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Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-141341 IOS Press

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Review

Phosphodiesterase Inhibition in Cognitive Decline

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Carolina Garc´ıa-Barrosoa , Ana Ugarteb,f , Mart´ın Mart´ınezc , Alberto J. Ricod,f , Jos´e Luis Lanciegod,f , Rafael Francoa,2 , Julen Oyarzabalb,f , Mar Cuadrado-Tejedora,e,1 and Ana Garc´ıa-Ostaa,1,∗

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of Alzheimer´s disease, Neurosciences Division, Centre for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain b Small Molecule Discovery Platform, Centre for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain c Neuroimaging Laboratory, Neurosciences Division, Centre for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain d Neurosciences Division, Centre for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain e Department of Anatomy, University of Navarra, Pamplona, Spain f Centro de Investigaci´ on Biom´edica en Red Enfermedades Neurodegenerativas (CIBERNED), Spain

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Accepted 17 July 2014

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Keywords: Cerebrospinal fluid, cGMP, memory enhancement, phosphodiesterase, tadalafil

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INTRODUCTION

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Abstract. Understanding the cellular and molecular processes involved in learning and memory will help in the development of safe and effective cognitive enhancers. The cAMP response element-binding (CREB) may be a universal modulator of processes required for memory formation, and increasing the levels of second messengers like cAMP and cGMP could ultimately lead to CREB activation. Phosphodiesterase (PDE) inhibitors regulate signaling pathways by elevating cAMP and/or cGMP levels, and they have been demonstrated to improve learning and memory in a number of rodent models of impaired cognition. The aim of this review is to summarize the outstanding progress that has been made in the application of PDE inhibitors for memory dysfunction. In addition, we have introduced some recent data we generated demonstrating that tadalafil could be considered as an optimal candidate for drug re-positioning and as a good candidate to enhance cognition.

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As life expectancy increases in general, the number of elderly people with dementia is rising worldwide. Furthermore, the diagnostic threshold between normal (expected age-associated cognitive changes) and pathological decline (cognitive changes that exceed 1 These

authors contributed equally to this work. 2 Present address: Department of Biochemistry and Molecular Biology, Universitat de Barcelona, Barcelona, Spain. ∗ Correspondence to: Ana Garc´ıa-Osta, Division of Neurosciences, CIMA, University of Navarra, Av. Pio XII 55, 31008 Pamplona, Spain. Tel.: +34 011 34 948 19 47 00 (2023); Fax: +34 011 34 948 19 47 15, E-mail: [email protected].

the expected decline) is poorly defined. Accordingly, a better understanding of the cellular and molecular processes involved in learning and memory are required in order to develop better diagnostic tools and treatments for diseases affecting cognitive domains, such as Alzheimer’s disease (AD). Similarly, understanding the mechanisms that underlie memory consolidation and natural/pathological cognitive decline will aid the development of safe and effective cognitive enhancers. What happens to our brain as we age? Whereas neuronal loss occurs upon aging and neurons do not grow back, synaptogenesis is a very dynamic process by which structural changes take place in the brain. Moreover, there are also dynamic processes in the brain that

ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

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PHOSPHODIESTERASE INHIBITION IN COGNITION

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Phosphodiesterases (PDEs) are enzymes that regulate intracellular signal transduction by hydrolyzing the cAMP and cGMP second messengers to their corresponding linear nucleotides. PDEs comprise a ubiquitous superfamily of enzymes that are grouped into 11 classes on with basis of their selectivity for cAMP and/or cGMP [12]: PDE types 4, 7, and 8 are specific for cAMP; types 5, 6, and 9 are specific for cGMP; and types 1–3, 10, and 11 degrade both cAMP and cGMP [13]. Most PDE sub-types are expressed in the brain (PDE1, PDE2, PDE3, PDE4, PDE5, PDE7, PDE8, PDE9, PDE10, and PDE11), particularly in areas involved in learning and memory. However, while PDE4 and PDE9 are expressed broadly across the central nervous system (CNS) [14], PDE5 transcripts are expressed in the pyramidal cell layers

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Signaling pathways

PDEs represent important biological targets for therapeutic interventions for a variety of disorders. The inhibitors of PDE5 are the best known examples (e.g., sildenafil, tadalafil, vardenafil), which are approved to treat erectile dysfunction and pulmonary artery hypertension. A selective PDE4 inhibitor, roflumilast, has been also approved to treat chronic obstructive pulmonary disease, and the PDE3 inhibitor milrinone for acute treatment of congestive heart failure. While all the approved therapeutic uses of PDEs inhibitors are for peripheral indications, its effect on the regulation of intracellular signaling makes PDEs attractive targets to enhance neural communication. The second messenger cAMP activates protein kinase A, which phosphorylates CREB [5] and thereby enhances the expression of genes that modulate synaptic plasticity. Similarly, cGMP (a messenger synthesized by guanylyl cyclase -GC) is activated by nitric oxide (NO), and the NO/cGMP pathway activates protein kinase G that can also induce CREB phosphorylation [7, 8]. Activation of CREB via these two pathways can induce molecular changes in the brain that affect memory formation and recently, much interest has focused on the cGMP pathway given the decreases in cGMP levels associated with aging [16]. Interestingly, cGMP levels are lower in the hippocampus but not in the cerebellum of 12-month-old but not 3-month-old rats [16]. The decreases in cGMP levels appear to be driven by increases in PDE expression and activity, which may be associated with neurodegeneration, decreased neurogenesis and cognitive decline in the elderly [16]. Indeed, cGMP signaling mediates long-term changes in synaptic activity in the hippocampus, amygdala, cerebellum, and other brain regions, and it contributes to distinct forms of learning and memory. At the molecular level, different cGMPdependent protein kinases appear to mediate the effects of cGMP on presynaptic neurotransmitter release and on postsynaptic neurons during long-term potentiation [8, 17, 18]. Indeed, cGMP-dependent protein kinases have been proposed to modulate cytoskeletal organization, vesicle and AMPA receptor trafficking, and gene expression through the phosphorylation of various substrates involved in synaptic plasticity (for review, see [19]). Taken together, these observations suggest that

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of the hippocampal CA1 and CA3, and in the granule cells of the dentate gyrus [15]. This restricted distribution suggests that PDE5 may fulfil an important role in cognition-related neural activity.

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actively strengthen synapses, a process that is essential for the formation of new memories. The formation and maturation of synapses requires de novo gene expression and protein synthesis, and it is therefore regulated at both the transcriptional and translational levels. This was initially demonstrated in mice administered an inhibitor of protein synthesis, puromycin [1]. Gene transcription was subsequent shown to be required for long-term memory in Aplysia, Drosophila, and rodents. This transcriptional control is in part mediated by the activation of the cAMP response element binding (CREB) [2–4], suggesting CREB to be a universal modulator of events involved in memory formation. Kinases in several signaling pathways can activate CREB by phosphorylating it at Ser133 [5, 6], and it can also be activated following an increase in the levels of both cAMP and cGMP [7, 8]. Significantly, phosphodiesterase (PDE) inhibitors regulate signaling pathways by elevating cAMP and/or cGMP levels, and they have been shown to improve learning in several rodent models of impaired cognition [9–11]. In the last decade, this class of drugs has been thought to constitute a novel strategy of restoring memory function in patients with dementia. Treatments that target signaling pathways involved in memory-related processes (in the normal brain) have the potential to delay cognitive decline. Thus, in this review we discuss recent advances in the treatment of cognitive decline through PDE inhibition. Finally, we focus on tadalafil, a selective inhibitor of PDE5, as a candidate cognition-enhancing drug.

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Fig. 1. Chemical structures of different PDE inhibitors.

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PDE inhibitors may constitute a promising means of ameliorating synaptic deficits, and more specifically, enhancing the memory of patients experiencing cognitive decline. In the case of PDE inhibitors that specifically prevent cGMP degradation (i.e., those targeting PDE types 5, 6, and 9), the improved neurological outcome may be due to enhanced cerebral blood-flow and glucose metabolism due to the vasoactive activity of cGMP [20]. In fact, a promising therapeutic strategy for cerebral ischemia is to boost NO-cGMP signaling by inhibiting PDE5 [21, 22]. Moreover, inhibitors of PDE5 (see next section), PDE9 (which is also selective for cGMP), PDE4 (cAMP-specific) and PDE1, PDE2, PDE3, and PDE10 have all been shown to enhance memory in animal models [11, 23].

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PDE1 isoforms (PDE1A, 1B, 1C) are expressed in different brain areas including hippocampus, cerebral

cortex, thalamus, and striatum 6 and 10, suggesting that it may play a role in memory function. Vinpocetine is a specific PDE1 inhibitor that has been shown to facilitate long-term potentiation [24], improve memory [25], and ameliorate streptozotocin-induced cognitive dysfunction in rats [26], and enhance performance in cognitive tests in humans [27]. Taking into account that one of the PDEs with high level of expression in brain, particularly, in the striatum and the dentate gyrus of the hippocampus, is PDE1B [28], novel and selective compounds of this isoform are needed as memory enhancers. Given its high levels of expression in limbic structures such as the cortex, amygdala, and hippocampus, and its ability to regulate both cAMP and cGMP, PDE2 is a potential target for memory-enhancing drugs. The effects of PDE2 inhibitors on cognition have been investigated using BAY 60–7550 (Fig. 1A), which improves memory in young and aged rats [29], in memory-impaired rats [30, 31], and in a mouse model of AD [32]. These results suggest that PDE2 inhibitors

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a novel therapeutic option for AD-related cognitive deficits. Recently, it has been shown that a potent inhibitor of PDE4B (orally bioavailable and brainpenetrant, GSK356278) enhances performance in a test of executive function in non-human primates with no adverse effects at any dose tested [48]. PDE7 is a high-affinity cAMP-specific PDE that is expressed in the brain and in peripheral tissues [14]. Specific inhibitors of PDE7 have potential to be used therapeutically to treat stroke [49], spinal cord injury [50], and Parkinson’s disease [51]. In a mouse model of AD, the PDE7 inhibitor S14 (Fig. 1E) was recently shown to attenuate memory impairment and the expression of histopathological markers of AD after four weeks of daily administration [52]. Indeed, new compounds (e.g., VP1.15, Fig. 1F) that combine PDE7 and GSK3␤ inhibitory activity have recently been developed as potential treatments for neurological disorders [53] and as cognitive enhancers [54]. PDE8 is one of the more recently discovered cAMPspecific PDEs and members of the PDE8 class are encoded by two distinct genes: PDE8A and PDE8B. While PDE8A is poorly expressed in the CNS, PDE8B is expressed in the hippocampus, striatum, and cerebellum. The loss of PDE8B in mice provokes enhanced contextual fear and spatial memory, suggesting that selective PDE8B inhibition may enhance cognition [55]. Therefore, the selective PDE8 inhibitor, PF04957325 (Fig. 1G) [56], or its analogues, may represent pharmacological tools with which to evaluate the therapeutic potential of this PDE in cognitive disorders. PDE9 displays the strongest affinity of all the PDE subtypes for cGMP (Km = 170 nM). Thus, PDE9 is an excellent target for drugs that aim to increase cGMP levels and hence, facilitate memory-related processes. However, PDE9 inhibitors also have a moderate effect on PDE1 [57], which could give rise to side effects if used to treat CNS diseases given the abundant expression of PDE1 in the brain. The selective PDE9 inhibitor PF-04447943 (Fig. 1H) is probably that which has been best studied in memory-related tasks, and it has been reported to elevate cGMP levels in the brain and cerebrospinal fluid (CSF) of rodents, and in the CSF of healthy human volunteers. Moreover, chronic administration of PF-04447943 in the Tg2576 mouse model of AD prevents dendritic spine loss in the hippocampus and memory impairment in early life (4-5 months-of-age) [58], and restores amyloid-induced deficits in long-term potentiation [59]. Accordingly, PF-04447943 is currently under clinical development for the treatment of AD [60].

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could be useful to treat disorders with a cognitive component. The current availability of numerous potent and selective PDE2 inhibitors means that their efficacy as cognitive enhancers can be easily and comprehensively evaluated [33]. PDE3 is widely expressed throughout the brain, including the cerebellum, frontal cortex, hypothalamus, and hippocampus [14, 34]. Cilostazol (Fig. 1B) is a selective PDE3 inhibitor that was originally used as an anti-platelet agent to treat subcortical vascular disease [35]. Given its favorable safety profile, cilostazol is another potential drug to the treat cognitive disorders and indeed, it was recently shown to enhance learning in wild type mice, an effect that was correlated with an increase in phosphorylated CREB-expressing cells in the dentate gyrus [36]. Cilostazol also significantly ameliorates cognitive impairment induced by intracerebral infusion of amyloid peptide in mice [37, 38]. Interestingly, this PDE3 inhibitor had beneficial effects on cognition in a pilot study of elderly patients with AD and cerebrovascular disease [39], indicating that cilostazol may ameliorates the pathology of AD by increasing regional cerebral blood flow and CREB phosphorylation. PDE4 is widely expressed in the CNS and consists of four genes (PDE4A, 4B, 4C, and 4D) encoding more than 20 different variants [40]. Many isoforms of PDE4 have been identified and the use of panPDE4 inhibitors (e.g., rolipram) enhances memory but causes side effects (emesis and nausea) that have precluded their clinical development [41, 42]. PDE4D is predominantly expressed in the CA1 region of the hippocampus, suggesting that this is the main subtype likely to be involved in mediating memory consolidation [43, 44]. In line with this view, knockdown of PDE4D in the hippocampus enhances learning without affecting emesis [45]. Furthermore, the inhibition of PDE4 by rolipram (Fig. 1C) in PDE4D-deficient mice has no effect on memory, pointing to a key role of PDE4D in memory processes [45]. The development of inhibitors that selectively target relevant PDE4 subtypes is thus a promising therapeutic approach. In rodents, PDE4D allosteric modulators induce similar improvements in cognition to rolipram, yet with reduced emetic potential [46]. Moreover, the selective PDE4D inhibitor 3-cyclopentyloxy-4methoxybenzaldehyde (GEBR-7b, Fig. 1D) is more effective than rolipram as a memory enhancer at doses that do not cause emesis in rodents [47]. Chronic administration of GEBR-7b was recently reported to improve spatial memory function in a mouse model of AD [44], suggesting that PDE4D inhibition constitutes

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PDE5 INHIBITION AND COGNITIVE ENHANCEMENT As indicated above, PDE inhibitors may serve to increase cGMP levels in a manner that could attenuate both neurodegeneration and the cognitive impairment associated with aging and/or dementia. The repurposing of PDE5 inhibitors as cognitive enhancers seems to be a promising approach to deal with these problems. Various PDE5 inhibitors are currently on the market for the treatment of erectile dysfunction and pulmonary arterial hypertension, including sildenafil, tadalafil, and vardenafil. These compounds have a good safety profile and they can be safely administered chronically in patients with pulmonary hypertension. The expression of PDE5 in brain areas involved in cognition (e.g., the hippocampus and cortex) [15] supports the hypothesis that PDE5 inhibition may affect memoryrelated processes (for review see [10, 63]). However, while cGMP-mediated neuroplasticity may underlie the enhancement of learning and memory in animals treated with PDE5 inhibitors, improved cerebral blood flow and glucose utilization may also contribute to the pro-cognitive action of these drugs [20]. The memory-enhancing effects of PDE5 inhibitors have been demonstrated in both physiological and pathological conditions (for review, see [11]). The beneficial effect of a PDE5 inhibitor (zaprinast) on memory was first described in the object recognition test nearly two decades ago [64]. However, zaprinast also inhibits PDE1, 9, 10, and 11, yet subsequently, selective PDE5 inhibition has been shown to improve the memory of animals in several learning and memory paradigms, such as passive avoidance, object recognition, and/or spatial memory tasks (Morris water maze, elevated plus-maze) [10, 11]. Furthermore, long lasting improvements in memory function in different

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pathological conditions and the recovery from memory deficits in mouse models of AD have been attributed to sildenafil [65–67], tadalafil [15], and icariin [68], all of which selectively inhibit PDE5. More recently, a new selective quinoline-based compound with an IC50 of 0.27 nM and a favorable pharmacokinetic profile has also been shown to rescue synaptic and memory defects in a mouse model of AD [69]. By regulating cGMP levels in the hippocampus, sildenafil also appears to be a good candidate to improve cognitive function in patients with Huntington’s disease [70], while tadalafil ameliorates memory impairment in a murine model of depression [71] and it alleviates ischemia-induced short-term memory impairment by suppressing neuronal apoptosis [21]. Additional benefits associated to PDE5 inhibitors may also be related to restoring cognitive function in aging and/or different forms of dementia. Sildenafil administration in rats with embolic stroke improves functional recovery even when administered one week after the induction of the ischemic injury [72], while pretreatment with tadalafil appears to significantly attenuate the effects of ischemiareperfusion injury in mice [22]. These outcomes are associated with enhanced angiogenesis, neurogenesis, and synaptogenesis [73, 74], further mechanisms by which PDE5 inhibition may enhance synaptic function and contribute to the amelioration of memory deficits. Interestingly, sildenafil administration ameliorated cognitive impairment and tau pathology in a senescent-accelerated mouse model [75]. In this line, it has been suggested that sildenafil may serve as a cognitive enhancer in age-related cognitive decline [76–78]. It was proposed that the induction of brainderived neurotrophic factor (BDNF) may contribute to the neuroprotective effects of sildenafil [79]. Indeed, upregulation of BDNF has also been observed in the hippocampus after a chronic sildenafil treatment in a mouse model of AD [66], and this may stimulate synaptic activity and protect neurons against apoptosis by promoting the production of the antioxidant Bcl-2 [80–82]. Consistent with this hypothesis, antiapoptotic effects of sildenafil were recently reported in aged mice [83]. Thus, PDE5 inhibitors may act at multiple sites in the brain and via several mechanisms, many of which result in improved memory function and that provide benefits in distinct pathological conditions that cause synaptic disturbances. Based on the enhancement of cognition observed in animal models after the administration of PDE5 inhibitors, a recent pilot study investigated the effects of repeated administration of

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PDE10A is a cAMP/cGMP dual-substrate PDE and PDE10 inhibitors (e.g., PF-2545920, Fig. 1I) have recently attracted interest for the treatment of Huntington’s disease [61] (given the high levels of PDE10 expression in striatal neurons) and schizophrenia [62]. Moreover, 10 patent applications have been filed claiming a positive effect of PDE10 inhibitors on learning and memory (http://www.epo.org). In summary, increases in cGMP and/or cAMP may promote CREB phosphorylation, which in turn could trigger long-lasting changes in gene expression and facilitate synaptic plasticity. Such events can be influenced by PDE inhibitors both in normal and pathological circumstances.

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Fig. 2. Chronic treatment with tadalafil enhances fear memory in aged mice. Vehicle-treated mice exhibited significantly less freezing behavior than their tadalafil-treated counterparts (*p ≤ 0.05) in the fear conditioning task. Data represent the percentage of time spent freezing during a 2 min test and the results are expressed as the mean ± SEM (n = 8–10 per group).

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PDE5 inhibition is a promising strategy to combat cognitive decline associated with both aging and a range of pathological conditions, such as AD. Substantial research efforts based on the use of animal models has yet to lead to the development of effective therapies for many CNS disorders. Nevertheless, it is possible that the repositioning of marketed drugs for which good preclinical data are available may facilitate the clinical development of new treatments for these unmet medical needs. The proven efficacy of PDE5 inhibitors as memory enhancers in animal models makes them good candidates for such repositioning [15, 71], as do their pharmacokinetic and safety profiles, even when administered chronically. For example, tadalafil can be administered orally once daily, which is highly desirable for patient management. Moreover, in addition to erectile dysfunction, tadalafil is currently administered chronically for the treatment of pulmonary hypertension [85, 86]. Taken together, these data suggest that tadalafil is an ideal candidate drug for repositioning as a memory enhancer. Thus, in the final part of this report we will describe what is currently known about the effects of chronic tadalafil treatment on cognitive function and hippocampal spine density in aged mice. Moreover, to demonstrate that cognitive enhancement is the result of the pharmacological action of tadalafil on the CNS, we have performed a detailed analysis of the CSF from non-human primates before and after tadalafil administration. As such, we experimentally determined the effective unbound tadalafil concentration in the brain in vivo and we evaluated its functional response by measuring cGMP levels in the CNS.

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the PDE5 inhibitor udenafil at 3 day intervals over 2 months [84], a regime that was found to improve cognitive function and somatization in patients with erectile dysfunction. Given the pharmacokinetic and safety profiles of the currently available PDE5 inhibitors and their demonstrated efficacy in animal models, further pilot studies and/or clinical trials should be performed to determine the potential of these drugs as memoryenhancers in different pathological conditions that involve memory loss.

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We analyzed the effects of chronic tadalafil treatment (15 mg/Kg/day, i.p.) for 5 weeks on age-related cognitive decline in 12–16 month-old mice, also eval-

uating freezing behavior, a measure of learned fear. After treatment, wild-type mice were subjected to a single conditioned stimulus-unconditioned stimulus pairing protocol to detect subtle deficits in learning [87]. Freezing responses were significantly enhanced by tadalafil (t(13) = 2.15, p = 0.05; Fig. 2), indicating that tadalafil treatment produces cognitive enhancement in an animal model of natural aging. Mice were also tested in the Morris water maze, a behavioral test that is widely used to evaluate spatial memory and that is sensitive to age-related cognitive decline [88]. Tadalafil did not produce an effect on escape latencies during the visible platform phase of the test (Fig. 3A, F(1,13) = 0,64, p = 0.44) and it had no effect on swimming speed (data not shown). The effects of treatment on escape latency in the hidden platform version of Morris water maze were also evaluated (using Two-way analysis of variance (ANOVA) with repeated measures) and significant interactions were observed between groups and time [F(4,52) = 2,78, p = 0.03]. Single effects were assessed using one-way ANOVA with repeated measures followed by posthoc Student’s t-tests, where appropriate (Fig. 3B). Tadalafil administration significantly reduced the escape latency over time (F(4,35) = 5,5, p = 0.002 versus F(4,30) = 1,83, p = 0.15 in control animals from the 3rd trial (t(14) = 3.46, p = 0.004; day 3 versus day 1), and the escape latency was significantly lower in tadalafil-treated mice than in control mice on day 3 (t(13) = 2.73, p = 0.02). Moreover, in the retention phase

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(day 4), tadalafil administration consistently enhanced the time spent in the target quadrant (t(13) = 2.03, p = 0.05; Fig. 3C).

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Fig. 3. Chronic treatment with tadalafil enhances memory in aged mice as measured in the Morris water maze. A) No significant differences in escape latency were found between groups during the visible platform phase of the Morris water maze test, results expressed as the mean ± SEM (n = 10-12 per group). B) The escape latency in the hidden-platform phase of the test, expressed as the mean ± SEM (n = 10–12 per group). While no change in escape latency was observed in vehicle-treated mice, the escape latency decreased in the mice that received tadalafil from the 3rd trial (*p ≤ 0.05, day 3 versus day 1). C) The percentage time spent in the target quadrant of a 15-s duration. The impaired retention in vehicle-treated mice on day 4 of training was reversed by tadalafil treatment (*p ≤ 0.05).

Neuronal changes underlying the effect of tadalafil on memory Dendritic spines constitute an anatomical substrate for the synaptic plasticity that underlies learning and memory. Since synapse loss appears to correlate well with the earliest signs of cognitive impairment [89, 90], we assessed whether the behavioral recovery induced by tadalafil reflects structural changes at the level of the dendritic spine. When we analyzed the dendritic spine density on hippocampal CA1 pyramidal neurons

in wild-type mice (12–16 month-old) using the Golgi impregnation technique [87], tadalafil administration for 7 weeks was associated with a significant increase in the spine density on apical dendrites (t(42) = 4.75, p < 0.001; Fig. 4), suggesting that changes in spine density may account for the improvements in memory induced by tadalafil. BDNF has been implicated in cognitive decline [91] and treatments that augment BDNF levels appear to have therapeutic potential in animal models of AD [92, 93]. Sildenafil promotes learning and memory in AD models through a CREB- and BDNF-dependent mechanism [65, 66], and indeed, the cognitive effects of tadalafil were associated with a significant increase in the levels of mature BDNF (14 kDa) in the

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hippocampus of tadalafil-treated mice (t(10.7) = 3.73, p = 0.003; Fig. 5). Plasma and CSF levels of tadalafil and cyclic nucleotides after oral administration to non-human primates

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The New Drug Application report (NDA22332; http://www.accessdata.fda.gov/drugsatfda docs/nda/2 009/022332s000 PharmR.pdf) submitted to the FDA reviewed and evaluated the pharmacological data for chronic tadalafil treatment in pulmonary arterial hypertension (approved in May 2009), indicating an effective and safe oral dose of 10 mg/Kg/day and 40 mg/day in rats and humans, respectively. Based on these data, we selected an oral dose of 2.4 mg/Kg for acute administration to Macaca fascilurais primates. After oral tadalafil administration (2.4 mg/Kg, n = 5), plasma and CSF levels of tadalafil and cyclic nucleotides (cGMP and cAMP) were determined at different time points (before and 1.5, 2, 2.5, and 3 h after administration) by high-performance liquid chromatography coupled to tandem mass spectrom-

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Fig. 4. Chronic treatment with tadalafil increases dendritic spine density in aged mice. A) Representative Golgi staining images of the apical dendrites on CA1 hippocampal pyramidal neurons. Scale bar, 10 ␮m. B) Chronic treatment with tadalafil resulted in a significant increase in the spine density of apical dendrites on hippocampal CA1 pyramidal neurons. The results are expressed as the mean ± SEM (n = 34–36 neurons; ***p ≤ 0.001).

Fig. 5. Chronic tadalafil treatment increased the expression of mature BDNF (mBDNF) in aged mice. The representative western blot in the figure depicts the mBDNF (13.5 kDa) and pro-BDNF (pBDNF, 32 kDa) in the hippocampus of control and tadalafil-treated mice. The histograms represent the mBDNF/pBDNF ratio. The data represent the mean ± SEM expressed as a percentage of the corresponding values in the control mice (n = 6–8 per group; **p ≤ 0.01).

etry (LC/MS-MS). These time points were selected based on the reported Tmax in humans (2 h) [86], the time after administration at which maximal drug concentration in plasma is achieved. LC-MS/MS is widely used to quantify small molecules like drugs or biomarkers due to its high selectivity in multiple reaction monitoring mode and its exceptional level of sensitivity, permitting the detection of analytes in the sub-nanomolar range. Furthermore, LC-MS/MS enables simultaneous analysis of several analytes, allowing both the drug and the biomarker to be quantified in the same run. Mass spectrometry quantification can be further improved by

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provides the highest possible analytical specificity for quantification. The Tmax for tadalafil was 2.5 h and the free CSF concentrations of tadalafil ranged from 6 to 10 nM (Fig. 6, Supplementary Tables 1 and 2), 6 to 11-fold higher than the reported IC50 for PDE5 (0.94 nM; http://www.accessdata.fda.gov/drugsatfda docs/nda/2 009/022332s000 PharmR.pdf). At this concentration, tadalafil should robustly inhibit central PDE5 and so we studied the functional impact of tadalafil by determining the cyclic nucleotide levels in the CNS before and after tadalafil administration. The cGMP levels differed significantly at different times after tadalafil administration [F(4,4) = 5.44, p = 0.005] (Fig. 6A) and this drug produced a significant increase in cGMP 2 h after administration (t(4) = 3.22, p = 0.03), with no significant differences in cAMP levels over time [F(4,4) = 1.26, p = 0.32] (Fig. 6B).

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Therapeutic strategies using drugs that regulate signaling pathways involved in memory formation (in the non-pathological CNS) have considerable potential to combat memory decline. PDEs in general, and cGMP-selective PDEs in particular, are promising targets for cognitive enhancement, even in natural aging. Although the effects of tadalafil on the impairment of brain function that accompanies aging in vivo, particularly its effects on cognitive impairment, have not been investigated to date, we have data suggesting that tadalafil acts as a memory enhancer in aged mice. This effect appears to be mediated by PDE5 inhibition within the CNS, as tadalafil levels in the CSF after oral administration in non-human primates (a surrogate measure of free drug concentration in the brain; Supplementary Table 2) are about one order of magnitude higher than the IC50 for PDE5 activity. In fact, the inhibition of PDE5 in neurons by tadalafil is confirmed by the significant increase in cGMP levels in the CSF. Together, our results provide preclinical evidence indicating that PDE5 inhibitors, and tadalafil in particular, are potential candidates for drug repositioning to treat pathological conditions that involve memory deterioration.

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Fig. 6. Temporal dynamics of tadalafil accumulation in the CSF after oral administration in non-human primates (2.4 mg/Kg). The corresponding functional response to tadalafil is reflected by the changes in cGMP (A) and cAMP (B) in the CNS. The results are expressed as the mean ± SEM (n = 5; *p ≤ 0.05). A repeated measures one-way ANOVA was used to test for significant differences over time in the mean levels of cGMP and cAMP after drug administration, and as parametric statistical tests were used, the data were normalized [94] after prior verification using the Kolmogorov-Smirnov test. Finally, a post-hoc t-test was used to identify significant differences in mean cGMP levels between samples taken at different time points before and after drug administration.

using a stable isotope-labelled analogue of the analyte as an internal standard, which compensates for variation in sample preparation and instrumental analysis, and for matrix-induced ion suppression. This is particularly useful when analyzing endogenous analytes, such as cyclic nucleotides, where the lack of blank matrix samples (free of analyte) means that standard curves are usually prepared in matrices that are distinct from the samples being analyzed. A stable isotope-labelled analogue of a compound is identical to the analyte in every way other than its mass and thus, it is the ideal internal standard. Therefore, the use of stable isotope-labelled analogues in LC-MS/MS

ACKNOWLEDGMENTS This study was supported by FIMA (Spain) and the FIS project (11/02861).

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Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=2457). SUPPLEMENTARY MATERIAL

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The supplementary material is available in the electronic version of this article: http://dx.doi.org/10.3233/ JAD-141341.

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[19]

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[4]

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[5]

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[6]

611 612 613 614

[7]

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Flexner JB, Flexner LB, Stellar E (1963) Memory in mice as affected by intracerebral puromycin. Science 141, 57-59. Impey S, Mark M, Villacres EC, Poser S, Chavkin C, Storm DR (1996) Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron 16, 973-982. Tully T (1997) Regulation of gene expression and its role in long-term memory and synaptic plasticity. Proc Natl Acad Sci U S A 94, 4239-4241. Tully T, Bourtchouladze R, Scott R, Tallman J (2003) Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov 2, 267-277. Gonzalez GA, Montminy MR (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59, 675-680. Dash PK, Karl KA, Colicos MA, Prywes R, Kandel ER (1991) cAMP response element-binding protein is activated by Ca2+/calmodulin- as well as cAMP-dependent protein kinase. Proc Natl Acad Sci U S A 88, 5061-5065. Lu YF, Kandel ER, Hawkins RD (1999) Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus. J Neurosci 19, 10250-10261. Lu YF, Hawkins RD (2002) Ryanodine receptors contribute to cGMP-induced late-phase LTP and CREB phosphorylation in the hippocampus. J Neurophysiol 88, 1270-1278. Blokland A, Menniti FS, Prickaerts J (2012) PDE inhibition and cognition enhancement. Expert Opin Ther Pat 22, 349354. Garcia-Osta A, Cuadrado-Tejedor M, Garcia-Barroso C, Oyarzabal J, Franco R (2012) Phosphodiesterases as therapeutic targets for Alzheimer’s disease. ACS Chem Neurosci 3, 832-844. Reneerkens OA, Rutten K, Steinbusch HW, Blokland A, Prickaerts J (2009) Selective phosphodiesterase inhibitors: A promising target for cognition enhancement. Psychopharmacology (Berl) 202, 419-443. Francis SH, Turko IV, Corbin JD (2001) Cyclic nucleotide phosphodiesterases: Relating structure and function. Prog Nucleic Acid Res Mol Biol 65, 1-52. Rybalkin SD, Hinds TR, Beavo JA (2013) Enzyme assays for cGMP hydrolyzing phosphodiesterases. Methods Mol Biol 1020, 51-62. Lakics V, Karran EH, Boess FG (2010) Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 59, 367-374. Garcia-Barroso C, Ricobaraza A, Pascual-Lucas M, Unceta N, Rico AJ, Goicolea MA, Salles J, Lanciego JL, Oyarzabal J, Franco R, Cuadrado-Tejedor M, Garcia-Osta A (2013) Tadalafil crosses the blood-brain barrier and reverses cognitive dysfunction in a mouse model of AD. Neuropharmacology 64, 114-123.

rre

[1]

co

595

REFERENCES

Un

594

Chalimoniuk M, Strosznajder JB (1998) Aging modulates nitric oxide synthesis and cGMP levels in hippocampus and cerebellum. Effects of amyloid beta peptide. Mol Chem Neuropathol 35, 77-95. Arancio O, Antonova I, Gambaryan S, Lohmann SM, Wood JS, Lawrence DS, Hawkins RD (2001) Presynaptic role of cGMP-dependent protein kinase during long-lasting potentiation. J Neurosci 21, 143-149. Son H, Lu YF, Zhuo M, Arancio O, Kandel ER, Hawkins RD (1998) The specific role of cGMP in hippocampal LTP. Learn Mem 5, 231-245. Kleppisch T, Feil R (2009) cGMP signalling in the mammalian brain: Role in synaptic plasticity and behaviour. Handb Exp Pharmacol 549-579. Reneerkens OA, Rutten K, Akkerman S, Blokland A, Shaffer CL, Menniti FS, Steinbusch HW, Prickaerts J (2012) Phosphodiesterase type 5 (PDE5) inhibition improves object recognition memory: Indications for central and peripheral mechanisms. Neurobiol Learn Mem 97, 370-379. Ko IG, Shin MS, Kim BK, Kim SE, Sung YH, Kim TS, Shin MC, Cho HJ, Kim SC, Kim SH, Kim KH, Shin DH, Kim CJ (2009) Tadalafil improves short-term memory by suppressing ischemia-induced apoptosis of hippocampal neuronal cells in gerbils. Pharmacol Biochem Behav 91, 629-635. Gulati P, Singh N (2014) Neuroprotective effect of tadalafil, a PDE-5 inhibitor, and its modulation by L-NAME in mouse model of ischemia-reperfusion injury. J Surg Res 186, 475483. Garc´ıa-Osta A, Cuadrado-Tejedor M, Garc´ıa-Barroso C, Oyarz´abal J, Franco R (2012) Phosphodiesterases as therapeutic targets for Alzheimer’s disease. ACS Chem Neurosci 3, 832-844. Molnar P, Gaal L (1992) Effect of different subtypes of cognition enhancers on long-term potentiation in the rat dentate gyrus in vivo. Eur J Pharmacol 215, 17-22. DeNoble VJ (1987) Vinpocetine enhances retrieval of a step-through passive avoidance response in rats. Pharmacol Biochem Behav 26, 183-186. Deshmukh R, Sharma V, Mehan S, Sharma N, Bedi KL (2009) Amelioration of intracerebroventricular streptozotocin induced cognitive dysfunction and oxidative stress by vinpocetine – a PDE1 inhibitor. Eur J Pharmacol 620, 49-56. Hindmarch I, Fuchs HH, Erzigkeit H (1991) Efficacy and tolerance of vinpocetine in ambulant patients suffering from mild to moderate organic psychosyndromes. Int Clin Psychopharmacol 6, 31-43. Polli JW, Kincaid RL (1992) Molecular cloning of DNA encoding a calmodulin-dependent phosphodiesterase enriched in striatum. Proc Natl Acad Sci U S A 89, 1107911083. Domek-Lopacinska K, Strosznajder JB (2008) The effect of selective inhibition of cyclic GMP hydrolyzing phosphodiesterases 2 and 5 on learning and memory processes and nitric oxide synthase activity in brain during aging. Brain Res 1216, 68-77. van Donkelaar EL, Rutten K, Blokland A, Akkerman S, Steinbusch HW, Prickaerts J (2008) Phosphodiesterase 2 and 5 inhibition attenuates the object memory deficit induced by acute tryptophan depletion. Eur J Pharmacol 600, 98-104. Reneerkens OA, Rutten K, Bollen E, Hage T, Blokland A, Steinbusch HW, Prickaerts J (2013) Inhibition of phoshodiesterase type 2 or type 10 reverses object memory deficits induced by scopolamine or MK-801. Behav Brain Res 236, 16-22.

roo f

588

C. Garc´ıa-Barroso et al. / Phosphodiesterase Inhibition in Cognitive Decline

or P

10

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710

C. Garc´ıa-Barroso et al. / Phosphodiesterase Inhibition in Cognitive Decline

718 719

[34]

720 721 722

[35]

723 724 725 726 727

[36]

728 729 730

[37]

731 732 733 734

[38]

735 736 737 738 739

[39]

740 741 742 743 744

[40]

745 746 747 748

[41]

749 750 751 752

[42]

753 754 755 756

[43]

757 758 759 760

[44]

761 762 763 764 765

[45]

766 767 768 769 770 771 772 773 774 775

[46]

[48]

[49]

[50]

[51]

roo f

717

or P

[33]

uth

716

Bruno O, Fedele E, Prickaerts J, Parker LA, Canepa E, Brullo C, Cavallero A, Gardella E, Balbi A, Domenicotti C, Bollen E, Gijselaers HJ, Vanmierlo T, Erb K, Limebeer CL, Argellati F, Marinari UM, Pronzato MA, Ricciarelli R (2011) GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses. Br J Pharmacol 164, 2054-2063. Rutter AR, Poffe A, Cavallini P, Davis TG, Schneck J, Negri M, Vicentini E, Montanari D, Arban R, Gray FA, Davies CH, Wren PB (2014) GSK356278, a potent, selective, brainpenetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species. J Pharmacol Exp Ther 350, 153-163. Redondo M, Brea J, Perez DI, Soteras I, Val C, Perez C, Morales-Garcia JA, Alonso-Gil S, Paul-Fernandez N, MartinAlvarez R, Cadavid MI, Loza MI, Perez-Castillo A, Mengod G, Campillo NE, Martinez A, Gil C (2012) Effect of phosphodiesterase 7 (PDE7) inhibitors in experimental autoimmune encephalomyelitis mice. Discovery of a new chemically diverse family of compounds. J Med Chem 55, 3274-3284. Paterniti I, Mazzon E, Gil C, Impellizzeri D, Palomo V, Redondo M, Perez DI, Esposito E, Martinez A, Cuzzocrea S (2011) PDE 7 inhibitors: New potential drugs for the therapy of spinal cord injury. PLoS One 6, e15937. Morales-Garcia JA, Redondo M, Alonso-Gil S, Gil C, Perez C, Martinez A, Santos A, Perez-Castillo A (2011) Phosphodiesterase 7 inhibition preserves dopaminergic neurons in cellular and rodent models of Parkinson disease. PLoS One 6, e17240. Perez-Gonzalez R, Pascual C, Antequera D, Bolos M, Redondo M, Perez DI, Perez-Grijalba V, Krzyzanowska A, Sarasa M, Gil C, Ferrer I, Martinez A, Carro E (2013) Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer’s disease. Neurobiol Aging 34, 2133-2145. Morales-Garcia JA, Palomo V, Redondo M, Alonso-Gil S, Gil C, Martinez A, Perez-Castillo A (2014) Crosstalk between phosphodiesterase 7 and glycogen synthase kinase-3: Two relevant therapeutic targets for neurological disorders. ACS Chem Neurosci 5, 194-204. Lipina TV, Palomo V, Gil C, Martinez A, Roder JC (2013) Dual inhibitor of PDE7 and GSK-3-VP1.15 acts as antipsychotic and cognitive enhancer in C57BL/6J mice. Neuropharmacology 64, 205-214. Tsai LC, Chan GC, Nangle SN, Shimizu-Albergine M, Jones GL, Storm DR, Beavo JA, Zweifel LS (2012) Inactivation of Pde8b enhances memory, motor performance, and protects against age-induced motor coordination decay. Genes Brain Behav 11, 837-847. Vang AG, Ben-Sasson SZ, Dong H, Kream B, DeNinno MP, Claffey MM, Housley W, Clark RB, Epstein PM, Brocke S (2010) PDE8 regulates rapid Teff cell adhesion and proliferation independent of ICER. PLoS One 5, e12011. Wunder F, Tersteegen A, Rebmann A, Erb C, Fahrig T, Hendrix M (2005) Characterization of the first potent and selective PDE9 inhibitor using a cGMP reporter cell line. Mol Pharmacol 68, 1775-1781. Verhoest PR, Fonseca KR, Hou X, Proulx-Lafrance C, Corman M, Helal CJ, Claffey MM, Tuttle JB, Coffman KJ, Liu S, Nelson F, Kleiman RJ, Menniti FS, Schmidt CJ, Vanase-Frawley M, Liras S (2012) Design and discovery of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3yl]-1-(tetrahydro-2H-pyr an-4-yl) -1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-4-one (PF-04447943), a selective brain

dA

715

[47]

[52]

cte

714

rre

713

Sierksma AS, Rutten K, Sydlik S, Rostamian S, Steinbusch HW, van den Hove DL, Prickaerts J (2013) Chronic phosphodiesterase type 2 inhibition improves memory in the APPswe/PS1dE9 mouse model of Alzheimer’s disease. Neuropharmacology 64, 124-136. Gomez L, Breitenbucher JG (2013) PDE2 inhibition: Potential for the treatment of cognitive disorders. Bioorg Med Chem Lett 23, 6522-6527. Xu Y, Zhang HT, O’Donnell JM (2011) Phosphodiesterases in the central nervous system: Implications in mood and cognitive disorders. Handb Exp Pharmacol, 447-485. O’Donnell ME, Badger SA, Sharif MA, Makar RR, McEneny J, Young IS, Lee B, Soong CV (2009) The effects of cilostazol on exercise-induced ischaemia-reperfusion injury in patients with peripheral arterial disease. Eur J Vasc Endovasc Surg 37, 326-335. Yanai S, Semba Y, Ito H, Endo S (2014) Cilostazol improves hippocampus-dependent long-term memory in mice. Psychopharmacology (Berl) 231, 2681-2693. Hiramatsu M, Takiguchi O, Nishiyama A, Mori H (2010) Cilostazol prevents amyloid beta peptide(25-35)-induced memory impairment and oxidative stress in mice. Br J Pharmacol 161, 1899-1912. Park SH, Kim JH, Bae SS, Hong KW, Lee DS, Leem JY, Choi BT, Shin HK (2011) Protective effect of the phosphodiesterase III inhibitor cilostazol on amyloid beta-induced cognitive deficits associated with decreased amyloid beta accumulation. Biochem Biophys Res Commun 408, 602-608. Sakurai H, Hanyu H, Sato T, Kume K, Hirao K, Kanetaka H, Iwamoto T (2013) Effects of cilostazol on cognition and regional cerebral blood flow in patients with Alzheimer’s disease and cerebrovascular disease: A pilot study. Geriatr Gerontol Int 13, 90-97. Conti M, Richter W, Mehats C, Livera G, Park JY, Jin C (2003) Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J Biol Chem 278, 5493-5496. Robichaud A, Savoie C, Stamatiou PB, Lachance N, Jolicoeur P, Rasori R, Chan CC (2002) Assessing the emetic potential of PDE4 inhibitors in rats. Br J Pharmacol 135, 113-118. Bruno O, Romussi A, Spallarossa A, Brullo C, Schenone S, Bondavalli F, Vanthuyne N, Roussel C (2009) New selective phosphodiesterase 4D inhibitors differently acting on long, short, and supershort isoforms. J Med Chem 52, 6546-6557. Rutten K, Misner DL, Works M, Blokland A, Novak TJ, Santarelli L, Wallace TL (2008) Enhanced long-term potentiation and impaired learning in phosphodiesterase 4D-knockout (PDE4D) mice. Eur J Neurosci 28, 625-632. Sierksma AS, van den Hove DL, Pfau F, Philippens M, Bruno O, Fedele E, Ricciarelli R, Steinbusch HW, Vanmierlo T, Prickaerts J (2014) Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D. Neuropharmacology 77, 120-130. Li YF, Cheng YF, Huang Y, Conti M, Wilson SP, O’Donnell JM, Zhang HT (2011) Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. J Neurosci 31, 172-183. Burgin AB, Magnusson OT, Singh J, Witte P, Staker BL, Bjornsson JM, Thorsteinsdottir M, Hrafnsdottir S, Hagen T, Kiselyov AS, Stewart LJ, Gurney ME (2010) Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol 28, 63-70.

co

[32]

712

Un

711

[53]

[54]

[55]

[56]

[57]

[58]

11

776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840

847

[60]

848 849 850 851

[61]

852 853 854 855 856

[62]

857 858 859 860 861 862 863 864

[63]

865 866 867 868

[64]

869 870 871 872

[65]

873 874 875 876 877

[66]

878 879 880 881 882

[67]

883 884 885 886 887

[68]

888 889 890 891 892

[69]

893 894 895 896 897 898

[70]

899 900 901 902 903 904 905

[71]

[73]

[74]

[75]

[76]

roo f

846

or P

845

[72]

well as suppresses apoptosis and enhances cell proliferation in the hippocampus of maternal-separated rat pups. Neurosci Lett 488, 26-30. Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, Zhang L, Chopp M (2002) Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 33, 2675-2680. Ding G, Jiang Q, Li L, Zhang L, Zhang ZG, Ledbetter KA, Gollapalli L, Panda S, Li Q, Ewing JR, Chopp M (2008) Angiogenesis detected after embolic stroke in rat brain using magnetic resonance T2*WI. Stroke 39, 1563-1568. Zhang L, Zhang RL, Wang Y, Zhang C, Zhang ZG, Meng H, Chopp M (2005) Functional recovery in aged and young rats after embolic stroke: Treatment with a phosphodiesterase type 5 inhibitor. Stroke 36, 847-852. Orejana L, Barros-Minones L, Jordan J, Puerta E, Aguirre N (2012) Sildenafil ameliorates cognitive deficits and tau pathology in a senescence-accelerated mouse model. Neurobiol Aging 33, 625 e611-620. Devan BD, Bowker JL, Duffy KB, Bharati IS, Jimenez M, Sierra-Mercado D Jr, Nelson CM, Spangler EL, Ingram DK (2006) Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition. Psychopharmacology (Berl) 183, 439-445. Devan BD, Sierra-Mercado D Jr, Jimenez M, Bowker JL, Duffy KB, Spangler EL, Ingram DK (2004) Phosphodiesterase inhibition by sildenafil citrate attenuates the learning impairment induced by blockade of cholinergic muscarinic receptors in rats. Pharmacol Biochem Behav 79, 691-699. Devan BD, Pistell PJ, Duffy KB, Kelley-Bell B, Spangler EL, Ingram DK (2014) Phosphodiesterase inhibition facilitates cognitive restoration in rodent models of age-related memory decline. NeuroRehabilitation 34, 101-111. Puerta E, Hervias I, Barros-Minones L, Jordan J, Ricobaraza A, Cuadrado-Tejedor M, Garcia-Osta A, Aguirre N (2010) Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF. Neurobiol Dis 38, 237-245. Barros-Minones L, Martin-de-Saavedra D, Perez-Alvarez S, Orejana L, Suquia V, Goni-Allo B, Hervias I, Lopez MG, Jordan J, Aguirre N, Puerta E. Inhibition of calpain-regulated p35/cdk5 plays a central role in sildenafil-induced protection against chemical hypoxia produced by malonate. Biochim Biophys Acta 1832, 705-717. Mattson MP, Culmsee C, Yu ZF (2000) Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res 301, 173-187. Tamatani M, Ogawa S, Nunez G, Tohyama M (1998) Growth factors prevent changes in Bcl-2 and Bax expression and neuronal apoptosis induced by nitric oxide. Cell Death Differ 5, 911-919. Puzzo D, Loreto C, Giunta S, Musumeci G, Frasca G, Podda MV, Arancio O, Palmeri A (2013) Effect of phosphodiesterase-5 inhibition on apoptosis and beta amyloid load in aged mice. Neurobiol Aging 35, 520-531. Shim YS, Pae CU, Cho KJ, Kim SW, Kim JC, Koh JS (2014) Effects of daily low-dose treatment with phosphodiesterase type 5 inhibitor on cognition, depression, somatization and erectile function in patients with erectile dysfunction: A double-blind, placebo-controlled study. Int J Impot Res 26, 76-80. Kulkarni SK, Patil CS (2004) Phosphodiesterase 5 enzyme and its inhibitors: Update on pharmacological and therapeutical aspects. Methods Find Exp Clin Pharmacol 26, 789-799.

uth

844

[77]

dA

[59]

cte

843

penetrant PDE9A inhibitor for the treatment of cognitive disorders. J Med Chem 55, 9045-9054. Kroker KS, Mathis C, Marti A, Cassel JC, Rosenbrock H, Dorner-Ciossek C (2014) PDE9A inhibition rescues amyloid beta-induced deficits in synaptic plasticity and cognition. Neurobiol Aging 35, 2072-2078. ClinicalTrials.gov. (2009) A study of PF-04447943 compared to placebo in subjects with mild to moderate Alzheimer’s disease, http://clinicaltrials.gov/ct2/show/NCT00930059, Accessed on 29 June 2012. Giralt A, Saavedra A, Carreton O, Arumi H, Tyebji S, Alberch J, Perez-Navarro E (2013) PDE10 inhibition increases GluA1 and CREB phosphorylation and improves spatial and recognition memories in a Huntington’s disease mouse model. Hippocampus 23, 684-695. Verhoest PR, Chapin DS, Corman M, Fonseca K, Harms JF, Hou X, Marr ES, Menniti FS, Nelson F, O’Connor R, Pandit J, Proulx-Lafrance C, Schmidt AW, Schmidt CJ, Suiciak JA, Liras S (2009) Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia. J Med Chem 52, 5188-5196. Devan BD, Bowker JL, Duffy KB, Bharati IS, Jimenez M, Sierra-Mercado D Jr, Nelson CM, Spangler EL, Ingram DK (2005) Phosphodiesterase type 5 (PDE5) inhibition and cognitive enhancement. Drugs Future 30, 725-736. Prickaerts J, Steinbusch HW, Smits JF, de Vente J (1997) Possible role of nitric oxide-cyclic GMP pathway in object recognition memory: Effects of 7-nitroindazole and zaprinast. Eur J Pharmacol 337, 125-136. Puzzo D, Staniszewski A, Deng SX, Privitera L, Leznik E, Liu S, Zhang H, Feng Y, Palmeri A, Landry DW, Arancio O (2009) Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer’s disease mouse model. J Neurosci 29, 8075-8086. Cuadrado-Tejedor M, Hervias I, Ricobaraza A, Puerta E, Perez-Roldan JM, Garcia-Barroso C, Franco R, Aguirre N, Garcia-Osta A (2011) Sildenafil restores cognitive function without affecting Ass burden in an Alzheimer’s disease mouse model. Br J Pharmacol 164, 2029-2041. Zhang J, Guo J, Zhao X, Chen Z, Wang G, Liu A, Wang Q, Zhou W, Xu Y, Wang C (2013) Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice. Behav Brain Res 250, 230-237. Jin F, Gong QH, Xu YS, Wang LN, Jin H, Li F, Li LS, Ma YM, Shi JS (2014) Icariin, a phoshphodiesterase-5 inhibitor, improves learning and memory in APP/PS1 transgenic mice by stimulation of NO/cGMP signalling. Int J Neuropsychopharmacol 17, 871-881. Fiorito J, Saeed F, Zhang H, Staniszewski A, Feng Y, Francis YI, Rao S, Thakkar DM, Deng SX, Landry DW, Arancio O (2013) Synthesis of quinoline derivatives: Discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer’s disease. Eur J Med Chem 60, 285294. Saavedra A, Giralt A, Arumi H, Alberch J, Perez-Navarro E (2013) Regulation of hippocampal cGMP levels as a candidate to treat cognitive deficits in Huntington’s disease. PLoS One 8, e73664. Baek SB, Bahn G, Moon SJ, Lee J, Kim KH, Ko IG, Kim SE, Sung YH, Kim BK, Kim TS, Kim CJ, Shin MS (2011) The phosphodiesterase type-5 inhibitor, tadalafil, improves depressive symptoms, ameliorates memory impairment, as

rre

842

co

841

C. Garc´ıa-Barroso et al. / Phosphodiesterase Inhibition in Cognitive Decline

Un

12

[78]

[79]

[80]

[81] [82]

[83]

[84]

[85]

906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970

C. Garc´ıa-Barroso et al. / Phosphodiesterase Inhibition in Cognitive Decline

978

[88]

979 980 981 982 983

[89]

984 985 986 987 988 989 990

[90]

[93]

[94]

roo f

977

[92]

or P

976

uth

975

Li G, Peskind ER, Millard SP, Chi P, Sokal I, Yu CE, Bekris LM, Raskind MA, Galasko DR, Montine TJ (2009) Cerebrospinal fluid concentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects. PLoS One 4, e5424. Nagahara AH, Mateling M, Kovacs I, Wang L, Eggert S, Rockenstein E, Koo EH, Masliah E, Tuszynski MH (2013) Early BDNF treatment ameliorates cell loss in the entorhinal cortex of APP transgenic mice. J Neurosci 33, 15596-15602. Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, Wang L, Blesch A, Kim A, Conner JM, Rockenstein E, Chao MV, Koo EH, Geschwind D, Masliah E, Chiba AA, Tuszynski MH (2009) Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 15, 331-337. van Albada SJ, Robinson PA (2007) Transformation of arbitrary distributions to the normal distribution with application to EEG test-retest reliability. J Neurosci Methods 161, 205211.

dA

[87]

[91]

cte

974

rre

973

Forgue ST, Patterson BE, Bedding AW, Payne CD, Phillips DL, Wrishko RE, Mitchell MI (2006) Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol 61, 280-288. Ricobaraza A, Cuadrado-Tejedor M, Marco S, Perez-Otano I, Garcia-Osta A (2012) Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus 22, 1040-1050. Ricobaraza A, Cuadrado-Tejedor M, Perez-Mediavilla A, Frechilla D, Del Rio J, Garcia-Osta A (2009) Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer’s disease mouse model. Neuropsychopharmacology 34, 1721-1732. Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE (2006) Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 103, 5161-5166. Smith DL, Pozueta J, Gong B, Arancio O, Shelanski M (2009) Reversal of long-term dendritic spine alterations in Alzheimer disease models. Proc Natl Acad Sci U S A 106, 16877-16882.

co

[86]

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Un

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Phosphodiesterase inhibition in cognitive decline.

Understanding the cellular and molecular processes involved in learning and memory will help in the development of safe and effective cognitive enhanc...
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