Memory-enhancing effects of GEBR-32a, a new PDE4D inhibitor holding promise for the treatment of Alzheimer's disease

Scientific Reports

Volumn 7, Issue , 2017, Pages

  Ricciarelli, Roberta ^a   Brullo, Chiara ^a   Prickaerts, Jos ^b   Arancio, Ottavio ^c   Villa, Carla ^a   Rebosio, Claudia ^a   Calcagno, Elisa ^a   Balbi, Matilde ^a   Van Hagen, Britt T J ^b   Argyrousi, Elentina K ^b,c   Zhang, Hong ^c   Pronzato, Maria Adelaide ^a   Bruno, Olga ^a   Fedele, Ernesto ^a,d  

^a UNIVERSITY OF GENOA   (Italy)

^b MAASTRICHT UNIVERSITY   (Netherlands)

^c New York Presbyterian Morgan Stanley Children's Hospital   (United States)

^d UNIVERSITY OF GENOA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIC AMP; ISOENZYME; PHOSPHODIESTERASE IV; PHOSPHODIESTERASE IV INHIBITOR; RECOMBINANT PROTEIN;

ALZHEIMER DISEASE; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL CULTURE; CHEMICAL STRUCTURE; DNA DAMAGE; DRUG EFFECT; HIPPOCAMPUS; HUMAN; INTRACELLULAR SPACE; LONG TERM POTENTIATION; MEMORY; METABOLISM; MOUSE; PSYCHOLOGY; SYNTHESIS; TRANSGENIC MOUSE;

ALZHEIMER DISEASE; ANIMALS; CELLS, CULTURED; CYCLIC AMP; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 4; DNA DAMAGE; HIPPOCAMPUS; HUMANS; INTRACELLULAR SPACE; ISOENZYMES; LONG-TERM POTENTIATION; MEMORY; MICE; MICE, TRANSGENIC; MOLECULAR STRUCTURE; PHOSPHODIESTERASE 4 INHIBITORS; RECOMBINANT PROTEINS;

EID: 85017462641     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep46320     Document Type: Article

References (57)

1. Kandel, E. R. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol. Brain. 5, 14 (2012).
2. Bliss, T. V. & Lomo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant pathway. J. Physiol. 232, 331-356 (1973).
3. Wong, S. T. et al. Calcium-stimulated adenylyl cyclase activity is critical for hippocampus dependent long-term memory and late phase LTP. Neuron. 23, 787-798 (1999).
4. Wang, H., Ferguson, G. D., Pineda, V. V., Cundiff, P. E. & Storm, D. R. Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP. Nat. Neurosci. 7, 635-642 (2004).
5. Zhang, M. & Wang, H. Mice overexpressing type 1 adenylyl cyclase show enhanced spatial memory flexibility in the absence of intact synaptic long-term depression. Learn. Mem. 20, 352-367 (2013).
6. Frey, U., Huang, Y. Y. & Kandel, E. R. Effects of cAMP simulate a latestage of LTP in hippocampal neurons. Science. 260, 1661-1664 (1993).
7. Huang, Y. Y. & Kandel, E. R. Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization. Learn Mem. 1, 74-82 (1994).
8. Abel, T. et al. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell. 88, 615-626 (1997).
9. Barco, A., Alarcon, J. M. & Kandel, E. R. Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell. 108, 689-703 (2002).
10. Koh, M. T., Thiele, T. E. & Bernstein, I. L. Inhibition of protein kinase A activity interferes with lon-term, but not short-term, memory of conditioned taste aversions. Behav. Neurosci. 116, 1070-1074 (2002).
11. Pittenger, C. et al. Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron. 34, 447-462 (2002).
12. Young, J. Z., Isiegas, C., Abel, T. & Nguyen, P. V. Metaplasticity of the late phase of long-term potentiation: a critical role for protein kinase A in synaptic tagging. Eur. J. Neurosci. 23, 1784-1794 (2006).
13. Gelinas, J. N. et al. Activation of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the hippocampus. Learn. Mem. 15, 403-411 (2008).
14. Ma, N., Abel, T. & Hernadez, P. J. Exchange protein activated by cAMP enhances long-term memory formation independent of protein kinase A. Learn. Mem. 16, 367-370 (2009).
15. Suzuki, A. et al. Upregulation of CREB-mediated transcription enhances both short- and long-term memory. J. Neurosci. 31, 8786-8802 (2011).
16. Kida, S. A functional role for CREB as a positive regulator of memory formation and LTP. Exp. Neurobiol. 21, 136-140 (2012).
17. Bollen, E. et al. Improved long-term memory via enhancing cGMP-PKG signaling requires cAMP-PKA signaling. Neuropsychopharmacology. 39, 2497-2505 (2014).
18. Richter W., Menniti F. S., Zhang H. T. & Conti M. PDE4 as target for cognition enhancement. Expert Opin. Ther. Targets. 17, 1011-1027 (2013).
19. Hansen III, R. T. & Zhang, H. T. Phosphodiesterase-4 modulation as potential therapeutic for cognitive loss in pathological and nonpathological aging: possibilities and pitfalls. Curr. Pharm. Des. 21, 291-302 (2015).
20. Heckman, P. R., Blokland, A., Ramaekers, J. & Prickaerts, J. Phosphodiesterase inhibitors as a target for cognition enhancement in aging and Alzheimer's disease: a translational overview. Curr. Pharm. Des. 21, 317-331 (2015).
21. Gurney, M. E., D'Amato, E. C. & Burgin, A. B. Phosphodiesterase-4 (PDE4) molecular pharmacology and Alzheimer's disease. Neurotherapeutics. 12, 49-56 (2015).
22. Heckman, P. R., Blokland, A., Ramaekers, J. & Prickaerts, J. PDE and cognitive processing: beyond the memory domain. Neurobiol. Learn. Mem. 119, 108-122 (2015).
23. Hebenstreit, G. F. et al. Rolipram in major depressive disorder: results of a double-blind comparative study with imipramine. Pharmacopsychiatry. 22, 156-160 (1989).
24. Ricciarelli, R. & Fedele, E. Phosphodiesterase 4D: an enzyme to remember. Br. J. Pharmacol. 172, 4785-4789 (2015).
25. Bruno, O. et al. New Selective phosphodiesterase 4D inhibitors differently acting on long, short, and supershort isoforms. J. Med. Chem. 52, 6546-6557 (2009).
26. Bruno, O. et al. GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses. Br. J. Pharmacol. 164, 2054-2063 (2011).
27. Brullo, C. et al. Synthesis, biological evaluation, and molecular modeling of new 3-(cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) related phosphodiesterase 4D (PDE4D) inhibitors. J. Med. Chem. 57, 7061-7072 (2014).
28. Sierksma, A. S. et al. Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D. Neuropharmacology. 77, 120-130 (2014).
29. Brullo, C. et al. Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors. Bioorg. Med. Chem. 23, 3426-3435 (2015).
30. Brullo, C. et al. New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment. Eur. J. Med. Chem. 124, 82-102 (2016).
31. Muller, K., Faeh, C. & Diederich F. Fluorine in pharmaceuticals: looking beyond intuition. Science. 317, 1881-1886 (2007).
32. Hagmann, W. K. The many roles for fluorine in medicinal chemistry. J. Med. Chem. 51, 4359-4369 (2008).
33. Park, B. K., Kitteringham, N. R. & O'Neill, P. M. Metabolism of fluorine-containing drugs. Ann. Rev. Pharmacol. Toxicol. 41, 443-470 (2001).
34. Eastman, K. J., Gillis, E. P. & Meanwell, N. A. Tactical applications of fluorine in drug design and development. In Fluorine in Heterocyclic Chemistry (ed. Nenajdenko, V.) Volume 1 1-54 (Springer International 2014).
35. Wang, J. et al. Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011). Chem Rev. 114, 2432-2506 (2014).
36. Krause, W. & Kuhne, G. Pharmacokinetics of rolipram in the rhesus and cynomolougs monkey, the rat and the rabbit. Studies on species differences. Xenobiotica. 18, 561-571 (1988).
37. Vanmierlo, T. et al. The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses. Behav. Brain Res. 303, 26-33 (2016).
38. Burgin, A. N. et al. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat. Biotechnol. 28, 63-70 (2010).
39. Sutcliffe, J. S. et al. Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis). PLoS One. 9, e102449 (2014).
40. Rutten, K. 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. 558, 107-112 (2007).
41. Hsiao, K. et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274, 99-102 (1996).
42. Vitolo, O. 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 99, 13217-13221 (2002).
43. 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. 2, e89 (2012).
44. Sanderson, T. M. & Sher, E. The role of phosphodiesterases in hippocampal synaptic plasticity. Neuropharmacology. 74, 86-95 (2013).
45. Robichaud, A. et al. Assessing the emetic potential of PDE4 inhibitors in rats. Br. J. Pharmacol. 135, 113-118 (2002).
46. Robichaud, A., Savoie, C., Stamatiou, P. B., Tattersall, F. D. & Chan, C. C. PDE4 inhibitors induce emesis in ferrets via a noradrenergic pathway. Neuropharmacology. 40, 262-269 (2001).
47. McLachlan, C. S. et al. Changes in PDE4D isoforms in the hippocampus of a patient with advanced Alzheimer disease. Arch. Neurol. 64, 456-457 (2007).
48. Gong, B. et al. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J. Clin. Invest. 114, 1624-1634 (2004).
49. Kraft, P. et al. The phosphodiesterase-4 inhibitor rolipram protects from ischemic stroke in mice bt reducing bllod-brain-barrier damage, inflammation and thrombosis. Exp. Neurol. 247, 80-90 (2013).
50. Caraci, F. et al. A key role for TGF-b1 in hippocampal synaptic plasticity and memory. Sci. Rep. 5, 11252 (2016).
51. Guo, H. et al. FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signalling and anti-inflammatory effects. Neuropharmacology 116, 260-269 (2017).
52. Marte, A. et al. Alterations of glutamate release in the spinal cord of mice with experimental autoimmune encephalomyelitis. J. Neurochem. 115, 343-352 (2010).
53. d'Abramo, C., Ricciarelli, R., Pronzato, M. A. & Davis, P. Troglitazone, a perixosome proliferator-activated receptor-gamma agonist, decreases tau phosphorylation in CHOtau4R cells. J. Neurochem. 98, 1068-1077 (2006).
54. Ennaceur, A. & Delacour, J. A new one-trial test for neurobiological studies of memory in rat. 1:Behavioral data. Behav. Brain Res. 31:47-59 (1988).
55. Rutten, K. et al. Phosphodiesterase inhibitors enhance object memory independent of cerebral blood flow and glucose utilization in rats. Neuropsychopharmacology. 34, 1914-1925 (2009).
56. Akkerman, S. et al. Object recognition testing: Methodological considerations on exploration and discrimination measures. Behav. Brain Res. 232, 335-347 (2012).
57. Akkerman, S., Prickaerts, J., Steinbusch, H. W. M. & Blokland, A. Object recognition testing: Statistical considerations. Behav. Brain Res. 232, 317-322 (2012).