• 1
    Francis, S. H., Blount, M. A., and Corbin, J. D. ( 2011) Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol. Rev. 91, 651690.
  • 2
    Conti, M. and Beavo, J. ( 2007) Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu. Rev. Biochem. 76, 481511.
  • 3
    Bender, A. T. and Beavo, J. A. ( 2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol. Rev. 58, 488520.
  • 4
    Cui, Q. and So, K. F. ( 2004) Involvement of cAMP in neuronal survival and axonal regeneration. Anat. Sci. Int. 79, 209212.
  • 5
    Lu, Y. F. and Hawkins, R. D. ( 2002) Ryanodine receptors contribute to cGMP-induced late-phase LTP and CREB phosphorylation in the hippocampus. J. Neurophysiol. 88, 12701278.
  • 6
    Merz, K., Herold, S., and Lie, D. C. ( 2011) CREB in adult neurogenesis—master and partner in the development of adult-born neurons? Eur. J. Neurosci. 33, 10781086.
  • 7
    Jancic, D., Lopez de Armentia, M., Valor, L. M., Olivares, R., and Barco, A. ( 2009) Inhibition of cAMP response element-binding protein reduces neuronal excitability and plasticity, and triggers neurodegeneration. Cereb. Cortex 19, 25352547.
  • 8
    Doronzo, G., Viretto, M., Russo, I., Mattiello, L., Di Martino, L., et al. ( 2011) Nitric oxide activates PI3-K and MAPK signalling pathways in human and rat vascular smooth muscle cells: influence of insulin resistance and oxidative stress. Atherosclerosis 216, 4453.
  • 9
    Bonni, A., Brunet, A., West, A. E., Datta, S. R., Takasu, M. A., et al. ( 1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 13581362.
  • 10
    Boucher, M. J., Morisset, J., Vachon, P. H., Reed, J. C., Laine, J., et al. ( 2000) MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells. J. Cell. Biochem. 79, 355369.
  • 11
    Jin, K., Mao, X. O., Zhu, Y., and Greenberg, D. A. ( 2002) MEK and ERK protect hypoxic cortical neurons via phosphorylation of Bad. J. Neurochem. 80, 119125.
  • 12
    Brunet, A., Datta, S. R., and Greenberg, M. E. ( 2001) Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr. Opin. Neurobiol. 11, 297305.
  • 13
    Meyer-Franke, A., Wilkinson, G. A., Kruttgen, A., Hu, M., Munro, E., et al. ( 1998) Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons. Neuron 21, 681693.
  • 14
    Chen, R. W., Williams, A. J., Liao, Z., Yao, C., Tortella, F. C., et al. ( 2007) Broad spectrum neuroprotection profile of phosphodiesterase inhibitors as related to modulation of cell-cycle elements and caspase-3 activation. Neurosci. Lett. 418, 165169.
  • 15
    Nakamizo, T., Kawamata, J., Yoshida, K., Kawai, Y., Kanki, R., et al. ( 2003) Phosphodiesterase inhibitors are neuroprotective to cultured spinal motor neurons. J. Neurosci. Res. 71, 485495.
  • 16
    Urushitani, M., Inoue, R., Nakamizo, T., Sawada, H., Shibasaki, H., et al. ( 2000) Neuroprotective effect of cyclic GMP against radical-induced toxicity in cultured spinal motor neurons. J. Neurosci. Res. 61, 443448.
  • 17
    Neumann, S., Bradke, F., Tessier-Lavigne, M., and Basbaum, A. I. ( 2002) Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. Neuron 34, 885893.
  • 18
    Nikulina, E., Tidwell, J. L., Dai, H. N., Bregman, B. S., and Filbin, M. T. ( 2004) The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Proc. Natl. Acad. Sci. USA 101, 87868790.
  • 19
    Qiu, J., Cai, D., Dai, H., McAtee, M., Hoffman, P. N., et al. ( 2002) Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34, 895903.
  • 20
    Tanaka, Y., Tanaka, R., Liu, M., Hattori, N., and Urabe, T. ( 2010) Cilostazol attenuates ischemic brain injury and enhances neurogenesis in the subventricular zone of adult mice after transient focal cerebral ischemia. Neuroscience 171, 13671376.
  • 21
    Zhang, R., Wang, Y., Zhang, L., Zhang, Z., Tsang, W., et al. ( 2002) Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 33, 26752680.
  • 22
    Ding, G., Jiang, Q., Li, L., Zhang, L., Zhang, Z. G., et al. ( 2008) Magnetic resonance imaging investigation of axonal remodeling and angiogenesis after embolic stroke in sildenafil-treated rats. J. Cereb. Blood Flow Metab. 28, 14401448.
  • 23
    Zhang, L., Zhang, R. L., Wang, Y., Zhang, C., Zhang, Z. G., et al. ( 2005) Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor. Stroke 36, 847852.
  • 24
    Menniti, F. S., Faraci, W. S., and Schmidt, C. J. ( 2006) Phosphodiesterases in the CNS: targets for drug development. Nat. Rev. Drug Discov. 5, 660670.
  • 25
    Shi, J., Qian, W., Yin, X., Iqbal, K., Grundke-Iqbal, I., et al. ( 2011) Cyclic AMP-dependent protein kinase regulates the alternative splicing of tau exon 10: a mechanism involved in tau pathology of Alzheimer disease. J. Biol. Chem. 286, 1463914648.
  • 26
    Hanger, D. P., Anderton, B. H., and Noble, W. ( 2009) Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol. Med. 15, 112119.
  • 27
    Bonkale, W. L., Cowburn, R. F., Ohm, T. G., Bogdanovic, N., and Fastbom, J. ( 1999) A quantitative autoradiographic study of [3H]cAMP binding to cytosolic and particulate protein kinase A in post-mortem brain staged for Alzheimer's disease neurofibrillary changes and amyloid deposits. Brain Res. 818, 383396.
  • 28
    Garcia-Jimenez, A., Cowburn, R. F., Ohm, T. G., Bogdanovic, N., Winblad, B., et al. ( 1999) Quantitative autoradiography of [3H]forskolin binding sites in post-mortem brain staged for Alzheimer's disease neurofibrillary changes and amyloid deposits. Brain Res. 850, 104117.
  • 29
    Liang, Z., Liu, F., Grundke-Iqbal, I., Iqbal, K., and Gong, C.-X. ( 2007) Down-regulation of cAMP-dependent protein kinase by over-activated calpain in Alzheimer disease brain. J. Neurochem. 103, 24622470.
  • 30
    Scott Bitner, R. ( 2011) Cyclic AMP response element-binding protein (CREB) phosphorylation: a mechanistic marker in the development of memory enhancing Alzheimer's disease therapeutics. Biochem. Pharmacol. 83, 705714.
  • 31
    Perez-Torres, S., Cortes, R., Tolnay, M., Probst, A., Palacios, J. M., et al. ( 2003) Alterations on phosphodiesterase type 7 and 8 isozyme mRNA expression in Alzheimer's disease brains examined by in situ hybridization. Exp. Neurol. 182, 322334.
  • 32
    Brun, A. and Englund, E. ( 1986) A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann. Neurol. 19, 253262.
  • 33
    McLachlan, C. S., Chen, M. L., Lynex, C. N., Goh, D. L., Brenner, S., et al. ( 2007) Changes in PDE4D isoforms in the hippocampus of a patient with advanced Alzheimer disease. Arch. Neurol. 64, 456457.
  • 34
    Zhang, H. T., Huang, Y., Suvarna, N. U., Deng, C., Crissman, A. M., et al. ( 2005) Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats. Psychopharmacology 179, 613619.
  • 35
    Sette, C. and Conti, M. ( 1996) 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. 271, 1652616534.
  • 36
    Domek-Lopacinska, K. U. and Strosznajder, J. B. ( 2010) Cyclic GMP and nitric oxide synthase in aging and Alzheimer's disease. Mol. Neurobiol. 41, 129137.
  • 37
    Blokland, A., Schreiber, R., and Prickaerts, J. ( 2006) Improving memory: a role for phosphodiesterases. Curr. Pharm. Des. 12, 25112523.
  • 38
    Saura, C. A. and Valero, J. ( 2011) The role of CREB signaling in Alzheimer's disease and other cognitive disorders. Rev. Neurosci. 22, 153169.
  • 39
    Ciani, E., Guidi, S., Bartesaghi, R., and Contestabile, A. ( 2002) Nitric oxide regulates cGMP-dependent cAMP-responsive element binding protein phosphorylation and Bcl-2 expression in cerebellar neurons: implication for a survival role of nitric oxide. J. Neurochem. 82, 12821289.
  • 40
    Reyes-Irisarri, E., Markerink-Van Ittersum, M., Mengod, G., and de Vente, J. ( 2007) Expression of the cGMP-specific phosphodiesterases 2 and 9 in normal and Alzheimer's disease human brains. Eur. J. Neurosci. 25, 33323338.
  • 41
    Boldrini, M., Underwood, M. D., Hen, R., Rosoklija, G. B., Dwork, A. J., et al. ( 2009) Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 34, 23762389.
  • 42
    Bremner, J. D., Narayan, M., Anderson, E. R., Staib, L. H., Miller, H. L., et al. ( 2000) Hippocampal volume reduction in major depression. Am. J. Psychiatry 157, 115118.
  • 43
    Sheline, Y. I., Gado, M. H., and Kraemer, H. C. ( 2003) Untreated depression and hippocampal volume loss. Am. J. Psychiatry 160, 15161518.
  • 44
    Sheline, Y. I., Wang, P. W., Gado, M. H., Csernansky, J. G., and Vannier, M. W. ( 1996) Hippocampal atrophy in recurrent major depression. Proc. Natl. Acad. Sci. USA 93, 39083913.
  • 45
    Tsopelas, C., Stewart, R., Savva, G. M., Brayne, C., Ince, P., et al. ( 2011) Neuropathological correlates of late-life depression in older people. Br. J. Psychiatry 198, 109114.
  • 46
    Cowburn, R. F., Marcusson, J. O., Eriksson, A., Wiehager, B., and O'Neill, C. ( 1994) Adenylyl cyclase activity and G-protein subunit levels in postmortem frontal cortex of suicide victims. Brain Res. 633, 297304.
  • 47
    Dowlatshahi, D., MacQueen, G. M., Wang, J. F., and Young, L. T. ( 1998) Increased temporal cortex CREB concentrations and antidepressant treatment in major depression. Lancet 352, 17541755.
  • 48
    Dwivedi, Y., Conley, R. R., Roberts, R. C., Tamminga, C. A., and Pandey, G. N. ( 2002) [(3)H]cAMP binding sites and protein kinase A activity in the prefrontal cortex of suicide victims. Am. J. Psychiatry 159, 6673.
  • 49
    Reiach, J. S., Li, P. P., Warsh, J. J., Kish, S. J., and Young, L. T. ( 1999) Reduced adenylyl cyclase immunolabeling and activity in postmortem temporal cortex of depressed suicide victims. J. Affect. Disord. 56, 141151.
  • 50
    Fujita, M., Hines, C. S., Zoghbi, S. S., Mallinger, A. G., Dickstein, L. P., et al. ( 2012) Downregulation of brain phosphodiesterase type IV measured with (11)C-(R)-rolipram positron emission tomography in major depressive disorder. Biol. Psychiatry 72, 548554.
  • 51
    O'Donnell, J. M. and Xu, Y. ( 2012) Evidence for global reduction in brain cyclic adenosine monophosphate signaling in depression. Biol. Psychiatry 72, 524525.
  • 52
    Wong, M. L., Whelan, F., Deloukas, P., Whittaker, P., Delgado, M., et al. ( 2006) Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response. Proc. Natl. Acad. Sci. USA 103, 1512415129.
  • 53
    Luo, H. R., Wu, G. S., Dong, C., Arcos-Burgos, M., Ribeiro, L., et al. ( 2009) Association of PDE11A global haplotype with major depression and antidepressant drug response. Neuropsychiatr. Dis. Treat. 5, 163170.
  • 54
    Reynolds, R., Roncaroli, F., Nicholas, R., Radotra, B., Gveric, D., et al. ( 2011) The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol. 122, 155170.
  • 55
    Bopp, T., Becker, C., Klein, M., Klein-Hessling, S., Palmetshofer, A., et al. ( 2007) Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J. Exp. Med. 204, 13031310.
  • 56
    Dong, R. P., Umezawa, Y., Ikushima, H., Munakata, Y., Schlossman, S. F., et al. ( 1997) Different regulatory effects of pentoxifylline on human T cell activation pathways. J. Clin. Immunol. 17, 247252.
  • 57
    Silva, J. C., Rocha, M. F., Lima, A. A., Brito, G. A., de Menezes, D. B., et al. ( 2000) Effects of pentoxifylline and nabumetone on the serum levels of IL-1β and TNFα in rats with adjuvant arthritis. Inflamm. Res. 49, 1419.
  • 58
    Folcik, V. A., Smith, T., O'Bryant, S., Kawczak, J. A., Zhu, B., et al. ( 1999) Treatment with BBB022A or rolipram stabilizes the blood–brain barrier in experimental autoimmune encephalomyelitis: an additional mechanism for the therapeutic effect of type IV phosphodiesterase inhibitors. J. Neuroimmunol. 97, 119128.
  • 59
    Mizrachi, K., Aricha, R., Feferman, T., Kela-Madar, N., Mandel, I., et al. ( 2010) Involvement of phosphodiesterases in autoimmune diseases. J. Neuroimmunol. 220, 4351.
  • 60
    Vonsattel, J. P., Myers, R. H., Stevens, T. J., Ferrante, R. J., Bird, E. D., et al. ( 1985) Neuropathological classification of Hungtington's disease. J. Neuropathol. Exp. Neurol. 44, 559577.
  • 61
    Lakics, V., Karran, E. H., and Boess, F. G. ( 2010) Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 59, 367374.
  • 62
    Xie, Z., Adamowicz, W. O., Eldred, W. D., Jakowski, A. B., Kleiman, R. J., et al. ( 2006) Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase. Neuroscience 139, 597607.
  • 63
    Hebb, A. L., Robertson, H. A., and Denovan-Wright, E. M. ( 2004) Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington's disease transgenic mice prior to the onset of motor symptoms. Neuroscience 123, 967981.
  • 64
    Polli, J. W. and Kincaid, R. L. ( 1994) Expression of a calmodulin-dependent phosphodiesterase isoform (PDE1B1) correlates with brain regions having extensive dopaminergic innervation. J. Neurosci. 14, 12511261.
  • 65
    Nishi, A. and Snyder, G. L. ( 2010) Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: biochemical and behavioral profiles of phosphodiesterase inhibition in dopaminergic neurotransmission. J. Pharmacol. Sci. 114, 616.
  • 66
    Foroud, T., Siemers, E., Kleindorfer, D., Bill, D. J., Hodes, M. E., et al. ( 1995) Cognitive scores in carriers of Huntington's disease gene compared to noncarriers. Ann. Neurol. 37, 657664.
  • 67
    Lawrence, A. D., Sahakian, B. J., Hodges, J. R., Rosser, A. E., Lange, K. W., et al. ( 1996) Executive and mnemonic functions in early Huntington's disease. Brain 119, 16331645.
  • 68
    Lemiere, J., Decruyenaere, M., Evers-Kiebooms, G., Vandenbussche, E., and Dom, R. ( 2004) Cognitive changes in patients with Huntington's disease (HD) and asymptomatic carriers of the HD mutation—a longitudinal follow-up study. J. Neurol. 251, 935942.
  • 69
    Giralt, A., Saavedra, A., Carreton, O., Xifro, X., Alberch, J., et al. ( 2011) Increased PKA signaling disrupts recognition memory and spatial memory: role in Huntington's disease. Hum. Mol. Genet. 20, 42324247.
  • 70
    Kuhlenbaumer, G., Ludemann, P., Schirmacher, A., De Vriendt, E., Hunermund, G., et al. ( 2004) Autosomal dominant striatal degeneration (ADSD): clinical description and mapping to 5q13-5q14. Neurology 62, 22032208.
  • 71
    Appenzeller, S., Schirmacher, A., Halfter, H., Baumer, S., Pendziwiat, M., et al. ( 2010) Autosomal-dominant striatal degeneration is caused by a mutation in the phosphodiesterase 8B gene. Am. J. Hum. Genet. 86, 8387.