • Nakagawa S, Kim JE, Lee R, et al. Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein. J Neurosci 2002;22:3673-82
  • Rutten K, Prickaerts J, Blokland A. Rolipram reverses scopolamine-induced and time-dependent memory deficits in object recognition by different mechanisms of action. Neurobiol Learn Mem 2006;85:132-8
  • Navakkode S, Sajikumar S, Frey JU. The type IV-specific phosphodiesterase inhibitor rolipram and its effect on hippocampal long-term potentiation and synaptic tagging. J Neurosci 2004;24:7740-4
  • Wiescholleck V, Manahan-Vaughan D. PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis. Transl Psychiatry 2012;2:e89
  • Giorgi M, Modica A, Pompili A, et al. The induction of cyclic nucleotide phosphodiesterase 4 gene (PDE4D) impairs memory in a water maze task. Behav Brain Res 2004;154:99-106
  • Yamashita N, Hayashi A, Baba J, et al. Rolipram, a phosphodiesterase-4-selective inhibitor, promotes the survival of cultured rat dopaminergic neurons. Jpn J Pharmacol 1997;75:155-9
  • Schaal SM, Garg MS, Ghosh M, et al. The therapeutic profile of rolipram, PDE target and mechanism of action as a neuroprotectant following spinal cord injury. PLoS One 2012;7:e43634
  • Sebastiani G, Morissette C, Lagace C, et al. The cAMP-specific phosphodiesterase 4B mediates Abeta-induced microglial activation. Neurobiol Aging 2006;27:691-701
  • Nikulina E, Tidwell JL, Dai HN, et al. The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Proc Natl Acad Sci USA 2004;101:8786-90
  • Giralt A, Saavedra A, Carreton O, et al. Increased PKA signaling disrupts recognition memory and spatial memory: role in Huntington's disease. Hum Mol Genet 2011;20:4232-47
  • Rutten K, Misner DL, Works M, et al. Enhanced long-term potentiation and impaired learning in phosphodiesterase 4D-knockout (PDE4D) mice. Eur J Neurosci 2008;28:625-32
  • Rutten K, Wallace TL, Works M, et al. Enhanced long-term depression and impaired reversal learning in phosphodiesterase 4B-knockout (PDE4B-/-) mice. Neuropharmacology 2011;61:138-47
  • Arnsten AF, Ramos BP, Birnbaum SG, et al. Protein kinase A as a therapeutic target for memory disorders: rationale and challenges. Trends Mol Med 2005;11:121-8
  • Hotte M, Dauphin F, Freret T, et al. A biphasic and brain-region selective down-regulation of cyclic adenosine monophosphate concentrations supports object recognition in the rat. PLoS One 2012;7:e32244
  • DeMarch Z, Giampa C, Patassini S, et al. Beneficial effects of rolipram in the R6/2 mouse model of Huntington's disease. Neurobiol Dis 2008;30:375-87
  • DeMarch Z, Giampa C, Patassini S, et al. Beneficial effects of rolipram in a quinolinic acid model of striatal excitotoxicity. Neurobiol Dis 2007;25:266-73
  • Heaslip RJ, Evans DY. Emetic, central nervous system, and pulmonary activities of rolipram in the dog. Eur J Pharmacol 1995;286:281-90
  • Hebenstreit GF, Fellerer K, Fichte K, et al. Rolipram in major depressive disorder: results of a double-blind comparative study with imipramine. Pharmacopsychiatry 1989;22:156-60
  • Cherry JA, Davis RL. Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect. J Comp Neurol 1999;407:287-301
  • Lamontagne S, Meadows E, Luk P, et al. Localization of phosphodiesterase-4 isoforms in the medulla and nodose ganglion of the squirrel monkey. Brain Res 2001;920:84-96
  • Mori F, Perez-Torres S, De Caro R, et al. The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D. J Chem Neuroanat 2010;40:36-42
  • Lehnart SE, Wehrens XH, Reiken S, et al. Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Cell 2005;123:25-35
  • Leroy J, Richter W, Mika D, et al. Phosphodiesterase 4B in the cardiac L-type Ca(2)(+) channel complex regulates Ca(2)(+) current and protects against ventricular arrhythmias in mice. J Clin Invest 2011;121:2651-61
  • Molina CE, Leroy J, Richter W, et al. Cyclic adenosine monophosphate phosphodiesterase type 4 protects against atrial arrhythmias. J Am Coll Cardiol 2012;59:2182-90
  • Gretarsdottir S, Thorleifsson G, Reynisdottir ST, et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet 2003;35:131-8
  • Losco PE, Evans EW, Barat SA, et al. The toxicity of SCH 351591, a novel phosphodiesterase-4 inhibitor, in Cynomolgus monkeys. Toxicol Pathol 2004;32:295-308
  • Calverley PM, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374:685-94
  • Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009;374:695-703
  • Iona S, Cuomo M, Bushnik T, et al. Characterization of the rolipram-sensitive, cyclic AMP-specific phosphodiesterases: identification and differential expression of immunologically distinct forms in the rat brain. Mol Pharmacol 1998;53:23-32
  • Johansson EM, Reyes-Irisarri E, Mengod G. Comparison of cAMP-specific phosphodiesterase mRNAs distribution in mouse and rat brain. Neurosci Lett 2012;525:1-6
  • Perez-Torres S, Miro X, Palacios JM, et al. Phosphodiesterase type 4 isozymes expression in human brain examined by in situ hybridization histochemistry and[3H]rolipram binding autoradiography. Comparison with monkey and rat brain. J Chem Neuroanat 2000;20:349-74
  • Lobban M, Shakur Y, Beattie J, et al. Identification of two splice variant forms of type-IVB cyclic AMP phosphodiesterase, DPD (rPDE-IVB1) and PDE-4 (rPDE-IVB2) in brain: selective localization in membrane and cytosolic compartments and differential expression in various brain regions. Biochem J 1994;304(Pt 2):399-406
  • McPhee I, Cochran S, Houslay MD. The novel long PDE4A10 cyclic AMP phosphodiesterase shows a pattern of expression within brain that is distinct from the long PDE4A5 and short PDE4A1 isoforms. Cell Signal 2001;13:911-18
  • McPhee I, Pooley L, Lobban M, et al. Identification, characterization and regional distribution in brain of RPDE-6 (RNPDE4A5), a novel splice variant of the PDE4A cyclic AMP phosphodiesterase family. Biochem J 1995;310(Pt 3):965-74
  • Miro X, Perez-Torres S, Puigdomenech P, et al. Differential distribution of PDE4D splice variant mRNAs in rat brain suggests association with specific pathways and presynaptical localization. Synapse 2002;45:259-69
  • Reyes-Irisarri E, Perez-Torres S, Miro X, et al. Differential distribution of PDE4B splice variant mRNAs in rat brain and the effects of systemic administration of LPS in their expression. Synapse 2008;62:74-9
  • Richter W, Jin SL, Conti M. Splice variants of the cyclic nucleotide phosphodiesterase PDE4D are differentially expressed and regulated in rat tissue. Biochem J 2005;388:803-11
  • Hansen G, Jin S, Umetsu DT, et al. Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D. Proc Natl Acad Sci USA 2000;97:6751-6
  • Jin SL, Goya S, Nakae S, et al. Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol 2010;126:1252-9. e12
  • Mehats C, Jin SL, Wahlstrom J, et al. PDE4D plays a critical role in the control of airway smooth muscle contraction. FASEB J 2003;17:1831-41
  • Jin SL, Conti M. Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses. Proc Natl Acad Sci USA 2002;99:7628-33
  • Mackenzie KF, Topping EC, Bugaj-Gaweda B, et al. Human PDE4A8, a novel brain-expressed PDE4 cAMP-specific phosphodiesterase that has undergone rapid evolutionary change. Biochem J 2008;411:361-9
  • Braun NN, Reutiman TJ, Lee S, et al. Expression of phosphodiesterase 4 is altered in the brains of subjects with autism. Neuroreport 2007;18:1841-4
  • Fatemi SH, Reutiman TJ, Folsom TD, et al. Phosphodiesterase-4A expression is reduced in cerebella of patients with bipolar disorder. Psychiatr Genet 2008;18:282-8
  • Vecsey CG, Baillie GS, Jaganath D, et al. Sleep deprivation impairs cAMP signalling in the hippocampus. Nature 2009;461:1122-5
  • Hajjhussein H, Suvarna NU, Gremillion C, et al. Changes in NMDA receptor-induced cyclic nucleotide synthesis regulate the age-dependent increase in PDE4A expression in primary cortical cultures. Brain Res 2007;1149:58-68
  • Ahmed T, Frey JU. Expression of the specific type IV phosphodiesterase gene PDE4B3 during different phases of long-term potentiation in single hippocampal slices of rats in vitro. Neuroscience 2003;117:627-38
  • Ahmed T, Frey JU. Phosphodiesterase 4B (PDE4B) and cAMP-level regulation within different tissue fractions of rat hippocampal slices during long-term potentiation in vitro. Brain Res 2005;1041:212-22
  • Ahmed T, Frey S, Frey JU. Regulation of the phosphodiesterase PDE4B3-isotype during long-term potentiation in the area dentata in vivo. Neuroscience 2004;124:857-67
  • Navakkode S, Sajikumar S, Frey JU. Mitogen-activated protein kinase-mediated reinforcement of hippocampal early long-term depression by the type IV-specific phosphodiesterase inhibitor rolipram and its effect on synaptic tagging. J Neurosci 2005;25:10664-70
  • Siuciak JA, McCarthy SA, Chapin DS, et al. Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology (Berl) 2008;197:115-26
  • Zhang HT, Huang Y, Masood A, et al. Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B). Neuropsychopharmacology 2008;33:1611-23
  • Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer's disease, role of cytokines. ScientificWorldJournal 2012;2012:756357
  • Millar JK, Pickard BS, Mackie S, et al. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 2005;310:1187-91
  • Murdoch H, Mackie S, Collins DM, et al. Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels. J Neurosci 2007;27:9513-24
  • Fatemi SH, King DP, Reutiman TJ, et al. PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia. Schizophr Res 2008;101:36-49
  • Numata S, Ueno S, Iga J, et al. Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population. J Psychiatr Res 2008;43:7-12
  • Pickard BS, Thomson PA, Christoforou A, et al. The PDE4B gene confers sex-specific protection against schizophrenia. Psychiatr Genet 2007;17:129-33
  • Tomppo L, Hennah W, Lahermo P, et al. Association between genes of Disrupted in schizophrenia 1 (DISC1) interactors and schizophrenia supports the role of the DISC1 pathway in the etiology of major mental illnesses. Biol Psychiatry 2009;65:1055-62
  • Kahler AK, Otnaess MK, Wirgenes KV, et al. Association study of PDE4B gene variants in Scandinavian schizophrenia and bipolar disorder multicenter case-control samples. Am J Med Genet B Neuropsychiatr Genet 2010;153B:86-96
  • Rastogi A, Zai C, Likhodi O, et al. Genetic association and post-mortem brain mRNA analysis of DISC1 and related genes in schizophrenia. Schizophr Res 2009;114:39-49
  • Fadda F, Rossetti ZL. Chronic ethanol consumption: from neuroadaptation to neurodegeneration. Prog Neurobiol 1998;56:385-431
  • Hu W, Lu T, Chen A, et al. Inhibition of phosphodiesterase-4 decreases ethanol intake in mice. Psychopharmacology (Berl) 2011;218:331-9
  • Wen RT, Zhang M, Qin WJ, et al. The phosphodiesterase-4 (PDE4) inhibitor rolipram decreases ethanol seeking and consumption in alcohol-preferring fawn-hooded rats. Alcohol Clin Exp Res 2012;36:2157-67
  • Robbins TW, Ersche KD, Everitt BJ. Drug addiction and the memory systems of the brain. Ann N Y Acad Sci 2008;1141:1-21
  • Wang ZZ, Zhang Y, Liu YQ, et al. RNA interference-mediated phosphodiesterase 4D splice variants knock-down in the prefrontal cortex produces antidepressant-like and cognition-enhancing effects. Br J Pharmacol 2013;168:1001-14
  • Schaefer TL, Braun AA, Amos-Kroohs RM, et al. A new model of Pde4d deficiency: genetic knock-down of PDE4D enzyme in rats produces an antidepressant phenotype without spatial cognitive effects. Genes Brain Behav 2012;11:614-22
  • Zhang HT, Huang Y, Jin SL, et al. Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology 2002;27:587-95
  • Duplantier AJ, Biggers MS, Chambers RJ, et al. Biarylcarboxylic acids and -amides: inhibition of phosphodiesterase type IV versus [3H]rolipram binding activity and their relationship to emetic behavior in the ferret. J Med Chem 1996;39:120-5
  • Souness JE, Rao S. Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases. Cell Signal 1997;9:227-36
  • Zhang HT, Zhao Y, Huang Y, et al. Antidepressant-like effects of PDE4 inhibitors mediated by the high-affinity rolipram binding state (HARBS) of the phosphodiesterase-4 enzyme (PDE4) in rats. Psychopharmacology (Berl) 2006;186:209-17
  • Jin S-LC, Richard F, Kuo W-P, et al. Impaired growth and fertility of cAMP-specific phosphodiesterase PDE4D-deficient mice. Proc Natl Acad Sci USA 1999;96: In press
  • Donnell AF, Dollings PJ, Butera JA, et al. Identification of pyridazino[4,5-b]indolizines as selective PDE4B inhibitors. Bioorg Med Chem Lett 2010;20:2163-7
  • Kranz M, Wall M, Evans B, et al. Identification of PDE4B Over 4D subtype-selective inhibitors revealing an unprecedented binding mode. Bioorg Med Chem 2009;17:5336-41
  • Mitchell CJ, Ballantine SP, Coe DM, et al. Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR. Bioorg Med Chem Lett 2010;20:5803-6
  • Naganuma K, Omura A, Maekawara N, et al. Discovery of selective PDE4B inhibitors. Bioorg Med Chem Lett 2009;19:3174-6
  • Aspiotis R, Deschenes D, Dube D, et al. The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors. Bioorg Med Chem Lett 2010;20:5502-5
  • Robichaud A, Stamatiou PB, Jin SL, et al. Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J Clin Invest 2002;110:1045-52
  • Baillie GS, Sood A, McPhee I, et al. Beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Proc Natl Acad Sci USA 2003;100:940-5
  • De Arcangelis V, Liu R, Soto D, et al. Differential association of phosphodiesterase 4D isoforms with beta2-adrenoceptor in cardiac myocytes. J Biol Chem 2009;284:33824-32
  • McCahill A, McSorley T, Huston E, et al. In resting COS1 cells a dominant negative approach shows that specific, anchored PDE4 cAMP phosphodiesterase isoforms gate the activation, by basal cyclic AMP production, of AKAP-tethered protein kinase A type II located in the centrosomal region. Cell Signal 2005;17:1158-73
  • Richter W, Day P, Agrawal R, et al. Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4. EMBO J 2008;27:384-93
  • Bolger GB, Baillie GS, Li X, et al. Scanning peptide array analyses identify overlapping binding sites for the signalling scaffold proteins, beta-arrestin and RACK1, in cAMP-specific phosphodiesterase PDE4D5. Biochem J 2006;398:23-36
  • Murdoch H, Vadrevu S, Prinz A, et al. Interaction between LIS1 and PDE4, and its role in cytoplasmic dynein function. J Cell Sci 2011;124:2253-66
  • Beduneau A, Saulnier P, Benoit JP. Active targeting of brain tumors using nanocarriers. Biomaterials 2007;28:4947-67
  • Patel MM, Goyal BR, Bhadada SV, et al. Getting into the brain: approaches to enhance brain drug delivery. CNS Drugs 2009;23:35-58
  • Alam MI, Beg S, Samad A, et al. Strategy for effective brain drug delivery. Eur J Pharm Sci 2010;40:385-403
  • Joshi S, Ornstein E, Bruce JN. Targeting the brain: rationalizing the novel methods of drug delivery to the central nervous system. Neurocrit Care 2007;6:200-12
  • Pasha S, Gupta K. Various drug delivery approaches to the central nervous system. Expert Opin Drug Deliv 2010;7:113-35
  • Potschka H. Targeting the brain–surmounting or bypassing the blood-brain barrier. Handb Exp Pharmacol 2010(197):411-31
  • Kalgutkar AS, Choo E, Taylor TJ, et al. Disposition of CP-671, 305, a selective phosphodiesterase 4 inhibitor in preclinical species. Xenobiotica 2004;34:755-70
  • Yeadon M, Clarke N, Ward J. Phosphodiesterase type 4 (PDE4) inhibition: the search for effective therapy with minimal side effects. In: Hansel TT, Barnes PJ, editors. New drugs and targets for asthma and COPD. Prog Respir Res. Volume 39 Karger; Basel: 2010. p. 269-78
  • Gekel I, Neher E. Application of an Epac activator enhances neurotransmitter release at excitatory central synapses. J Neurosci 2008;28:7991-8002
  • Gelinas JN, Banko JL, Peters MM, et al. Activation of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the hippocampus. Learn Mem 2008;15:403-11
  • Laurent AC, Breckler M, Berthouze M, et al. Role of Epac in brain and heart. Biochem Soc Trans 2012;40:51-7
  • Ma N, Abel T, Hernandez PJ. Exchange protein activated by cAMP enhances long-term memory formation independent of protein kinase A. Learn Mem 2009;16:367-70
  • Mironov SL, Skorova EY. Stimulation of bursting in pre-Botzinger neurons by Epac through calcium release and modulation of TRPM4 and K-ATP channels. J Neurochem 2011;117:295-308
  • Ostroveanu A, van der Zee EA, Eisel UL, et al. Exchange protein activated by cyclic AMP 2 (Epac2) plays a specific and time-limited role in memory retrieval. Hippocampus 2010;20:1018-26
  • Peace AG, Shewan DA. New perspectives in cyclic AMP-mediated axon growth and guidance: the emerging epoch of Epac. Brain Res Bull 2011;84:280-8
  • Ster J, De Bock F, Guerineau NC, et al. Exchange protein activated by cAMP (Epac) mediates cAMP activation of p38 MAPK and modulation of Ca2+-dependent K+ channels in cerebellar neurons. Proc Natl Acad Sci USA 2007;104:2519-24
  • Benarroch EE. HCN channels: function and clinical implications. Neurology 2013;80:304-10
  • Craven KB, Zagotta WN. CNG and HCN channels: two peas, one pod. Annu Rev Physiol 2006;68:375-401

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.