Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer's disease

Pérez‐González, Rocío; Pascual, Consuelo; Antequera, Desireé; Bolós, Marta; Redondo, Miriam; Pérez, Daniel I.; Pérez‐Grijalba, Virginia; Krzyzanowska, Agnieszka; Sarasa, Manuel; Gil, Carmen; Ferrer, Isidro; Martı́nez, Ana; Carro, Eva

doi:10.1016/j.neurobiolaging.2013.03.011

Cited by 84 publications

(55 citation statements)

References 59 publications

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“…As these enzymes control the levels of cAMP and/or cyclic GMP in cells that are crucial for neural function, PDE inhibitors represent promising candidate drugs for the treatment of altered cognition states (García-Osta et al, 2012). The effectiveness of repeated administration of PDE3 inhibitor (cilostazol), PDE4 inhibitor (rolipram or GEBR-7b), PDE5 inhibitor (sildenafil or tadalafil), PDE7 inhibitor (S14), and PDE9A inhibitor (BAY 73e6691) has been demonstrated in several model animals of AD (Bruno et al, 2011;Cheng et al, 2010;García-Barroso et al, 2013;Gong et al, 2004;Kroker et al, 2014;Li et al, 2011;Peng et al, 2014;Perez-Gonzalez et al, 2013;Sierksma et al, 2013Sierksma et al, , 2014.…”

Section: Resultsmentioning

confidence: 99%

Accumulation of carboxy-terminal fragments of APP increases phosphodiesterase 8B

Kametani

Haga

2015

Neurobiology of Aging

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Section: Resultsmentioning

confidence: 99%

Accumulation of carboxy-terminal fragments of APP increases phosphodiesterase 8B

Kametani

Haga

2015

Neurobiology of Aging

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“…Preclinical research into PDE7 inhibitors and AD is currently starting to emerge [91]. Consequently, PDE7 inhibitors are not under clinical investigation for CNS indications.…”

Section: Phosphodiesterasementioning

confidence: 99%

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Prickaerts

Heckman

Blokland

2017

Expert Opinion on Investigational Drugs

153

168

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Introduction: Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer's disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies. Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD. PDE inhibitors will also be discussed with respect to adverse effects including safety and tolerability. Expert opinion: The limited available data of clinical studies with PDE inhibitors tested in different populations of AD patients do not allow the drawing of any concrete conclusion yet. Currently, studies with a PDE3 (cilostazol) or PDE9 inhibitor (BI 409,306) are still ongoing in patients with MCI or AD, respectively. Studies with PDE4 inhibitors (HT-0712, roflumilast and BPN14770) in healthy elderly and elderly with age-associated memory impairments indicate that the optimum dose and/or inhibiting the most relevant PDE isoform hold great promise when tested in the appropriate population of patients with MCI or AD eventually. ARTICLE HISTORY

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“…In this context, we have recently shown the anti-inflammatory and neuroprotective effects of the cAMP-specific phosphodiesterase 7 (PDE7) inhibitors in animal models of spinal cord injury, stroke, Parkinson´s and Alzheimer´s diseases, and MS29303132333435363738. Although their effect on remyelination remains unknown, previous data from our group have shown that PDE7 inhibitors favour the differentiation and survival of mouse cortical OPCs and the differentiation of adult human OPCs in vitro 39.…”

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confidence: 99%

Promoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis

Medina‐Rodriguez

Bribián

Boyd

et al. 2017

Sci Rep

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Multiple Sclerosis (MS) is a neurodegenerative disease where immune-driven demyelination occurs with inefficient remyelination, but therapies are limited, especially those to enhance repair. Here, we show that the dual phosphodiesterase (PDE)7- glycogen synthase kinase (GSK)3 inhibitor, VP3.15, a heterocyclic small molecule with good pharmacokinetic properties and safety profile, improves in vivo remyelination in mouse and increases both adult mouse and adult human oligodendrocyte progenitor cell (OPC) differentiation, in addition to its immune regulatory action. The dual inhibition is synergistic, as increasing intracellular levels of cAMP by cyclic nucleotide PDE inhibition both suppresses the immune response and increases remyelination, and in addition, inhibition of GSK3 limits experimental autoimmune encephalomyelitis in mice. This combination of an advantageous effect on the immune response and an enhancement of repair, plus demonstration of its activity on adult human OPCs, leads us to propose dual PDE7-GSK3 inhibition, and specifically VP3.15, as a neuroprotective and neuroreparative disease-modifying treatment for MS.

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Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer's disease

Cited by 84 publications

References 59 publications

Accumulation of carboxy-terminal fragments of APP increases phosphodiesterase 8B

Accumulation of carboxy-terminal fragments of APP increases phosphodiesterase 8B

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Promoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis

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