A Mechanistic Rationale for PDE-4 Inhibitors to Treat Residual Cognitive Deficits in Acquired Brain Injury

Author(s): Rudy Schreiber*, Romain Hollands, Arjan Blokland

Journal Name: Current Neuropharmacology

Volume 18 , Issue 3 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Patients with acquired brain injury (ABI) suffer from cognitive deficits that interfere significantly with their daily lives. These deficits are long-lasting and no treatment options are available. A better understanding of the mechanistic basis for these cognitive deficits is needed to develop novel treatments. Intracellular cyclic adenosine monophosphate (cAMP) levels are decreased in ABI. Herein, we focus on augmentation of cAMP by PDE4 inhibitors and the potentially synergistic mechanisms in traumatic brain injury. A major acute pathophysiological event in ABI is the breakdown of the blood-brain-barrier (BBB). Intracellular cAMP pathways are involved in the subsequent emergence of edema, inflammation and hyperexcitability. We propose that PDE4 inhibitors such as roflumilast can improve cognition by modulation of the activity in the cAMPPhosphokinase A-Ras-related C3 botulinum toxin substrate (RAC1) inflammation pathway. In addition, PDE4 inhibitors can also directly enhance network plasticity and attenuate degenerative processes and cognitive dysfunction by increasing activity of the canonical cAMP/phosphokinase- A/cAMP Responsive Element Binding protein (cAMP/PKA/CREB) plasticity pathway. Doublecourtin and microtubule-associated protein 2 are generated following activation of the cAMP/PKA/CREB pathway and are decreased or even absent after injury. Both proteins are involved in neuronal plasticity and may consist of viable markers to track these processes. It is concluded that PDE4 inhibitors may consist of a novel class of drugs for the treatment of residual symptoms in ABI attenuating the pathophysiological consequences of a BBB breakdown by their anti-inflammatory actions via the cAMP/PKA/RAC1 pathway and by increasing synaptic plasticity via the cAMP/PKA/CREB pathway. Roflumilast improves cognition in young and elderly humans and would be an excellent candidate for a proof of concept study in ABI patients.

Keywords: Blood brain barrier, cell adhesion molecules, cyclic adenosine monophosphate, cytokines, neuroinflammation, traumatic brain injury.

[1]
Kleindorfer, D.; Kissela, B.; Schneider, A.; Woo, D.; Khoury, J.; Miller, R.; Alwell, K.; Gebel, J.; Szaflarski, J.; Pancioli, A.; Jauch, E.; Moomaw, C.; Shukla, R.; Broderick, J.P.; Neuroscience, I. Eligibility for recombinant tissue plasminogen activator in acute ischemic stroke: a population-based study. Stroke, 2004, 35(2), e27-e29.
[http://dx.doi.org/10.1161/01.STR.0000109767.11426.17] [PMID: 14739423]
[2]
Detante, O.; Jaillard, A.; Moisan, A.; Barbieux, M.; Favre, I.M.; Garambois, K.; Hommel, M.; Remy, C. Biotherapies in stroke. Rev. Neurol. (Paris), 2014, 170(12), 779-798.
[http://dx.doi.org/10.1016/j.neurol.2014.10.005] [PMID: 25459115]
[3]
Abdullahi, W.; Tripathi, D.; Ronaldson, P.T. Blood-brain barrier dysfunction in ischemic stroke: targeting tight junctions and transporters for vascular protection. Am. J. Physiol. Cell Physiol., 2018, 315(3), C343-C356.
[http://dx.doi.org/10.1152/ajpcell.00095.2018] [PMID: 29949404]
[4]
Albert-Weißenberger, C.; Sirén, A.L.; Kleinschnitz, C. Ischemic stroke and traumatic brain injury: the role of the kallikrein-kinin system. Prog. Neurobiol., 2013, 101-102, 65-82.
[http://dx.doi.org/10.1016/j.pneurobio.2012.11.004] [PMID: 23274649]
[5]
Che, X.; Fang, Y.; Si, X.; Wang, J.; Hu, X.; Reis, C.; Chen, S. The role of gaseous molecules in traumatic brain injury: An updated review. Front. Neurosci., 2018, 12, 392.
[http://dx.doi.org/10.3389/fnins.2018.00392] [PMID: 29937711]
[6]
Jiang, X.; Andjelkovic, A.V.; Zhu, L.; Yang, T.; Bennett, M.V.L.; Chen, J.; Keep, R.F.; Shi, Y. Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog. Neurobiol., 2018, 163-164, 144-171.
[http://dx.doi.org/10.1016/j.pneurobio.2017.10.001] [PMID: 28987927]
[7]
Maegele, M.; Schöchl, H.; Menovsky, T.; Maréchal, H.; Marklund, N.; Buki, A.; Stanworth, S. Coagulopathy and haemorrhagic progression in traumatic brain injury: advances in mechanisms, diagnosis, and management. Lancet Neurol., 2017, 16(8), 630-647.
[http://dx.doi.org/10.1016/S1474-4422(17)30197-7] [PMID: 28721927]
[8]
Narne, P.; Pandey, V.; Phanithi, P.B. Role of nitric oxide and hydrogen sulfide in ischemic stroke and the emergent epigenetic underpinnings. Mol. Neurobiol., 2018, 56, 1749-1769.
[PMID: 29926377]
[9]
O’leary, R.A.; Nichol, A.D. Pathophysiology of severe traumatic brain injury. J. Neurosurg. Sci., 2018, 62(5), 542-548.
[PMID: 29790727]
[10]
Wilkinson, D. A.; Pandey, A. S.; Thompson, B. G.; Keep, R. F.; Hua, Y.; Xi, G. Injury mechanisms in acute intracerebral hemorrhage., Neuropharmacology, 2018, 134(Pt B), 240-248.
[http://dx.doi.org/10.1016/j.neuropharm.2017.09.033]
[11]
Hemphill, M.A.; Dabiri, B.E.; Gabriele, S.; Kerscher, L.; Franck, C.; Goss, J.A.; Alford, P.W.; Parker, K.K. A possible role for integrin signaling in diffuse axonal injury. PLoS One, 2011, 6(7)e22899
[http://dx.doi.org/10.1371/journal.pone.0022899] [PMID: 21799943]
[12]
Prakash, R.; Carmichael, S.T. Blood-brain barrier breakdown and neovascularization processes after stroke and traumatic brain injury. Curr. Opin. Neurol., 2015, 28(6), 556-564.
[http://dx.doi.org/10.1097/WCO.0000000000000248] [PMID: 26402408]
[13]
Schlegel, N.; Waschke, J. cAMP with other signaling cues converges on Rac1 to stabilize the endothelial barrier- a signaling pathway compromised in inflammation. Cell Tissue Res., 2014, 355(3), 587-596.
[http://dx.doi.org/10.1007/s00441-013-1755-y] [PMID: 24322391]
[14]
Munshi, A.; Das, S. Genetic Understanding of Stroke Treatment: Potential Role for Phosphodiesterase Inhibitors. Adv. Neurobiol., 2017, 17, 445-461.
[http://dx.doi.org/10.1007/978-3-319-58811-7_16] [PMID: 28956342]
[15]
Titus, D.J.; Oliva, A.A.; Wilson, N.M.; Atkins, C.M. Phosphodiesterase inhibitors as therapeutics for traumatic brain injury. Curr. Pharm. Des., 2015, 21(3), 332-342.
[http://dx.doi.org/10.2174/1381612820666140826113731] [PMID: 25159077]
[16]
Duman, R.S.; Nestler, E.J. Functional Roles for CAMP and CGMP. In: Basic Neurochemistry: Molecular, Cellular and Medical Aspects, (6th Edition); Siegel, G. J.; Agranoff, B. W.; Albers, R. W.; Price, D., Eds.; Lippincott-Raven: Philadelphia, 1999.
[17]
Vardjan, N.; Zorec, R. Excitable Astrocytes: Ca(2+)- and cAMP-Regulated Exocytosis. Neurochem. Res., 2015, 40(12), 2414-2424.
[http://dx.doi.org/10.1007/s11064-015-1545-x] [PMID: 25732760]
[18]
Veremeyko, T.; Yung, A.W.Y.; Dukhinova, M.; Kuznetsova, I.S.; Pomytkin, I.; Lyundup, A.; Strekalova, T.; Barteneva, N.S.; Ponomarev, E.D. Cyclic AMP pathway suppress autoimmune neuroinflammation by inhibiting functions of encephalitogenic CD4 T cells and enhancing M2 macrophage polarization at the Site of inflammation. Front. Immunol., 2018, 9, 50.
[http://dx.doi.org/10.3389/fimmu.2018.00050] [PMID: 29422898]
[19]
Deitmer, J.W.; Verkhratsky, A.J.; Lohr, C. Calcium signalling in glial cells. Cell Calcium, 1998, 24(5-6), 405-416.
[http://dx.doi.org/10.1016/S0143-4160(98)90063-X] [PMID: 10091009]
[20]
Fimia, G.M.; Sassone-Corsi, P. Cyclic AMP signalling. J. Cell Sci., 2001, 114(Pt 11), 1971-1972.
[PMID: 11493633]
[21]
Shi, G.X.; Rehmann, H.; Andres, D.A. A novel cyclic AMP-dependent Epac-Rit signaling pathway contributes to PACAP38-mediated neuronal differentiation. Mol. Cell. Biol., 2006, 26(23), 9136-9147.
[http://dx.doi.org/10.1128/MCB.00332-06] [PMID: 17000774]
[22]
Kang, E.J.; Major, S.; Jorks, D.; Reiffurth, C.; Offenhauser, N.; Friedman, A.; Dreier, J.P. Blood-brain barrier opening to large molecules does not imply blood-brain barrier opening to small ions. Neurobiol. Dis., 2013, 52, 204-218.
[http://dx.doi.org/10.1016/j.nbd.2012.12.007] [PMID: 23291193]
[23]
Haley, M.J.; Lawrence, C.B. The blood-brain barrier after stroke: Structural studies and the role of transcytotic vesicles. J. Cereb. Blood Flow Metab., 2017, 37(2), 456-470.
[http://dx.doi.org/10.1177/0271678X16629976] [PMID: 26823471]
[24]
Yang, C.; Hawkins, K.E.; Dore, S.; Candelario-Jalil, E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am. J. Physiol. Cell Physiol., 2018, 316, C135-C153.
[PMID: 30379577]
[25]
Reffelmann, T.; Kloner, R.A. The “no-reflow” phenomenon: basic science and clinical correlates. Heart, 2002, 87(2), 162-168.
[http://dx.doi.org/10.1136/heart.87.2.162] [PMID: 11796561]
[26]
Dietrich, W.D.; Alonso, O.; Halley, M. Early microvascular and neuronal consequences of traumatic brain injury: a light and electron microscopic study in rats. J. Neurotrauma, 1994, 11(3), 289-301.
[http://dx.doi.org/10.1089/neu.1994.11.289] [PMID: 7996583]
[27]
Liu, S.; Yu, C.; Yang, F.; Paganini-Hill, A.; Fisher, M.J. Phosphodiesterase inhibitor modulation of brain microvascular endothelial cell barrier properties. J. Neurol. Sci., 2012, 320(1-2), 45-51.
[http://dx.doi.org/10.1016/j.jns.2012.06.005] [PMID: 22819056]
[28]
Folcik, V.A.; Smith, T.; O’Bryant, S.; Kawczak, J.A.; Zhu, B.; Sakurai, H.; Kajiwara, A.; Staddon, J.M.; Glabinski, A.; Chernosky, A.L.; Tani, M.; Johnson, J.M.; Tuohy, V.K.; Rubin, L.L.; Ransohoff, R.M. 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., 1999, 97(1-2), 119-128.
[http://dx.doi.org/10.1016/S0165-5728(99)00063-6] [PMID: 10408965]
[29]
Belayev, L.; Busto, R.; Ikeda, M.; Rubin, L.L.; Kajiwara, A.; Morgan, L.; Ginsberg, M.D. Protection against blood-brain barrier disruption in focal cerebral ischemia by the type IV phosphodiesterase inhibitor BBB022: a quantitative study. Brain Res., 1998, 787(2), 277-285.
[http://dx.doi.org/10.1016/S0006-8993(97)01499-6] [PMID: 9518648]
[30]
Hinson, H.E.; Rowell, S.; Schreiber, M. Clinical evidence of inflammation driving secondary brain injury: a systematic review. J. Trauma Acute Care Surg., 2015, 78(1), 184-191.
[http://dx.doi.org/10.1097/TA.0000000000000468] [PMID: 25539220]
[31]
Smith, C.; Gentleman, S.M.; Leclercq, P.D.; Murray, L.S.; Griffin, W.S.; Graham, D.I.; Nicoll, J.A. The neuroinflammatory response in humans after traumatic brain injury. Neuropathol. Appl. Neurobiol., 2013, 39(6), 654-666.
[http://dx.doi.org/10.1111/nan.12008] [PMID: 23231074]
[32]
Kamel, H.; Iadecola, C. Brain-immune interactions and ischemic stroke: clinical implications. Arch. Neurol., 2012, 69(5), 576-581.
[http://dx.doi.org/10.1001/archneurol.2011.3590] [PMID: 22782509]
[33]
Ramlackhansingh, A.F.; Brooks, D.J.; Greenwood, R.J.; Bose, S.K.; Turkheimer, F.E.; Kinnunen, K.M.; Gentleman, S.; Heckemann, R.A.; Gunanayagam, K.; Gelosa, G.; Sharp, D.J. Inflammation after trauma: microglial activation and traumatic brain injury. Ann. Neurol., 2011, 70(3), 374-383.
[http://dx.doi.org/10.1002/ana.22455] [PMID: 21710619]
[34]
Walter, H.L.; Walberer, M.; Rueger, M.A.; Backes, H.; Wiedermann, D.; Hoehn, M.; Neumaier, B.; Graf, R.; Fink, G.R.; Schroeter, M. In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke. Neuroscience, 2015, 292, 71-80.
[http://dx.doi.org/10.1016/j.neuroscience.2015.02.024] [PMID: 25701708]
[35]
Johnson, V.E.; Stewart, J.E.; Begbie, F.D.; Trojanowski, J.Q.; Smith, D.H.; Stewart, W. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain, 2013, 136(Pt 1), 28-42.
[http://dx.doi.org/10.1093/brain/aws322] [PMID: 23365092]
[36]
Etherton, M.R.; Wu, O.; Cougo, P.; Giese, A.K.; Cloonan, L.; Fitzpatrick, K.M.; Kanakis, A.S.; Boulouis, G.; Karadeli, H.H.; Lauer, A.; Rosand, J.; Furie, K.L.; Rost, N.S. Integrity of normal-appearing white matter and functional outcomes after acute ischemic stroke. Neurology, 2017, 88(18), 1701-1708.
[http://dx.doi.org/10.1212/WNL.0000000000003890] [PMID: 28381507]
[37]
Weishaupt, N.; Zhang, A.; Deziel, R.A.; Tasker, R.A.; Whitehead, S.N. Prefrontal ischemia in the rat leads to secondary damage and inflammation in remote gray and white matter regions. Front. Neurosci., 2016, 10, 81.
[http://dx.doi.org/10.3389/fnins.2016.00081] [PMID: 26973455]
[38]
Titus, D.J.; Wilson, N.M.; Freund, J.E.; Carballosa, M.M.; Sikah, K.E.; Furones, C.; Dietrich, W.D.; Gurney, M.E.; Atkins, C.M. Chronic cognitive dysfunction after traumatic brain injury is improved with a phosphodiesterase 4B inhibitor. J. Neurosci., 2016, 36(27), 7095-7108.
[http://dx.doi.org/10.1523/JNEUROSCI.3212-15.2016] [PMID: 27383587]
[39]
Atkins, C.M.; Falo, M.C.; Alonso, O.F.; Bramlett, H.M.; Dietrich, W.D. Deficits in ERK and CREB activation in the hippocampus after traumatic brain injury. Neurosci. Lett., 2009, 459(2), 52-56.
[http://dx.doi.org/10.1016/j.neulet.2009.04.064] [PMID: 19416748]
[40]
Radeva, M.Y.; Waschke, J. Mind the gap: mechanisms regulating the endothelial barrier. Acta Physiol. (Oxf.), 2018, 222(1)
[http://dx.doi.org/10.1111/apha.12860] [PMID: 28231640]
[41]
Titus, D.J.; Sakurai, A.; Kang, Y.; Furones, C.; Jergova, S.; Santos, R.; Sick, T.J.; Atkins, C.M. Phosphodiesterase inhibition rescues chronic cognitive deficits induced by traumatic brain injury. J. Neurosci., 2013, 33(12), 5216-5226.
[http://dx.doi.org/10.1523/JNEUROSCI.5133-12.2013] [PMID: 23516287]
[42]
Zhu, J.; Mix, E.; Winblad, B. The antidepressant and antiinflammatory effects of rolipram in the central nervous system. CNS Drug Rev., 2001, 7(4), 387-398.
[http://dx.doi.org/10.1111/j.1527-3458.2001.tb00206.x] [PMID: 11830756]
[43]
Yoshikawa, M.; Suzumura, A.; Tamaru, T.; Takayanagi, T.; Sawada, M. Effects of phosphodiesterase inhibitors on cytokine production by microglia. Mult. Scler., 1999, 5(2), 126-133.
[http://dx.doi.org/10.1177/135245859900500210] [PMID: 10335522]
[44]
Gerlo, S.; Kooijman, R.; Beck, I.M.; Kolmus, K.; Spooren, A.; Haegeman, G.; Cyclic, A.M.P. Cyclic AMP: a selective modulator of NF-κB action. Cell. Mol. Life Sci., 2011, 68(23), 3823-3841.
[http://dx.doi.org/10.1007/s00018-011-0757-8] [PMID: 21744067]
[45]
Zou, Z.Q.; Chen, J.J.; Feng, H.F.; Cheng, Y.F.; Wang, H.T.; Zhou, Z.Z.; Guo, H.B.; Zheng, W.; Xu, J.P. Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of the cAMP/PKA/CREB Signaling Pathway and NF-κB Inhibition. J. Pharmacol. Exp. Ther., 2017, 362(1), 67-77.
[http://dx.doi.org/10.1124/jpet.116.239608] [PMID: 28450469]
[46]
Chen, J.; Yu, H.; Zhong, J.; Feng, H.; Wang, H.; Cheng, Y.; Zou, Z.; Huang, C.; Zhou, Z.; Zheng, W.; Xu, J. The phosphodiesterase-4 inhibitor, FCPR16, attenuates ischemia-reperfusion injury in rats subjected to middle cerebral artery occlusion and reperfusion. Brain Res. Bull., 2018, 137, 98-106.
[http://dx.doi.org/10.1016/j.brainresbull.2017.11.010] [PMID: 29155261]
[47]
Kandel, E.R. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol. Brain, 2012, 5, 14.
[http://dx.doi.org/10.1186/1756-6606-5-14] [PMID: 22583753]
[48]
Kandel, E.R. The molecular biology of memory storage: a dialog between genes and synapses. Biosci. Rep., 2004, 24(4-5), 475-522.
[http://dx.doi.org/10.1007/s10540-005-2742-7] [PMID: 16134023]
[49]
Segal, M.; Murphy, D.D. CREB activation mediates plasticity in cultured hippocampal neurons. Neural Plast., 1998, 6(3), 1-7.
[http://dx.doi.org/10.1155/NP.1998.1] [PMID: 9920677]
[50]
Brown, J.P.; Couillard-Després, S.; Cooper-Kuhn, C.M.; Winkler, J.; Aigner, L.; Kuhn, H.G. Transient expression of doublecortin during adult neurogenesis. J. Comp. Neurol., 2003, 467(1), 1-10.
[http://dx.doi.org/10.1002/cne.10874] [PMID: 14574675]
[51]
Johnson, G.V.; Jope, R.S. The role of microtubule-associated protein 2 (MAP-2) in neuronal growth, plasticity, and degeneration. J. Neurosci. Res., 1992, 33(4), 505-512.
[http://dx.doi.org/10.1002/jnr.490330402] [PMID: 1484385]
[52]
Maurice, D.H.; Ke, H.; Ahmad, F.; Wang, Y.; Chung, J.; Manganiello, V.C. Advances in targeting cyclic nucleotide phosphodiesterases. Nat. Rev. Drug Discov., 2014, 13(4), 290-314.
[http://dx.doi.org/10.1038/nrd4228] [PMID: 24687066]
[53]
DeNinno, M.P. Future directions in phosphodiesterase drug discovery. Bioorg. Med. Chem. Lett., 2012, 22(22), 6794-6800.
[http://dx.doi.org/10.1016/j.bmcl.2012.09.028] [PMID: 23046962]
[54]
Bender, A.T.; Beavo, J.A. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol. Rev., 2006, 58(3), 488-520.
[http://dx.doi.org/10.1124/pr.58.3.5] [PMID: 16968949]
[55]
Prickaerts, J.; Heckman, P.R.A.; Blokland, A. Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease. Expert Opin. Investig. Drugs, 2017, 26(9), 1033-1048.
[http://dx.doi.org/10.1080/13543784.2017.1364360] [PMID: 28772081]
[56]
Van Duinen, M.A.; Sambeth, A.; Heckman, P.R.A.; Smit, S.; Tsai, M.; Lahu, G.; Uz, T.; Blokland, A.; Prickaerts, J. Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults. Neuropharmacology, 2018, 131, 31-38.
[http://dx.doi.org/10.1016/j.neuropharm.2017.12.019] [PMID: 29241652]
[57]
Blokland, A.; Van Duinen, M.A.; Sambeth, A.; Heckman, P.R.A.; Tsai, M.; Lahu, G.; Uz, T.; Prickaerts, J. 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.
[http://dx.doi.org/10.1016/j.neurobiolaging.2019.01.014] [PMID: 30776650]
[58]
Gilleen, J.; Farah, Y.; Davison, C.; Kerins, S.; Valdearenas, L.; Uz, T.; Lahu, G.; Tsai, M.; Ogrinc, F.; Reichenberg, A.; Williams, S. C.; Mehta, M. A.; Shergill, S. S. An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients. Psychopharmacology (Berl), 2018.
[http://dx.doi.org/10.1007/s00213-018-5134-y]
[59]
Hebenstreit, G.F.; Fellerer, K.; Fichte, K.; Fischer, G.; Geyer, N.; Meya, U.; Sastre-y-Hernández, M.; Schöny, W.; Schratzer, M.; Soukop, W. Rolipram in major depressive disorder: results of a double-blind comparative study with imipramine. Pharmacopsychiatry, 1989, 22(4), 156-160.
[http://dx.doi.org/10.1055/s-2007-1014599] [PMID: 2668980]
[60]
Wilson, N.M.; Titus, D.J.; Oliva, A.A., Jr; Furones, C.; Atkins, C.M. Traumatic Brain Injury Upregulates Phosphodiesterase Expression in the Hippocampus. Front. Syst. Neurosci., 2016, 10, 5.
[http://dx.doi.org/10.3389/fnsys.2016.00005] [PMID: 26903822]
[61]
Atkins, C.M.; Oliva, A.A., Jr; Alonso, O.F.; Pearse, D.D.; Bramlett, H.M.; Dietrich, W.D. Modulation of the cAMP signaling pathway after traumatic brain injury. Exp. Neurol., 2007, 208(1), 145-158.
[http://dx.doi.org/10.1016/j.expneurol.2007.08.011] [PMID: 17916353]
[62]
Titus, D.J.; Furones, C.; Kang, Y.; Atkins, C.M. Age-dependent alterations in cAMP signaling contribute to synaptic plasticity deficits following traumatic brain injury. Neuroscience, 2013, 231, 182-194.
[http://dx.doi.org/10.1016/j.neuroscience.2012.12.002] [PMID: 23238576]
[63]
He, Z.; He, B.; Behrle, B.L.; Fejleh, M.P.; Cui, L.; Paule, M.G.; Greenfield, L.J. Ischemia-induced increase in microvascular phosphodiesterase 4D expression in rat hippocampus associated with blood brain barrier permeability: effect of age. ACS Chem. Neurosci., 2012, 3(6), 428-432.
[http://dx.doi.org/10.1021/cn2001156] [PMID: 22860212]
[64]
Park, K.; Biederer, T. Neuronal adhesion and synapse organization in recovery after brain injury. Future Neurol., 2013, 8(5), 555-567.
[http://dx.doi.org/10.2217/fnl.13.35] [PMID: 24489481]
[65]
Abel, T.; Kandel, E. Positive and negative regulatory mechanisms that mediate long-term memory storage. Brain Res. Brain Res. Rev., 1998, 26(2-3), 360-378.
[http://dx.doi.org/10.1016/S0165-0173(97)00050-7] [PMID: 9651552]
[66]
Sanz, M.J.; Cortijo, J.; Morcillo, E.J. PDE4 inhibitors as new anti-inflammatory drugs: effects on cell trafficking and cell adhesion molecules expression. Pharmacol. Ther., 2005, 106(3), 269-297.
[http://dx.doi.org/10.1016/j.pharmthera.2004.12.001] [PMID: 15922015]
[67]
Fleming, Y.M.; Frame, M.C.; Houslay, M.D. PDE4-regulated cAMP degradation controls the assembly of integrin-dependent actin adhesion structures and REF52 cell migration. J. Cell Sci., 2004, 117(Pt 11), 2377-2388.
[http://dx.doi.org/10.1242/jcs.01096] [PMID: 15126637]
[68]
Yasuda, R.; Murakoshi, H. The mechanisms underlying the spatial spreading of signaling activity. Curr. Opin. Neurobiol., 2011, 21(2), 313-321.
[http://dx.doi.org/10.1016/j.conb.2011.02.008] [PMID: 21429735]
[69]
Li, L.X.; Cheng, Y.F.; Lin, H.B.; Wang, C.; Xu, J.P.; Zhang, H.T. Prevention of cerebral ischemia-induced memory deficits by inhibition of phosphodiesterase-4 in rats. Metab. Brain Dis., 2011, 26(1), 37-47.
[http://dx.doi.org/10.1007/s11011-011-9235-0] [PMID: 21327879]
[70]
Imanishi, T.; Sawa, A.; Ichimaru, Y.; Miyashiro, M.; Kato, S.; Yamamoto, T.; Ueki, S. Ameliorating effects of rolipram on experimentally induced impairments of learning and memory in rodents. Eur. J. Pharmacol., 1997, 321(3), 273-278.
[http://dx.doi.org/10.1016/S0014-2999(96)00969-7] [PMID: 9085037]
[71]
Santiago, A.; Soares, L.M.; Schepers, M.; Milani, H.; Vanmierlo, T.; Prickaerts, J.; Weffort de Oliveira, R.M. Roflumilast promotes memory recovery and attenuates white matter injury in aged rats subjected to chronic cerebral hypoperfusion. Neuropharmacology, 2018, 138, 360-370.
[http://dx.doi.org/10.1016/j.neuropharm.2018.06.019] [PMID: 29933009]
[72]
Chiaretti, A.; Antonelli, A.; Genovese, O.; Pezzotti, P.; Rocco, C.D.; Viola, L.; Riccardi, R. Nerve growth factor and doublecortin expression correlates with improved outcome in children with severe traumatic brain injury. J. Trauma, 2008, 65(1), 80-85.
[http://dx.doi.org/10.1097/TA.0b013e31805f7036] [PMID: 18580535]
[73]
Pastori, C.; Regondi, M.C.; Librizzi, L.; de Curtis, M. Early excitability changes in a novel acute model of transient focal ischemia and reperfusion in the in vitro isolated guinea pig brain. Exp. Neurol., 2007, 204(1), 95-105.
[http://dx.doi.org/10.1016/j.expneurol.2006.09.023] [PMID: 17141221]
[74]
Wang, H.; Gaur, U.; Xiao, J.; Xu, B.; Xu, J.; Zheng, W. Targeting phosphodiesterase 4 as a potential therapeutic strategy for enhancing neuroplasticity following ischemic stroke. Int. J. Biol. Sci., 2018, 14(12), 1745-1754.
[http://dx.doi.org/10.7150/ijbs.26230] [PMID: 30416389]
[75]
Soares, L.M.; Prickaerts, J.; Milani, H.; Del Bel, E.; Steinbusch, H.W.; de Oliveira, R.M. Phosphodiesterase Inhibition as a Therapeutic Target for Brain Ischemia. CNS Neurol. Disord. Drug Targets, 2015, 14(8), 1012-1023.
[http://dx.doi.org/10.2174/1871527314666150909114249] [PMID: 26350339]
[76]
Mackic, J.B.; Stins, M.; Jovanovic, S.; Kim, K.S.; Bartus, R.T.; Zlokovic, B.V. Cereport (RMP-7) increases the permeability of human brain microvascular endothelial cell monolayers. Pharm. Res., 1999, 16(9), 1360-1365.
[http://dx.doi.org/10.1023/A:1018938722768] [PMID: 10496650]
[77]
Loane, D.J.; Kumar, A.; Stoica, B.A.; Cabatbat, R.; Faden, A.I. Progressive neurodegeneration after experimental brain trauma: association with chronic microglial activation. J. Neuropathol. Exp. Neurol., 2014, 73(1), 14-29.
[http://dx.doi.org/10.1097/NEN.0000000000000021] [PMID: 24335533]
[78]
Nagakura, A.; Niimura, M.; Takeo, S. Effects of a phosphodiesterase IV inhibitor rolipram on microsphere embolism-induced defects in memory function and cerebral cyclic AMP signal transduction system in rats. Br. J. Pharmacol., 2002, 135(7), 1783-1793.
[http://dx.doi.org/10.1038/sj.bjp.0704629] [PMID: 11934820]
[79]
Titus, D.J.; Wilson, N.M.; Alcazar, O.; Calixte, D.A.; Dietrich, W.D.; Gurney, M.E.; Atkins, C.M. A negative allosteric modulator of PDE4D enhances learning after traumatic brain injury. Neurobiol. Learn. Mem., 2018, 148, 38-49.
[http://dx.doi.org/10.1016/j.nlm.2017.12.008] [PMID: 29294383]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 18
ISSUE: 3
Year: 2020
Page: [188 - 201]
Pages: 14
DOI: 10.2174/1570159X17666191010103044
Price: $65

Article Metrics

PDF: 20
HTML: 2