Tadalafil crosses the blood–brain barrier and reverses cognitive dysfunction in a mouse model of AD

García‐Barroso, Carolina; Ricobaraza, Ana; Pascual‐Lucas, María; Unceta, Nora; Rico, Alberto J.; Goicolea, M. Aránzazu; Sallés, Joan; Lanciego, José L.; Oyarzábal, Julen; Franco, Rafael; Cuadrado‐Tejedor, Mar; García‐Osta, Ana

doi:10.1016/j.neuropharm.2012.06.052

Cited by 153 publications

(156 citation statements)

References 52 publications

(69 reference statements)

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“…Puzzo et al [130] first demonstrated the preclinical efficacy of PDE5 inhibitors in AD mouse models and the findings were later confirmed by other groups [131][132][133]. Among reported PDE5 inhibitors, tadalafil and sildenafil can penetrate into the brain and ameliorate synaptic, learning, and memory deficits by modulating the cyclic guanosine monophosphate intracellular signaling pathway [130,134].…”

Section: Phosphodiesterase 5 Inhibitorsmentioning

confidence: 90%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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Summary Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.

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Section: Phosphodiesterase 5 Inhibitorsmentioning

confidence: 90%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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“…Finally, the inhibition of HDAC6 may facilitate the degradation of misfolded proteins, such as Aβ and pTau (Sung et al, 2012;Yu et al, 2013;Zhang et al, 2014). Although different studies have demonstrated that HDACi or PDE5i improved cognitive deficits in animal models of AD, their role on amyloid pathology is controversial (Benito et al, 2015;Cuadrado-Tejedor et al, 2011b;Garcia-Barroso et al, 2013;Puzzo et al, 2009;Qing et al, 2008;Ricobaraza et al, 2009;Rumbaugh et al, 2015;Zhang and Schluesener, 2013). These differences may be because of the selectivity and potency of each compound and the different animal models and treatments employed.…”

Section: Discussionmentioning

confidence: 99%

“…The synergistic effect should lead to achieve a degree of histone 3 acetylation that is not possible with HDAC6-selective inhibitors (eg, Ricolinostat) and, on the other hand, these new molecules will also achieve a degree of tubulin acetylation that has been impossible to obtain with the FDA-approved class I inhibitor, valproic acid (Gurvich et al, 2004). Moreover, the compounds proposed will have better brain permeability than the FDA-approved HDAC (Kazantsev and Thompson, 2008) and PDE5 inhibitors (eg, Sildenafil and Tadalafil, with a logBBo0) (Garcia-Barroso et al, 2013;Gomez-Vallejo et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…After 3 weeks of treatment, we used the MWM test to evaluate the working and reference memory function in Tg2576 mice (Garcia-Barroso et al, 2013). In addition, after a 4-week washout period of the drugs, a reversal phase of MWM was carried out.…”

Section: Morris Water Maze Test (Mwm)mentioning

confidence: 99%

“…PDE5 is upregulated in AD brains, often in conjunction with a decrease in cGMP in the cerebrospinal fluid (CSF) of AD patients , drawing attention to the possible therapeutic potential of PDE5 inhibitors in AD (Cuadrado-Tejedor et al, 2011a;Garcia-Barroso et al, 2013;Puzzo et al, 2009). It has been proposed that the activation of the cGMP/cAMP-responsive element-binding protein (CREB) pathway, which is crucial for memory formation, may contribute to the amelioration of AD symptoms observed with PDE5 inhibitors in animal models Puzzo et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

Cuadrado‐Tejedor

García‐Barroso

Sánchez‐Arias

et al. 2016

Neuropsychopharmacol

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The targeting of two independent but synergistic enzymatic activities, histone deacetylases (HDACs, class I and HDAC6) and phosphodiesterase 5 (PDE5), has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMPresponsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission. Thus, CM-414 may serve as the starting point to discover balanced dual inhibitors with an optimal efficacy and safety profile for clinical testing on AD patients.

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The PASTIS trial: Testing tadalafil for possible use in vascular cognitive impairment

Pauls

Binnie

Benjamin

et al. 2022

Alzheimer's & Dementia

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Introduction: There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI. Methods:In a double-blind, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling.Results: Tadalafil increased CBF non-significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (-7.8, -4.9 mmHg; P < .001). No serious adverse events were observed.

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Tadalafil crosses the blood–brain barrier and reverses cognitive dysfunction in a mouse model of AD

Cited by 153 publications

References 52 publications

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

The PASTIS trial: Testing tadalafil for possible use in vascular cognitive impairment

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