P.R.A. Heckman

Phosphodiesterase Inhibitors as a Target for Cognition Enhancement in Aging and Alzheimer's Disease: A Translational Overview

Phosphodiesterase inhibitors (PDE-Is) enhance cAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Since both cAMP and cGMP signaling are essential in a variety of cellular functions, including neuroplasticity and neuroprotection, PDE-Is are receiving increased attention as possible targets for treatment of age-related cognitive decline as well as Alzheimers disease (AD). In this review we will give a translational overview of the preclinical and clinical data on PDE-Is and cognition enhancement focusing on aging and AD. PDE2, 4 and 5 inhibitors improved memory performance in both aged animals and models of AD. Treatment with a PDE3-I or PDE7-I has not been tested in aged animals yet, but in mouse models of AD both PDE-Is improved memory performance. Unfortunately, there are no peer-reviewed studies on the effects of PDE-I treatment in aged human subjects except the possible positive effect on memory impairment of the PDE1-I vinpocetine. Three other types of PDE-Is have been tested on cognition in mild to moderate AD patients: the PDE3-I cilostazol is being tested as a co-treatment to the acetylcholinesterase inhibitor donepezil, but with inconsistent results; the PDE4-I MK-0952 has been tested, although the outcome has not been disclosed yet; and the PDE9-I PF- 04447943 was reported to have no effects on cognition. Obviously, the demonstration of clinical proof of concept for cognition enhancing effects of PDE-Is and the generation of isoform selective PDE-Is are the final hurdles to overcome in developing safe and efficacious novel PDE-Is for the treatment of age-associated cognitive decline or AD.

PDE and cognitive processing : beyond the memory domain

Phosphodiesterase inhibitors (PDE-Is) enhance cAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Both cAMP and cGMP signaling are essential for a variety of cellular functions and exert their effects both pre- and post-synaptically. Either of these second messengers relays and amplifies incoming signals at receptors on the cell surface making them important elements in signal transduction cascades and essential in cellular signaling in a variety of cell functions including neurotransmitter release and neuroprotection. Consequently, these processes can be influenced by PDE-Is as they increase cAMP and/or cGMP concentrations. PDE-Is have been considered as possible therapeutic agents to treat impaired memory function linked to several brain disorders, including depression, schizophrenia and Alzheimers disease (AD). This review will, however, focus on the possible role of phosphodiesterases (PDEs) in cognitive decline beyond the memory domain. Here we will discuss the involvement of PDEs on three related domains: attention, information filtering (sensory- and sensorimotor gating) and response inhibition (drug-induced hyperlocomotion). Currently, these are emerging cognitive domains in the field of PDE research. Here we discuss experimental studies and the potential beneficial effects of PDE-I drugs on these cognitive domains, as effects of PDE-Is on these domains could potentially influence effects on memory performance. Overall, PDE4 seems to be the most promising target for all domains discussed in this review.

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

ABSTRACT 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.

Phosphodiesterase inhibition and regulation of dopaminergic frontal and striatal functioning: clinical implications

Background: The fronto-striatal circuits are the common neurobiological basis for neuropsychiatric disorders, including schizophrenia, Parkinson’s disease, Huntington’s disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and Tourette’s syndrome. Fronto-striatal circuits consist of motor circuits, associative circuits, and limbic circuits. All circuits share 2 common features. First, all fronto-striatal circuits consist of hyper direct, direct, and indirect pathways. Second, all fronto-striatal circuits are modulated by dopamine. Intracellularly, the effect of dopamine is largely mediated through the cyclic adenosine monophosphate/protein kinase A signaling cascade with an additional role for the cyclic guanosine monophosphate/protein kinase G pathway, both of which can be regulated by phosphodiesterases. Phosphodiesterases are thus a potential target for pharmacological intervention in neuropsychiatric disorders related to dopaminergic regulation of fronto-striatal circuits. Methods: Clinical studies of the effects of different phosphodiesterase inhibitors on cognition, affect, and motor function in relation to the fronto-striatal circuits are reviewed. Results: Several selective phosphodiesterase inhibitors have positive effects on cognition, affect, and motor function in relation to the fronto-striatal circuits. Conclusion: Increased understanding of the subcellular localization and unraveling of the signalosome concept of phosphodiesterases including its function and dysfunction in the fronto-striatal circuits will contribute to the design of new specific inhibitors and enhance the potential of phosphodiesterase inhibitors as therapeutics in fronto-striatal circuits.

Translational issues with the development of cognition enhancing drugs.

Franco and Cedazo-Minguez, in their review, raised the issue that animal models have a poor predictability with respect to drug development in the field of Alzheimer’s disease (AD) (1). Although this critical paper touches upon highly relevant issues in the development of new drugs, various other factors can be suggested, which also complicate the translation from animal studies to human studies. Here, we briefly discuss these issues relating to the development of cognition enhancers.

Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults

ABSTRACT The need for new and effective treatments for dementia remains indisputably high. Phosphodiesterase inhibitors (PDE‐Is) have proven efficacy as cognitive enhancers based on their positive effects in numerous preclinical studies. Especially the PDE4 subfamily is of interest due to its expression in the hippocampus, the key structure for memory formation. The current study investigates the memory enhancing effects of the clinically approved PDE4‐I roflumilast in a test battery including the Verbal Learning Task (VLT) combined with electroencephalography (EEG) recording. This acute study was conducted according to a double‐blind, randomized, placebo‐controlled, 4‐way crossover design. Three capsulated dosages of roflumilast HCl (Daxas) and a placebo were administered in four study periods. Administration occurred 1 h before testing to reach maximal plasma concentrations. Memory performance was assessed using a 30 word Verbal Learning Task. The number of words recalled both immediately and after 45 min and 24 h were included as outcome measures. EEG was recorded during the cognitive tasks on the first day. Different event‐related potentials (ERPs) were considered with special emphasis on P600, as this peak has been related to word learning. Memory performance was significantly improved after acute administration of 100 &mgr;g roflumilast. Specifically, immediate recall performance on the VLT increased 2–3 words, accompanied by an enhanced P600 peak during word presentation at the third learning trial. No side effects typical for PDE4‐Is were reported for the lowest and effective dose of 100 &mgr;g roflumilast. The current proof‐of‐concept study shows for the first time the potential of low‐dose roflumilast administration as a memory enhancer in humans. HighlightsEffects of the PDE4 inhibitor roflumilast on verbal word memory were tested in healthy subjects.Memory performance was measured with the Verbal Learning Task.Immediate recall performance was improved at a non‐emetic dose of 100 &mgr;g.Effect was accompanied by an enhanced P600 peak during word presentation.Acute roflumilast administration improves immediate recall in healthy young human subjects.

Phosphodiesterase 4 inhibition affects both the direct and indirect pathway : an electrophysiological study examining the tri-phasic response in the substantia nigra pars reticulata

Fronto-striatal circuits constitute the neurobiological basis of many neuropsychiatric disorders. Part of the intracellular signaling within these circuits, including its dopaminergic modulation, is regulated by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling cascade. Based on the overall expression in human fronto-striatal circuitry, we tested the effects of a cAMP selective phosphodiesterase 4 (PDE4) inhibitor on the tri-phasic response in the dorsomedial substantia nigra pars reticulata (SNr) upon stimulation of the infralimbic cortex in rats. Our results show for the first time that stimulation of the cognitive infralimbic cortex leads to a tri-phasic response in SNr neurons. In addition and in line with previous biochemical and behavioral studies, PDE4 inhibition by roflumilast affects the direct pathway as well as the indirect pathway of which the latter appears more sensitive than the former.

From Age-Related Cognitive Decline to Alzheimer’s Disease: A Translational Overview of the Potential Role for Phosphodiesterases

Phosphodiesterase inhibitors (PDE-Is) are pharmacological compounds enhancing cAMP and/or cGMP signaling. Both these substrates affect neural communication by influencing presynaptic neurotransmitter release and postsynaptic intracellular pathways after neurotransmitter binding to its receptor. Both cAMP and cGMP play an important role in a variety of cellular functions including neuroplasticity and neuroprotection. This chapter provides a translational overview of the effects of different classes of PDE-Is on cognition enhancement in age-related cognitive decline and Alzheimers disease (AD). The most effective PDE-Is in preclinical models of aging and AD appear to be PDE2-Is, PDE4-Is and PDE5-Is. Clinical studies are relatively sparse and so far PDE1-Is and PDE4-Is showed some promising results. In the future, the demonstration of clinical proof of concept and the generation of isoform selective PDE-Is are the hurdles to overcome in developing safe and efficacious novel PDE-Is for the treatment of age-related cognitive decline and cognitive dysfunction in AD.

Phosphodiesterase inhibition and modulation of corticostriatal and hippocampal circuits: Clinical overview and translational considerations

HighlightsCorticostriatal and hippocampal circuits constitute the neurobiological basis for many neuropsychiatric disorders.PDE1, 4 and 10 inhibitors seem interesting for corticostriatal disorders due to their modulation of DAergic system.PDE3, 4 and 9 inhibitors are currently most promising for hippocampal disorders.So far, the wealth of positive preclinical data has not been able to be translated to convincing clinical efficacy.The local net amount of cAMP and/or cGMP will eventually determine the cellular and functional fate. &NA; The corticostriatal and hippocampal circuits contribute to the neurobiological underpinnings of several neuropsychiatric disorders, including Alzheimers disease, Parkinsons disease and schizophrenia. Based on biological function, these circuits can be clustered into motor circuits, associative/cognitive circuits and limbic circuits. Together, dysfunctions in these circuits produce the wide range of symptoms observed in related neuropsychiatric disorders. Intracellular signaling in these circuits is largely mediated through the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway with an additional role for the cyclic guanosine monophosphate (cGMP)/ protein kinase G (PKG) pathway, both of which can be regulated by phosphodiesterase inhibitors (PDE inhibitors). Through their effects on cAMP response element‐binding protein (CREB) and Dopamine‐ and cAMP‐Regulated PhosphoProtein MR 32 kDa (DARPP‐32), cyclic nucleotide pathways are involved in synaptic transmission, neuron excitability, neuroplasticity and neuroprotection. In this clinical review, we provide an overview of the current clinical status, discuss the general mechanism of action of PDE inhibitors in relation to the corticostriatal and hippocampal circuits and consider several translational challenges.

Acute administration of roflumilast enhances sensory gating in healthy young humans in a randomized trial

IntroductionSensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer’s disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating.MethodsThe current study investigated the effects of the PDE4 inhibitor roflumilast in a sensory gating paradigm in 20 healthy young human volunteers (age range 18–30 years). We applied a placebo-controlled randomized cross-over design and tested three doses (100, 300, 1000 μg).ResultsResults show that roflumilast improves sensory gating in healthy young human volunteers only at the 100-μg dose. The effective dose of 100 μg is five times lower than the clinically approved dose for the treatment of acute exacerbations in chronic obstructive pulmonary disease (COPD). No side-effects, such as nausea and emesis, were observed at this dose. This means roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study.ConclusionThe PDE4 inhibitor roflumilast has a favorable side-effect profile at a cognitively effective dose and could be considered as a treatment in disorders affected by disrupted sensory gating.