|Year : 2018 | Volume
| Issue : 3 | Page : 126-130
Phosphodiesterase 7B1 as therapeutic target for treatment of cognitive dysfunctions in multiple sclerosis
Arthi Balsundaram, Darling Chellathai
Department of Pharmacology, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu, India
|Date of Submission||11-Jun-2018|
|Date of Decision||12-Aug-2018|
|Date of Acceptance||12-Oct-2018|
|Date of Web Publication||18-Dec-2018|
Department of Pharmacology, Sri Ramachandra Medical College and Research Institute, Porur, Chennai - 600 116, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Multiple sclerosis (MS) is an autoimmune, chronic degenerative neuroinflammatory disorder affecting younger age groups of the United States of America and Europe. MS prevalence studies in India have shown that India is no longer a low-risk zone. Many studies have shown the seriousness of cognitive impairments (CIs) and its types caused in MS. In this review, the pathological basis for CI in various stages of MS was reviewed and revealed to provide a basis for the treatment. Role of phosphodiesterase 7B1 (PDE7B1) inhibitors in treating CI related to MS were also stated in this review. The literature for this review was collected from PubMed and Embase.
Keywords: Chronic degenerative neuroinflammatory disease, cognitive dysfunction, demyelinating disorder, memory, multiple sclerosis, phosphodiesterase 7B1
|How to cite this article:|
Balsundaram A, Chellathai D. Phosphodiesterase 7B1 as therapeutic target for treatment of cognitive dysfunctions in multiple sclerosis. J Pharmacol Pharmacother 2018;9:126-30
|How to cite this URL:|
Balsundaram A, Chellathai D. Phosphodiesterase 7B1 as therapeutic target for treatment of cognitive dysfunctions in multiple sclerosis. J Pharmacol Pharmacother [serial online] 2018 [cited 2019 May 23];9:126-30. Available from: http://www.jpharmacol.com/text.asp?2018/9/3/126/247701
| Introduction|| |
Cognitive impairment (CI) in multiple sclerosis (MS) was considered as heterogeneous. However, there are studies which have stated the pathological basis for deviation of cognitive functions in MS, contributing to factors such as defects in neural conductions in brain, deviation of biochemical components, and up-regulation of cyclic adenosine monophosphate (AMP)-specific phosphodiesterases (PDE).,,, Furthermore, this was considered as an early symptom unnoticed in MS. This review also stated many PDE7 inhibitors stated in different disease conditions and showed that they could be potential for treatment of CI's in MS. The role of PDE7B in CI's of MS patients was reviewed using the literature from PubMed and Embase.
| Multiple Sclerosis|| |
MS is a chronic neuroinflammatory and autoimmune disorder affecting the central nervous system. This disease incidence varies from onset at 18 years, progressing up to 40 years, rare after 50 years of age and more prevalent in the USA and European countries.,,, In the USA, it was reported that 250000–350000 people were suffering from MS and in European countries, the prevalence rate was 83 for every 1 lakh population. In India, the prevalence of MS was reported as 8.3 for every 1 lakh population. Many studies reported the higher incidence rate in female population than male., The etiology included genetic and environmental factors.,,,, Genetic factors were reported to be associated with risk of MS. DRβ1 allele 15.01 of human leukocyte antigen gene located on Chromosome 6 was considered responsible for MS., Another factor included was familial recurrence which was reported to have 20% risk. An inverse relation was observed with a degree of consanguinity ranging from 2.77% to 0.88%. MS risk was 24%–34% in monozygotic twins and 2%–3% in dizygotic twins. The environmental factors include the Epstein–Barr virus, infectious mononucleosis, Vitamin D, smoking, commensal gut flora, childhood and adolescence, vascular comorbidities, and gestational environmental influences like month of birth. Smoking was reported to cause MS and also to aggravate the disease progression. Most of the disease risk was associated with the Epstein–Barr virus and infectious mononucleosis. It was reported that in the northern hemisphere, the births in May were more prone to MS than in November.
The pathological features of MS include initiation of inflammation in white matter resulting finally in axon loss. This features characteristic “focal plaques” which are inflammatory lesions in the white matter due to demyelination. This further progresses to a range of axonal loss and later results in gliosis. Inflammatory processes include the crossing of the blood-brain barrier by autoreactive T cells, secretion of cytokines, antibody induction by plasma cells which results in damage of tissue within the plaque. The axonal injury which is secondary event caused due to myelin damage in this disease process was described in two models. “Outside-in” model states axonal injury might be caused due to lesion arising from myelin. “Inside-out” model states that secondary myelin injury might be triggered by primary axonal injury. This results in diffuse atrophy of gray and white matter as disease progresses. In further progression, the plaques are rare. The preexisting plaques consist of activated microglia at their border causing low-grade inflammation. Because of this slow and gradual expansion of plaque and secondary demyelination occurs. Lucchinetti et al. reported that cerebral cortex was also affected in MS. Clinical features of MS include optic neuritis, cerebellar symptoms, sensory deficits exhibited mostly by relapsing type or initial stages. The progressive type may show spinal symptoms such as spasticity, ataxic gait, paresis, and corticospinal dysfunctions. This dysfunction or disability in MS is measured by the expanded disability status scale (EDSS). Based on disease progression and clinical course, the patients were grouped under the following categories. They are relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive-relapsing MS (PRMS). RRMS is the initial stage of the disease including 85% of the MS patients and changes to SPMS including 75% on progression. Forty percent of the patients gradually progress to PPMS. 15% of patients were reported to be in PRMS type from the onset of MS., A study reported that an EDSS score of 6 is attained by 7 years and 12.5 years in PPMS and SPMS category patients, respectively. The diagnosis of MS includes magnetic resonance imaging of the central nervous system, cerebrospinal fluid examination with clinical correlation.
| Cognitive Impairment in Multiple Sclerosis|| |
CI symptoms were considered as the earliest symptoms in the initial stages of MS. Cognitive dysfunctions in MS patients were considered as heterogeneous type. A study revealed MS as a causal factor for CI. Cross-sectional studies showed CI in 45%–60% MS patients and among these 20%–30% had severe dementia in their final stages. Memory, executive function, processing speed, information processing, efficient verbal fluency, visuospatial analysis, and attention are the cognitive functions impaired in MS patients. Processing speed impairment and memory impairment are the most commonly affected cognitive functions in MS. Processing speed is the amount of work done in a given time and memory is the amount of information learned and recalled. These cognitive functions were evaluated in MS patients by cognitive batteries. The most commonly used are the brief visuospatial memory test-revised (BVMT-R), California verbal learning test–II (CVLT-II) and symbol digit modalities test (SDMT). SDMT was considered as most sensitive test in MS patients. 40%–65% of MS patients showed impairment in memory function, but some reported that encoding and storage capacity is not breached. Benedict et al. reported that 30%–55% of MS patients showed memory impairment (using BVMT-R, CVLT-II). Acquisition of new knowledge was found as a difficult task in MS patients. Speed of information processing was found to be affected in 20%–30% of MS cases and this was considered as key deficit which had an impact in work environment. The reason for this slowed down of information processing was contributed to impaired conduction property of demyelinating neurons. Attention function impairment was reported in 25% of MS patients. Benedict et al. reported that 28%–52% of MS patients showed impairment in processing speed (using SDMT). Studies related cognitive deficits in MS to changes in thalamic nuclei,,, and hippocampus.,,
| Phosphodiesterase 7 and Cognitive Impairment in Multiple Sclerosis|| |
PDE7 is cyclic adenosine monophosphate (cAMP) specific hydrolysing enzyme. This enzyme exists in two isoforms, namely, PDE7A and PDE7B. These two isoforms exists in various transcripts. PDE7A exists as PDE7A1, PDE7A2, PDE7A3 and PDE7B exists as PDE7B1, PDE7B2, and PDE7B3. Dopaminergic D1 receptors was considered to activate PDE7B1 enzymes further playing a major role in cAMP/protein kinase A (PKA)/cAMP response element binding protein (CREB) pathway regulation, particularly in the striatum. This was reported to affect cognition. Activation of PDE7B1 causes decrease in levels of cAMP which may have a deteriorating effect. cAMP was considered to have a protective effect on demyelinating neurons. Furthermore, increased striatal dopamine levels were reported in MS. This increased dopamine levels were reported to increase pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin 10 through D1 receptors.
D1 receptor pathway in the corticostriatal circuit
Dopaminergic receptor D1, play an important role in motor control. Furthermore, D1 regulates long-term memory by triggering G-proteins. Gαs/olf subunit of G-protein activates the C2 site of adenylate cyclase. This causes binding of C1 and C2 resulting in the synthesis of cAMP from adenosine triphosphate., cAMP activates guanine nucleotide exchange factors (GEFs). This turns on Ras-proximate 1 which induces mitogen-activated protein kinase (MAPK) signaling.,, MAPK causes phosphorylation of CREB which finally triggers the translational and transcription factors resulting in formation of long-term memory., Phosphorylation of CREB is also triggered directly by PKA. This mechanism of long-term potentiation of memory is found, not only in hippocampus but also seen in the striatum and frontal cortex.,,,,, PDE7B1, majorly localized in the striatum of the brain is a known hydrolyzing enzyme specific to the cAMP. PDE7B1 reduces the levels of cAMP, thus reducing its physiological effects. Inhibition of PDE7B1 may elevate the levels of the cAMP in the striatum of the brain [Figure 1].
|Figure 1: D1R/cyclic adenosine monophosphate/cyclic adenosine monophosphate response element binding pathway. C2/AC: C2 sub-unit of Adenylyl cyclase, cAMP: Cyclic Adenosine monophosphate, GEF: Guanine nucleotide exchange factors, Rap1: Ras-proximate 1, MAPK1: Mitogen-activated protein kinase 1, CREB: CAMP response element binding protein, PKA: Protein kinase A, PDE7B1: Phosphodiesterase 7B1|
Click here to view
| Role of Phosphodiesterase 7B1 Inhibitors in Cognitive Impairment|| |
PDE7B1 inhibition was represented for the treatment of airway inflammatory diseases. IBFB-211913 is a new PDE7 inhibitor under development for treatment of asthma, autoimmune diseases, and psoriasis.,
Increasing the levels of cAMP and decreasing the increased expression of cAMP-specific PDE could be potential combination effect in treatment of MS-related CI. PDE7 inhibitors have shown protective effects in similar pathological events. So a scope for its beneficial importance in treatment of MS and its related CI could be given. S14, 5-imino-1, 2, 4-thiadiazole (VP1.15) were two PDE inhibitors proved to enhance cAMP levels in spinal cord injury mice model while VP1.15, quinazoline (TC3.6) showed remyelinating effects in an in vitro study with oligodendrocyte precursor cells. Enhanced Foxp3 levels was also reported with TC3.6, proving its neuroprotective effects. VP1.15 was reported to enhance early attention processing. A small molecule PDE7 inhibitor with heterocyclic structure (S14) was proved to antagonize microglial activation. This PDE inhibitor also showed improvement in cognitive functions., Till now, the PDE7 inhibitors available in the market are isoxazole derivative compounds, benzo(thio)pyranoimidazolone derivatives. Many other PDE7 inhibitors were shown to have a neuroprotective effects in MS condition but did not reveal about the effects on CI's.,,
| Conclusion|| |
In this review, MS was shown to have a significant role in developing cognitive dysfunctions due to its effects in hippocampus and corticostriatal regions in brain. PDE7B1 was shown to be an important interventional site for the treatment of CI's in MS. Exploring and producing effective PDE7B1 inhibitors for the treatment CI in MS and studies revealing their effectiveness in preclinical and clinical research are required as 65% of MS patients were shown to have CI's.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Guimarães J, Sá MJ. Cognitive dysfunction in multiple sclerosis. Front Neurol 2012;3:74.
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;25:3332-8.
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;21:317-31.
Domek-Łopacińska KU, Strosznajder JB. Cyclic GMP and nitric oxide synthase in aging and Alzheimer's disease. Mol Neurobiol 2010;41:129-37.
Perez-Torres S, Mengod G. cAMP-specific phosphodiesterases expression in Alzheimer's disease brains. Int Congr Ser 2003;1251:127-38.
Schulz D, Kopp B, Kunkel A, Faiss JH. Cognition in the early stage of multiple sclerosis. J Neurol 2006;253:1002-10.
Calabresi PA. Diagnosis and management of multiple sclerosis. Am Fam Physician 2004;70:1935-44.
Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000;343:938-52.
Confavreux C, Vukusic S. Natural history of multiple sclerosis: A unifying concept. Brain 2006;129:606-16.
Singh VK, Mehrotra S, Agarwal SS. The paradigm of th1 and Th2 cytokines: Its relevance to autoimmunity and allergy. Immunol Res 1999;20:147-61.
Pugliatti M, Rosati G, Carton H, Riise T, Drulovic J, Vécsei L, et al.
The epidemiology of multiple sclerosis in Europe. Eur J Neurol 2006;13:700-22.
Alonso A, Hernán MA. Temporal trends in the incidence of multiple sclerosis: A systematic review. Neurology 2008;71:129-35.
Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 2010;9:520-32.
Evans C, Beland SG, Kulaga S, Wolfson C, Kingwell E, Marriott J, et al.
Incidence and prevalence of multiple sclerosis in the Americas: A systematic review. Neuroepidemiology 2013;40:195-210.
Gourraud PA, Harbo HF, Hauser SL, Baranzini SE. The genetics of multiple sclerosis: An up-to-date review. Immunol Rev 2012;248:87-103.
Lin R, Charlesworth J, van der Mei I, Taylor BV. The genetics of multiple sclerosis. Pract Neurol 2012;12:279-88.
Robertson NP, Fraser M, Deans J, Clayton D, Walker N, Compston DA. Age-adjusted recurrence risks for relatives of patients with multiple sclerosis. Brain 1996;119(Pt 2):449-55.
Hansen T, Skytthe A, Stenager E, Petersen HC, Brønnum-Hansen H, Kyvik KO. Concordance for multiple sclerosis in Danish twins: An update of a nationwide study. Mult Scler 2005;11:504-10.
Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: The role of infection. Ann Neurol 2007;61:288-99.
Ascherio A, Munger KL, Simon KC. Vitamin D and multiple sclerosis. Lancet Neurol 2010;9:599-612.
Wingerchuk DM. Smoking: Effects on multiple sclerosis susceptibility and disease progression. Ther Adv Neurol Disord 2012;5:13-22.
Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C, et al.
Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 2011;479:538-41.
Elian M, Nightingale S, Dean G. Multiple sclerosis among United Kingdom-born children of immigrants from the Indian subcontinent, Africa and the West Indies. J Neurol Neurosurg Psychiatry 1990;53:906-11.
Marrie RA, Rudick R, Horwitz R, Cutter G, Tyry T, Campagnolo D, et al.
Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis. Neurology 2010;74:1041-7.
Willer CJ, Dyment DA, Sadovnick AD, Rothwell PM, Murray TJ, Ebers GC. Timing of birth and risk of multiple sclerosis: Population based study. BMJ 2005;330:120.
Lassmann H, Brück W, Lucchinetti CF. The immunopathology of multiple sclerosis: An overview. Brain Pathol 2007;17:210-8.
Stys PK, Zamponi GW, van Minnen J, Geurts JJ. Will the real multiple sclerosis please stand up? Nat Rev Neurosci 2012;13:507-14.
Lucchinetti CF, Popescu BF, Bunyan RF, Moll NM, Roemer SF, Lassmann H, et al.
Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 2011;365:2188-97.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 1983;33:1444-52.
Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: Results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on clinical trials of new agents in multiple sclerosis. Neurology 1996;46:907-11.
Cree BA. Multiple sclerosis. In: Brust JC, editor. Current Diagnosis and Treatment in Neurology. New York: McGraw-Hill Medical; 2007.
Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol 2008;7:1139-51.
Rao SM, Grafman J, DiGuilio D, Mittenberg W, Bernardin L, Leo GJ, et al
. Memory dysfunction in multiple sclerosis: Its relation to working memory, semantic encoding and implicit learning. Neuropsychology 1993;7:364-74.
Sumowski JF, Benedict R, Enzinger C, Filippi M, Geurts JJ, Hamalainen P, et al.
Cognition in multiple sclerosis: State of the field and priorities for the future. Neurology 2018;90:278-88.
Rocca MA, Amato MP, De Stefano N, Enzinger C, Geurts JJ, Penner IK, et al.
Clinical and imaging assessment of cognitive dysfunction in multiple sclerosis. Lancet Neurol 2015;14:302-17.
Thornton AE, Raz N, Tucke KA. Memory in multiple sclerosis: Contextual encoding deficits. J Int Neuropsychol Soc 2002;8:395-409.
Benedict RH, Cookfair D, Gavett R, Gunther M, Munschauer F, Garg N, et al.
Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). J Int Neuropsychol Soc 2006;12:549-58.
Archibald CJ, Fisk JD. Information processing efficiency in patients with multiple sclerosis. J Clin Exp Neuropsychol 2000;22:686-701.
Nebel K, Wiese H, Seyfarth J, Gizewski ER, Stude P, Diener HC, et al.
Activity of attention related structures in multiple sclerosis patients. Brain Res 2007;1151:150-60.
Schoonheim MM, Popescu V, Rueda Lopes FC, Wiebenga OT, Vrenken H, Douw L, et al.
Subcortical atrophy and cognition: Sex effects in multiple sclerosis. Neurology 2012;79:1754-61.
Houtchens MK, Benedict RH, Killiany R, Sharma J, Jaisani Z, Singh B, et al.
Thalamic atrophy and cognition in multiple sclerosis. Neurology 2007;69:1213-23.
Pinter D, Khalil M, Pichler A, Langkammer C, Ropele S, Marschik PB, et al.
Predictive value of different conventional and non-conventional MRI-parameters for specific domains of cognitive function in multiple sclerosis. Neuroimage Clin 2015;7:715-20.
Bisecco A, Rocca MA, Pagani E, Mancini L, Enzinger C, Gallo A, et al.
Connectivity-based parcellation of the thalamus in multiple sclerosis and its implications for cognitive impairment: A multicenter study. Hum Brain Mapp 2015;36:2809-25.
Sicotte NL, Kern KC, Giesser BS, Arshanapalli A, Schultz A, Montag M, et al.
Regional hippocampal atrophy in multiple sclerosis. Brain 2008;131:1134-41.
Small SA, Schobel SA, Buxton RB, Witter MP, Barnes CA. A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci 2011;12:585-601.
Rocca MA, Longoni G, Pagani E, Boffa G, Colombo B, Rodegher M, et al. In vivo
evidence of hippocampal dentate gyrus expansion in multiple sclerosis. Hum Brain Mapp 2015;36:4702-13.
Michaeli T. PDE7. In: Beavo JA, Francis SH, Houslay MD, editors. Cyclic Nucleotide Phosphodiesterases in Health and Disease. Boca Raton: CRC Press; 2006. p. 195-203.
Sasaki T, Kotera J, Omori K. Transcriptional activation of phosphodiesterase 7B1 by dopamine D1 receptor stimulation through the cyclic AMP/cyclic AMP-dependent protein kinase/cyclic AMP-response element binding protein pathway in primary striatal neurons. J Neurochem 2004;89:474-83.
Bałkowiec-Iskra E, Kurkowska-Jastrzebska I, Joniec I, Ciesielska A, Członkowska A, Członkowski A, et al.
Dopamine, serotonin and noradrenaline changes in the striatum of C57BL mice following myelin oligodendrocyte glycoprotein (MOG) 35-55 and complete Freund adjuvant (CFA) administration. Acta Neurobiol Exp (Wars) 2007;67:379-88.
Besser MJ, Ganor Y, Levite M. Dopamine by itself activates either D2, D3 or D1/D5 dopaminergic receptors in normal human T-cells and triggers the selective secretion of either IL-10, TNFalpha or both. J Neuroimmunol 2005;169:161-71.
Ghanta M, Panchanathan E, Lakkakula BV, Narayanaswamy A. Retrospection on the role of soluble guanylate cyclase in Parkinson's disease. J Pharmacol Pharmacother 2017;8:87-91.
] [Full text]
Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR. Crystal structure of the catalytic domains of adenylyl cyclase in a complex with gsalpha. GTPgammaS. Science 1997;278:1907-16.
Sunahara RK, Taussig R. Isoforms of mammalian adenylyl cyclase: Multiplicities of signaling. Mol Interv 2002;2:168-84.
Altschuler DL, Peterson SN, Ostrowski MC, Lapetina EG. Cyclic AMP-dependent activation of Rap1b. J Biol Chem 1995;270:10373-6.
Bos JL, de Rooij J, Reedquist KA. Rap1 signalling: Adhering to new models. Nat Rev Mol Cell Biol 2001;2:369-77.
Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, et al.
Afamily of cAMP-binding proteins that directly activate Rap1. Science 1998;282:2275-9.
Neves SR, Ram PT, Iyengar R. G protein pathways. Science 2002;296:1636-9.
Guan Z, Giustetto M, Lomvardas S, Kim JH, Miniaci MC, Schwartz JH, et al.
Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure. Cell 2002;111:483-93.
Calabresi P, Pisani A, Mercuri NB, Bernardi G. Long-term potentiation in the striatum is unmasked by removing the voltage-dependent magnesium block of NMDA receptor channels. Eur J Neurosci 1992;4:929-35.
Lovinger DM, Tyler E. Synaptic transmission and modulation in the neostriatum. Int Rev Neurobiol 1996;39:77-111.
Selemon LD. A role for synaptic plasticity in the adolescent development of executive function. Transl Psychiatry 2013;3:e238.
Arnsten AF, Ramos BP, Birnbaum SG, Taylor JR. Protein kinase A as a therapeutic target for memory disorders: Rationale and challenges. Trends Mol Med 2005;11:121-8.
Maren S. Synaptic transmission and plasticity in the amygdala. An emerging physiology of fear conditioning circuits. Mol Neurobiol 1996;13:1-22.
Girault JA. Integrating neurotransmission in striatal medium spiny neurons. Adv Exp Med Biol 2012;970:407-29.
Vergne F, Bernardelli P, Chevalier E. PDE7 Inhibitors: Chemistry and Potential Therapeutic Utilites. Annu Rep Med Chem 2005;40:227-41.
Farber JM. Mig and IP-10: CXC chemokines that target lymphocytes. J Leukoc Biol 1997;61:246-57.
Paterniti I, Mazzon E, Gil C, Impellizzeri D, Palomo V, Redondo M, et al.
PDE 7 inhibitors: New potential drugs for the therapy of spinal cord injury. PLoS One 2011;6:e15937.
Medina-Rodríguez EM, Arenzana FJ, Pastor J, Redondo M, Palomo V, García de Sola R, et al.
Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival. Cell Mol Life Sci 2013;70:3449-62.
González-García C, Bravo B, Ballester A, Gómez-Pérez R, Eguiluz C, Redondo M, et al.
Comparative assessment of PDE 4 and 7 inhibitors as therapeutic agents in experimental autoimmune encephalomyelitis. Br J Pharmacol 2013;170:602-13.
Lipina TV, Palomo V, Gil C, Martinez A, Roder JC. Dual inhibitor of PDE7 and GSK-3-VP1.15 acts as antipsychotic and cognitive enhancer in C57BL/6J mice. Neuropharmacology 2013;64:205-14.
Morales-Garcia JA, Redondo M, Alonso-Gil S, Gil C, Perez C, Martinez A, et al.
Phosphodiesterase 7 inhibition preserves dopaminergic neurons in cellular and rodent models of Parkinson disease. PLoS One 2011;6:e17240.
Perez-Gonzalez R, Pascual C, Antequera D, Bolos M, Redondo M, Perez DI, et al.
Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer's disease. Neurobiol Aging 2013;34:2133-45.
Blokland A, Menniti FS, Prickaerts J. PDE inhibition and cognition enhancement. Expert Opin Ther Pat 2012;22:349-54.
Vaccaro W, Roberge JY, Leftheris K, Pitts WJ, Barbosa J. United states Patent No. US6838559B2
. Bristol-Myers Squibb Co., Princeton, NJ (US). U.S. Patent and Trademark Office; 2005.
Pitts W, Barbosa J, Guo J. International Publication Patent No. WO2002087513A2
. Bristol-Myers Squibb Co., Princeton, NJ (US). Patent Cooperation treaty, World Intellectual Property Organization, International Bureau; 2002.
Darwin Discovery Limited. International Publication Patent No. WO2000068230A1
. Cambridge Science Park, Milton Road, Cambridge, United Kingdom. Patent Cooperation treaty, World Intellectual Property Organization, International Bureau; 2000.