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Current Drug Targets


ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

Review Article

Cyclic Nucleotides Signaling and Phosphodiesterase Inhibition: Defying Alzheimer’s Disease

Author(s): Vivek K. Sharma, Thakur G. Singh* and Shareen Singh

Volume 21 , Issue 13 , 2020

Page: [1371 - 1384] Pages: 14

DOI: 10.2174/1389450121666200727104728

Price: $65


Defects in brain functions associated with aging and neurodegenerative diseases benefit insignificantly from existing options, suggesting that there is a lack of understanding of pathological mechanisms. Alzheimer’s disease (AD) is such a nearly untreatable, allied to age neurological deterioration for which only the symptomatic cure is available and the agents able to mould progression of the disease, is still far away. The altered expression of phosphodiesterases (PDE) and deregulated cyclic nucleotide signaling in AD has provoked a new thought of targeting cyclic nucleotide signaling in AD. Targeting cyclic nucleotides as an intracellular messenger seems to be a viable approach for certain biological processes in the brain and controlling substantial. Whereas, the synthesis, execution, and/or degradation of cyclic nucleotides has been closely linked to cognitive deficits. In relation to cognition, the cyclic nucleotides (cAMP and cGMP) have an imperative execution in different phases of memory, including gene transcription, neurogenesis, neuronal circuitry, synaptic plasticity and neuronal survival, etc. AD is witnessed by impairments of these basic processes underlying cognition, suggesting a crucial role of cAMP/cGMP signaling in AD populations. Phosphodiesterase inhibitors are the exclusive set of enzymes to facilitate hydrolysis and degradation of cAMP and cGMP thereby, maintains their optimum levels initiating it as an interesting target to explore. The present work reviews a neuroprotective and substantial influence of PDE inhibition on physiological status, pathological progression and neurobiological markers of AD in consonance with the intensities of cAMP and cGMP.

Keywords: Alzheimer's disease, cognition, cAMP, cGMP, CREB, cyclic nucleotides.

Graphical Abstract
Heckman PR, Wouters C, Prickaerts J. Phosphodiesterase inhibitors as a target for cognition enhancement in aging and Alzheimer’s disease: a translational overview. Curr Pharm Des 2015; 21(3): 317-31.
[] [PMID: 25159073]
Sharma K. Cholinesterase inhibitors as Alzheimer’s therapeutics. (Review). Mol Med Rep 2019; 20(2): 1479-87. [Review].
[PMID: 31257471]
García-Osta A, Cuadrado-Tejedor M, García-Barroso C, Oyarzábal J, Franco R. Phosphodiesterases as therapeutic targets for Alzheimer’s disease. ACS Chem Neurosci 2012; 3(11): 832-44.
[] [PMID: 23173065]
Cummings J, Lee G, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2018. Alzheimers Dement (N Y) 2018; 4: 195-214.
[] [PMID: 29955663]
Liu S, Li X, Gao J, Liu Y, Shi J, Gong Q. Icariside II, a phosphodiesterase-5 inhibitor, attenuates beta-amyloid-induced cognitive deficits via BDNF/TrkB/CREB signaling. Cell Physiol Biochem 2018; 49(3): 985.
[] [PMID: 30196289]
Hassan M, Raza H, Abbasi MA, Moustafa AA, Seo SY. The exploration of novel Alzheimer’s therapeutic agents from the pool of FDA approved medicines using drug repositioning, enzyme inhibition and kinetic mechanism approaches. Biomed Pharmacother 2019; 109: 2513-26.
[] [PMID: 30551512]
Wu Y, Li Z, Huang YY, Wu D, Luo HB. Novel Phosphodiesterase Inhibitors for Cognitive Improvement in Alzheimer’s Disease. J Med Chem 2018; 61(13): 5467-83.
[] [PMID: 29363967]
Hung SY, Fu WM. Drug candidates in clinical trials for Alzheimer’s disease. J Biomed Sci 2017; 24(1): 47.
[] [PMID: 28720101]
Chang X, Wang J, Jiang H, Shi L, Xie J. Hyperpolarization-activated cyclic nucleotidegated channels: an emerging role in neurodegenerative diseases. Front Mol Neurosci 2019; 12: 141.
[] [PMID: 31231190]
Kumar A, Sharma V, Singh VP, et al. Herbs to curb cyclic nucleotide phosphodiesterase and their potential role in Alzheimer’s disease. Mech Ageing Dev 2015; 149: 75-87.
[] [PMID: 26050556]
McPhee I, Gibson LC, Kewney J, et al. Cyclic nucleotide signalling: a molecular approach to drug discovery for Alzheimer's disease 2005; 1331-2.
Tibbo AJ, Tejeda GS, Baillie GS. Understanding PDE4's function in Alzheimer’s disease; a target for novel therapeutic approaches. Biochem Soc Trans 2019; 47(5): 1557-65.
[] [PMID: 31642904]
Sallustio F, Studer V. Targeting new pharmacological approaches for alzheimer’s disease: potential for statins and phosphodiesterase inhibitors. CNS Neurol Disord Drug Targets 2016; 15(6): 647-59.
[] [PMID: 27189469]
Knott EP, Assi M, Rao SNR, Ghosh M, Pearse DD. Phosphodiesterase inhibitors as a therapeutic approach to neuroprotection and repair. Int J Mol Sci 2017; 18(4): 696.
[] [PMID: 28338622]
Mehats C, Andersen CB, Filopanti M, Jin SL, Conti M. Cyclic nucleotide phosphodiesterases and their role in endocrine cell signaling. Trends Endocrinol Metab 2002; 13(1): 29-35.
[] [PMID: 11750860]
Greengard P. The neurobiology of slow synaptic transmission. Science 2001; 294(5544): 1024-30.
[] [PMID: 11691979]
Ahmad F, Murata T, Shimizu K, Degerman E, Maurice D, Manganiello V. Cyclic nucleotide phosphodiesterases: important signaling modulators and therapeutic targets. Oral Dis 2015; 21(1): e25-50.
[] [PMID: 25056711]
Ricciarelli R, Brullo C, Prickaerts J, et al. Memory-enhancing effects of GEBR-32a, a new PDE4D inhibitor holding promise for the treatment of Alzheimer’s disease. Sci Rep 2017; 7: 46320.
[] [PMID: 28402318]
Ugarte A, Gil-Bea F, García-Barroso C, et al. Decreased levels of guanosine 3′, 5′-monophosphate (cGMP) in cerebrospinal fluid (CSF) are associated with cognitive decline and amyloid pathology in Alzheimer’s disease. Neuropathol Appl Neurobiol 2015; 41(4): 471-82.
[] [PMID: 25488891]
Pérez-Torres S, Cortés R, Tolnay M, Probst A, Palacios JM, Mengod G. Alterations on phosphodiesterase type 7 and 8 isozyme mRNA expression in Alzheimer’s disease brains examined by in situ hybridization. Exp Neurol 2003; 182(2): 322-34.
[] [PMID: 12895443]
Heldin CH, Lu B, Evans R, Gutkind JS. Signals and receptors. Cold Spring Harb Perspect Biol 2016; 8(4)a005900
[] [PMID: 27037414]
Newton AC, Bootman MD, Scott JD. Second messengers. Cold Spring Harb Perspect Biol 2016; 8(8)a005926
[] [PMID: 27481708]
Kaiser A. Druggable targets in cyclic nucleotide signaling pathways in apicomplexan parasites and kinetoplastids against disabling protozoan diseases in humans. Int J Mol Sci 2019; 20(1): 138.
[] [PMID: 30609697]
Francis SH, Blount MA, Corbin JD. Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev 2011; 91(2): 651-90.
[] [PMID: 21527734]
Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 2007; 76: 481-511.
[] [PMID: 17376027]
Nabavi SM, Talarek S, Listos J, et al. Phosphodiesterase inhibitors say NO to Alzheimer’s disease. Food Chem Toxicol 2019.134110822
[] [PMID: 31536753]
Bergantin LB, Caricati-Neto A. Challenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca(2+)/cAMP intracellular signalling interaction. Eur J Pharmacol 2016; 788: 255-60.
[] [PMID: 27349146]
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(18): 10518-22.
[] [PMID: 12930888]
Linder JUC. III adenylyl cyclases: molecular mechanisms of catalysis and regulation. Cellular and molecular life sciences. CMLS 2005; 63: 1736-51.
Calebiro D, Maiellaro I. cAMP signaling microdomains and their observation by optical methods. Front Cell Neurosci 2014; 8: 350.
[] [PMID: 25389388]
Corbin JD, Francis SH. Cyclic GMP phosphodiesterase-5: target of sildenafil. J Biol Chem 1999; 274(20): 13729-32.
[] [PMID: 10318772]
Liang Z, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Down-regulation of cAMP dependent protein kinase by over-activated calpain in Alzheimer disease brain. J Neurochem 2007; 103(6): 2462-70.
[] [PMID: 17908236]
Domek-Łopacińska KU, Strosznajder JB. Cyclic GMP and nitric oxide synthase in aging and Alzheimer’s disease. Mol Neurobiol 2010; 41(2-3): 129-37.
[] [PMID: 20213343]
Kelly MP. Cyclic nucleotide signaling changes associated with normal aging and age-related diseases of the brain. Cell Signal 2018; 42: 281-91.
[] [PMID: 29175000]
Saura CA, Valero J. The role of CREB signaling in Alzheimer’s disease and other cognitive disorders. Rev Neurosci 2011; 22(2): 153-69.
[] [PMID: 21476939]
Ciani E, Guidi S, Bartesaghi R, Contestabile A. 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 2002; 82(5): 1282-9.
[] [PMID: 12358775]
Rapôso C, Luna RLDA, Nunes AKS, Thomé R, Peixoto CA. Role of iNOS-NO-cGMP signaling in modulation of inflammatory and myelination processes. Brain Res Bull 2014; 104: 60-73.
[] [PMID: 24727400]
Peixoto CA, Nunes AKS, Garcia-Osta A. Phosphodiesterase-5 Inhibitors: action on the signaling pathways of neuroinflammation, neurodegeneration, and cognition. Mediators Inflamm 2015.2015940207
[] [PMID: 26770022]
Bollen E, Prickaerts J. Phosphodiesterases in neurodegenerative disorders. IUBMB Life 2012; 64(12): 965-70.
[] [PMID: 23129425]
Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 2006; 109(3): 366-98.
[] [PMID: 16102838]
Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 2014; 13(4): 290-314.
[] [PMID: 24687066]
Xu Y, Zhang HT, O’Donnell JM. Phosphodiesterases in the central nervous system: implications in mood and cognitive disorders. Phosphodiesterases as Drug Targets 2011; pp. 447-85.
Zhang HT. Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. Curr Pharm Des 2009; 15(14): 1688-98.
[] [PMID: 19442182]
Shimizu-Albergine M, Rybalkin SD, Rybalkina IG, et al. Individual cerebellar Purkinje cells express different cGMP phosphodiesterases (PDEs): in vivo phosphorylation of cGMP-specific PDE (PDE5) as an indicator of cGMP-dependent protein kinase (PKG) activation. J Neurosci 2003; 23(16): 6452-9.
[] [PMID: 12878685]
Wang ZZ, Zhang Y, Zhang HT, Li YF. Phosphodiesterase: an interface connecting cognitive deficits to neuropsychiatric and neurodegenerative diseases. Curr Pharm Des 2015; 21(3): 303-16.
[] [PMID: 25159069]
Conti M. Phosphodiesterases and cyclic nucleotide signaling in endocrine cells. Mol Endocrinol 2000; 14(9): 1317-27.
[] [PMID: 10976911]
Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses. Science 2001; 294(5544): 1030-8.
[] [PMID: 11691980]
Heckman PRA, Blokland A, Bollen EPP, Prickaerts J. Phosphodiesterase inhibition and modulation of corticostriatal and hippocampal circuits: Clinical overview and translational considerations. Neurosci Biobehav Rev 2018; 87: 233-54.
[] [PMID: 29454746]
Prickaerts J, Heckman PRA, Blokland A. Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease. Expert Opin Investig Drugs 2017; 26(9): 1033-48.
[] [PMID: 28772081]
Lu YF, Hawkins RD. Ryanodine receptors contribute to cGMPinduced late-phase LTP and CREB phosphorylation in the hippocampus. J Neurophysiol 2002; 88(3): 1270-8.
[] [PMID: 12205148]
Jancic D, Lopez de Armentia M, Valor LM, Olivares R, Barco A. Inhibition of cAMP response element-binding protein reduces neuronal excitability and plasticity, and triggers neurodegeneration. Cereb Cortex 2009; 19(11): 2535-47.
[] [PMID: 19213815]
Tanwar M, Khera L, Haokip N, Kaul R, Naorem A, Kateriya S. Modulation of cyclic nucleotide-mediated cellular signaling and gene expression using photoactivated adenylyl cyclase as an optogenetic tool. Sci Rep 2017; 7(1): 12048.
[] [PMID: 28935957]
Lu YF, Kandel ER, Hawkins RD. Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus. J Neurosci 1999; 19(23): 10250-61.
[] [PMID: 10575022]
Alford S, Frenguelli BG, Schofield JG, Collingridge GL. Characterization of Ca2+ signals induced in hippocampal CA1 neurones by the synaptic activation of NMDA receptors. J Physiol 1993; 469(1): 693-716.
[] [PMID: 8271224]
Bliss TV, Collingridge GL. A synaptic model of memory: long term potentiation in the hippocampus. Nature 1993; 361(6407): 31-9.
[] [PMID: 8421494]
Doronzo G, Viretto M, Russo I, et al. 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 2011; 216(1): 44-53.
[] [PMID: 21316056]
Meyer-Franke A, Wilkinson GA, Kruttgen A, et al. Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons. Neuron 1998; 21(4): 681-93.
[] [PMID: 9808456]
Brunet A, Datta SR, Greenberg ME. Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol 2001; 11(3): 297-305.
[] [PMID: 11399427]
Zhang C, Lueptow LM, Zhang HT, O’Donnell JM, Xu Y. The role of phosphodiesterase-2 in psychiatric and neurodegenerative disorders. Adv Neurobiol 2017; 17: 307-47.
[] [PMID: 28956338]
Frölich L, Wunderlich G, Thamer C, Roehrle M, Garcia M Jr, Dubois B. Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer’s disease. Alzheimers Res Ther 2019; 11(1): 18.
[] [PMID: 30755255]
Kullmann DM. Silent synapses: what are they telling us about long-term potentiation? Philos Trans R Soc Lond B Biol Sci 2003; 358(1432): 727-33.
[] [PMID: 12740119]
Shors TJ, Seib TB, Levine S, Thompson RF. Inescapable versus escapable shock modulates long-term potentiation in the rat hippocampus. Science 1989; 244(4901): 224-6.
[] [PMID: 2704997]
Reierson GW, Guo S, Mastronardi C, Licinio J, Wong ML. cGMP signaling, phosphodiesterases and major depressive disorder. Curr Neuropharmacol 2011; 9(4): 715-27.
[] [PMID: 22654729]
Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 2006; 7(9): 697-709.
[] [PMID: 16924259]
Marcello E, Epis R, Di Luca M. Amyloid flirting with synaptic failure: towards a comprehensive view of Alzheimer’s disease pathogenesis. Eur J Pharmacol 2008; 585(1): 109-18.
[] [PMID: 18377893]
Bailey CH, Bartsch D, Kandel ER. Toward a molecular definition of long-term memory storage. Proc Natl Acad Sci USA 1996; 93(24): 13445-52.
[] [PMID: 8942955]
Lavaur J, Bernard F, Trifilieff P, et al. A TAT-DEF-Elk-1 peptide regulates the cytonuclear trafficking of Elk-1 and controls cytoskeleton dynamics. J Neurosci 2007; 27(52): 14448-58.
[] [PMID: 18160653]
Suzuki S, Zhou H, Neumaier JF, Pham TA. Opposing functions of CREB and MKK1 synergistically regulate the geometry of dendritic spines in visual cortex. J Comp Neurol 2007; 503(5): 605-17.
[] [PMID: 17559089]
Schepers M, Tiane A, Paes D, et al. Targeting phosphodiesterases towards a tailor-made approach in multiple sclerosis treatment. Front Immunol 2019; 10: 1727.
[] [PMID: 31396231]
Rojo LE, Fernández JA, Maccioni AA, Jimenez JM, Maccioni RB. Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res 2008; 39(1): 1-16.
[] [PMID: 18067990]
Sánchez AJ, Puerta C, Ballester S, González P, Arriaga A, García-Merino A. Rolipram impairs NF-kappaB activity and MMP-9 expression in experimental autoimmune encephalomyelitis. J Neuroimmunol 2005; 168(1-2): 13-20.
[] [PMID: 16182379]
Aizawa T, Wei H, Miano JM, Abe J, Berk BC, Yan C. Role of phosphodiesterase 3 in NO/cGMP-mediated antiinflammatory effects in vascular smooth muscle cells. Circ Res 2003; 93(5): 406-13.
[] [PMID: 12919948]
Weber NC, Blumenthal SB, Hartung T, Vollmar AM, Kiemer AK. ANP inhibits TNF-α-induced endothelial MCP-1 expression--involvement of p38 MAPK and MKP-1. J Leukoc Biol 2003; 74(5): 932-41.
[] [PMID: 12960255]
Kamthong PJ, Wu M. Inhibitor of nuclear factor-kappaB induction by cAMP antagonizes interleukin-1-induced human macrophage-colony-stimulating-factor expression. Biochem J 2001; 356(Pt 2): 525-30.
[] [PMID: 11368781]
Gerlo S, Kooijman R, Beck IM, Kolmus K, Spooren A, Haegeman G. Cyclic AMP: a selective modulator of NF-κB action. Cell Mol Life Sci 2011; 68(23): 3823-41.
[] [PMID: 21744067]
Lomas O, Zaccolo M. Phosphodiesterases maintain signaling fidelity via compartmentalization of cyclic nucleotides. Physiology (Bethesda) 2014; 29(2): 141-9.
[] [PMID: 24583770]
Santos AI, Carreira BP, Nobre RJ, Carvalho CM, Araújo IM. Stimulation of neural stem cell proliferation by inhibition of phosphodiesterase 5. Stem cells international 2014 2014.
Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza PV, Abrous DN. Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci USA 2003; 100(24): 14385-90.
[] [PMID: 14614143]
Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ. Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 1999; 2(3): 260-5.
[] [PMID: 10195219]
Fuchs E, Gould E. Mini-review: in vivo neurogenesis in the adult brain: regulation and functional implications. Eur J Neurosci 2000; 12(7): 2211-4.
[] [PMID: 10947799]
Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001; 24(1): 677-736.
[] [PMID: 11520916]
Beaumont V, Zucker RS. Enhancement of synaptic transmission by cyclic AMP modulation of presynaptic Ih channels. Nat Neurosci 2000; 3(2): 133-41.
[] [PMID: 10649568]
Chesnokova V, Pechnick RN, Wawrowsky K. Chronic peripheral inflammation, hippocampal neurogenesis, and behavior. Brain Behav Immun 2016; 58: 1-8.
[] [PMID: 26802985]
Wang H, Xu J, Lazarovici P, Quirion R, Zheng W. cAMP response element-binding protein (creb): a possible signaling molecule link in the pathophysiology of schizophrenia. Front Mol Neurosci 2018; 11: 255.
[] [PMID: 30214393]
Heinrich PC, Behrmann I, Müller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 1998; 334(Pt 2): 297-314.
[] [PMID: 9716487]
Cao F, Hata R, Zhu P, et al. Overexpression of SOCS3 inhibits astrogliogenesis and promotes maintenance of neural stem cells. J Neurochem 2006; 98(2): 459-70.
[] [PMID: 16805839]
Scott Bitner R. Cyclic AMP response element-binding protein (CREB) phosphorylation: a mechanistic marker in the development of memory enhancing Alzheimer’s disease therapeutics. Biochem Pharmacol 2012; 83(6): 705-14.
[] [PMID: 22119240]
Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action. Nat Neurosci 2005; 83(6): 705-14.
[PMID: 15917833]
Lu Y, Christian K, Lu B. BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 2008; 89(3): 312-23.
[] [PMID: 17942328]
Arai H, Ichimiya Y, Kosaka K, Moroji T, Iizuka R. Neurotransmitter changes in early- and late-onset alzheimer-type dementia. Prog Neuropsychopharmacol Biol Psychiatry 1992; 16(6): 883-90.
[] [PMID: 1381103]
Rutten K, Lieben C, Smits L, Blokland A. The PDE4 inhibitor rolipram reverses object memory impairment induced by acute tryptophan depletion in the rat. Psychopharmacology (Berl) 2007; 192(2): 275-82.
[] [PMID: 17265077]
Puzzo D, Sapienza S, Arancio O, Palmeri A. Role of phosphodiesterase 5 in synaptic plasticity and memory. Neuropsychiatr Dis Treat 2008; 4(2): 371-87.
[] [PMID: 18728748]
Kaundal M, Zameer S, Najmi AK, Parvez S, Akhtar M. Betulinic acid, a natural PDE inhibitor restores hippocampal cAMP/cGMP and BDNF, improve cerebral blood flow and recover memory deficits in permanent BCCAO induced vascular dementia in rats. Eur J Pharmacol 2018; 832: 56-66.
[] [PMID: 29778746]
Jin N, Qian W, Yin X, et al. CREB regulates the expression of neuronal glucose transporter 3: a possible mechanism related to impaired brain glucose uptake in Alzheimer’s disease. Nucleic Acids Res 2013; 41(5): 3240-56.
[] [PMID: 23341039]
Ho JE, Arora P, Walford GA, et al. Effect of phosphodiesterase inhibition on insulin resistance in obese individuals. J Am Heart Assoc 2014; 3(5)e001001
[] [PMID: 25213566]
Hill KD, Eckhauser AW, Marney A, Brown NJ. Phosphodiesterase 5 inhibition improves β-cell function in metabolic syndrome. Diabetes Care 2009; 32(5): 857-9.
[] [PMID: 19196886]
Dundore RL, Clas DM, Wheeler LT, et al. Zaprinast increases cyclic GMP levels in plasma and in aortic tissue of rats. Eur J Pharmacol 1993; 249(3): 293-7.
[] [PMID: 8287916]
Selkoe DJ. Normal and abnormal biology of the beta-amyloid precursor protein. Annu Rev Neurosci 1994; 17(1): 489-517.
[] [PMID: 8210185]
Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416(6880): 535-9.
[] [PMID: 11932745]
Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science 2002; 298(5594): 789-91.
[] [PMID: 12399581]
Wang C, Guo J, Guo R. Effect of XingPiJieYu decoction on spatial learning and memory and cAMP-PKA-CREB-BDNF pathway in rat model of depression through chronic unpredictable stress. BMC Complement Altern Med 2017; 17(1): 73.
[] [PMID: 28118829]
Reyes-Irisarri E, Markerink-Van Ittersum M, Mengod G, de Vente J. Expression of the cGMP-specific phosphodiesterases 2 and 9 in normal and Alzheimer’s disease human brains. Eur J Neurosci 2007; 25(11): 3332-8.
[] [PMID: 17553001]
Dickey CA, Gordon MN, Mason JE, et al. Amyloid suppresses induction of genes critical for memory consolidation in APP + PS1 transgenic mice. J Neurochem 2004; 88(2): 434-42.
[] [PMID: 14690531]
Alberini CM, Kandel ER. The regulation of transcription in memory consolidation. Cold Spring Harb Perspect Biol 2014; 7(1)a021741
[] [PMID: 25475090]
CuadradoTejedor M, Hervias I, Ricobaraza A, Sildenafil restores cognitive function without affecting b-amyloid burden in a mouse model of Alzheimer’s disease. Br J Pharmacol 2011; 164(8): 2029-41.
[] [PMID: 21627640]
Jadhav S, Avila J, Schöll M, et al. A walk through tau therapeutic strategies. Acta Neuropathol Commun 2019; 7(1): 22.
[] [PMID: 30767766]
Tomidokoro Y, Harigaya Y, Matsubara E, et al. Brain Abeta amyloidosis in APPsw mice induces accumulation of presenilin-1 and tau. J Pathol 2001; 194(4): 500-6.
[] [PMID: 11523060]
Toda N, Okamura T. Cigarette smoking impairs nitric oxide mediated cerebral blood flow increase: Implications for Alzheimer’s disease. J Pharmacol Sci 2016; 131(4): 223-32.
[] [PMID: 27530818]
Ha KS, Kim KM, Kwon YG, et al. Nitric oxide prevents 6-hydroxydopamine-induced apoptosis in PC12 cells through cGMP dependent PI3 kinase/Akt activation. FASEB J 2003; 17(9): 1036-47.
[] [PMID: 12773486]
Takuma K, Phuagphong P, Lee E, Mori K, Baba A, Matsuda T. Anti-apoptotic effect of cGMP in cultured astrocytes: inhibition by cGMP-dependent protein kinase of mitochondrial permeable transition pore. J Biol Chem 2001; 276(51): 48093-9.
[] [PMID: 11677240]
Kulkarni SK, Patil CS. Phosphodiesterase 5 enzyme and its inhibitors: update on pharmacological and therapeutical aspects. Methods Find Exp Clin Pharmacol 2004; 26(10): 789-99.
[] [PMID: 15672122]
Hebb ALO, Robertson HA, Denovan-Wright EM. Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington’s disease transgenic mice prior to the onset of motor symptoms. Neuroscience 2004; 123(4): 967-81.
[] [PMID: 14751289]
Chapman TM, Goa KL. Cilostazol: a review of its use in intermittent claudication. Am J Cardiovasc Drugs 2003; 3(2): 117-38.
[] [PMID: 14727939]
Medina AE. Therapeutic utility of phosphodiesterase type I inhibitors in neurological conditions Frontiers in Neuroscience Neuropharmacology 2011. 5Article 21
Snyder GL, Prickaerts J, Wadenberg ML, et al. Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats. Psychopharmacology (Berl) 2016; 233(17): 3113-24.
[] [PMID: 27342643]
Wang L, Xiaokaiti Y, Wang G, et al. Inhibition of PDE2 reverses beta amyloid induced memory impairment through regulation of PKA/PKG-dependent neuro-inflammatory and apoptotic pathways. Sci Rep 2017; 7(1): 12044.
[] [PMID: 28935920]
Park SH, Kim JH, Bae SS, et al. Protective effect of the phosphodiesterase III inhibitor cilostazol on amyloid β-induced cognitive deficits associated with decreased amyloid β accumulation. Biochem Biophys Res Commun 2011; 408(4): 602-8.
[] [PMID: 21530492]
Kitamura A, Manso Y, Duncombe J, et al. Long-term cilostazol treatment reduces gliovascular damage and memory impairment in a mouse model of chronic cerebral hypoperfusion. Sci Rep 2017; 7(1): 4299.
[] [PMID: 28655874]
Yanai S, Toyohara J, Ishiwata K, Ito H, Endo S. Long-term cilostazol administration ameliorates memory decline in senescence accelerated mouse prone 8 (SAMP8) through a dual effect on cAMP and blood-brain barrier. Neuropharmacology 2017; 116: 247-59.
[] [PMID: 27979612]
Zhu L, Yang JY, Xue X, et al. A novel phosphodiesterase-5 Inhibitor: Yonkenafil modulates neurogenesis, gliosis to improve cognitive function and ameliorates amyloid burden in an APP/PS1 transgenic mice model. Mech Ageing Dev 2015; 150: 34-45.
[] [PMID: 26200391]
Sheng C, Xu P, Zhou K, Deng D, Zhang C, Wang Z. Icariin Attenuates Synaptic and Cognitive Deficits in an Aβ1–42-Induced Rat Model of Alzheimer’s Disease BioMed Res Int 2017 2017.
Yan L, Deng Y, Gao J, et al. Icariside II effectively reduces spatial learning and memory impairments in Alzheimer’s disease model mice targeting beta-amyloid production. Front Pharmacol 2017; 8: 106.
[] [PMID: 28337142]
Morales-Garcia JA, Echeverry-Alzate V, Alonso-Gil S, et al. Phosphodiesterase7 inhibition activates adult neurogenesis in hippocampus and subventricular zone in vitro and in vivo. Stem Cells 2017; 35(2): 458-72.
[] [PMID: 27538853]
Tsai LC, Chan GC, Nangle SN, et al. Inactivation of Pde8b enhances memory, motor performance, and protects against age-induced motor coordination decay. Genes Brain Behav 2012; 11(7): 837-47.
[] [PMID: 22925203]
Kroker KS, Rast G, Giovannini R, Marti A, Dorner-Ciossek C, Rosenbrock H. Inhibition of acetylcholinesterase and phosphodiesterase-9A has differential effects on hippocampal early and late LTP. Neuropharmacology 2012; 62(5-6): 1964-74.
[] [PMID: 22245562]
Cardinale A, Fusco FR. Inhibition of phosphodiesterases as a strategy to achieve neuroprotection in Huntington’s disease. CNS Neurosci Ther 2018; 24(4): 319-28.
[] [PMID: 29500937]
Menniti FS, Stephen Faraci W, Christopher JS. Phosphodiesterases in the CNS: targets for drug development Drug discovery 2006; 5: 661-70.
[] [PMID: 29500937]
Zhang C, Xu Y, Chowdhary A, et al. Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice. Neuropsychopharmacology 2018; 43(11): 2299-309.
[] [PMID: 30131563]
Blokland A, Van Duinen MA, Sambeth A, et al. Acute treatment with the PDE4 inhibitor roflumilast improves verbal word memory in healthy old individuals: a double-blind placebo-controlled study. Neurobiol Aging 2019; 77: 37-43.
[] [PMID: 30776650]
Xu B, Wang T, Xiao J, et al. FCPR03, a novel phosphodiesterase 4 inhibitor, alleviates cerebral ischemia/reperfusion injury through activation of the AKT/GSK3β/β-catenin signaling pathway. Biochem Pharmacol 2019; 163: 234-49.
[] [PMID: 30797872]
Azevedo MF, Faucz FR, Bimpaki E, et al. Clinical and molecular genetics of the phosphodiesterases (PDEs). Endocr Rev 2014; 35(2): 195-233.
[] [PMID: 24311737]
Xu Ying , Yang Mingxin, Zhang Han-Ting, et al. A selective phosphodiesterase 4D inhibitor BPN14770 reverses beta amyloidinduced memory impairment in humanized PDE4D mice FASEB J 2019; 33: 806.4.
Rosenbrock H, Giovannini R, Schänzle G, et al. The novel phosphodiesterase 9a inhibitor bi 409306 increases cyclic guanosine monophosphate levels in the brain, promotes synaptic plasticity, and enhances memory function in rodents. J Pharmacol Exp Ther 2019; 371(3): 633-41.
[] [PMID: 31578258]
Vanmierlo T, Creemers P, Akkerman S, et al. The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses. Behav Brain Res 2016; 303: 26-33.
[] [PMID: 26794595]
Umar T, Hoda N. Selective inhibitors of phosphodiesterases: therapeutic promise for neurodegenerative disorders. MedChemComm 2015; 6: 2063-80.
Li H, Zuo J, Tang W. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Front Pharmacol 2018; 9: 1048.
[] [PMID: 30386231]

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