The contribution of Parkin, PINK1 and DJ-1 genes to selective neuronal degeneration in Parkinson's disease.

Parkinson's disease (PD) is characterised by selective and severe degeneration of the substantia nigra pars compacta and the locus coeruleus (LC), which underlies the most prominent symptoms. Although α-synuclein accumulation has long been established to play a causal role in the disease, it alone cannot explain the selective degenerative pattern. Recent evidence shows that the selective vulnerability could arise due to the large presence of cytosolic catecholamines and Ca2+ ions in the substantia nigra pars compacta and LC specifically that can be aberrantly affected by α-synuclein accumulation. Moreover, each has its own toxic potential, and disturbance of one can exacerbate the toxic effects of the others. This presents a mechanism unique to these areas that can lead to a vicious degenerative cycle. Interestingly, in familial variants of PD, the exact same brain areas are affected, implying the underlying process is likely the same. However, the exact disease mechanisms of many of these genetic variants remain unclear. Here, we review the effects of the PD-related genes Parkin, PINK1 and DJ-1. We establish that these mutant varieties can set in motion the same degenerative process involving α-synuclein, cytosolic catecholamines and Ca2+ . Additionally, we show indications that model organisms might not accurately represent all components of this central mechanism, explaining why Parkin, PINK1 and DJ-1 model organisms often lack a convincing PD-like phenotype.

A brief period of sleep deprivation negatively impacts the acquisition, consolidation, and retrieval of object-location memories.

Memory is a cognitive concept and refers to the storage of information over a longer time period. It exists of a series of complementary processes; acquisition, consolidation, and retrieval. Each of these processes has its own partly unique neurobiological signature. Sleep deprivation is known to impair hippocampus-dependent long-term memories. Many studies have used extended periods of wakefulness, affecting all three memory processes, thereby making it unable to determine how each of the processes is affected by sleep loss, separately. Others have extensively examined the effects on memory consolidation, showing the detrimental effect of sleep deprivation during the consolidation process on memory formation. Few studies have investigated how memory acquisition and its retrieval are affected by sleep loss. In the present study, we therefore assessed in mice how sleep deprivation negatively impacts memory acquisition, consolidation, and retrieval, in the Object Location Memory task. Mice were sleep deprived for six hours at the beginning of the light phase using the gentle handling method, 1) directly preceding the learning trial (acquisition), 2) immediately after the learning trial (consolidation), or 3) directly preceding the test trial (retrieval). Memory was assessed at either a 24-h or 1-h interval. Using this approach, we show for the first time that six hours of sleep deprivation attenuates the acquisition, consolidation, and retrieval of object-location memories in mice.

Phosphodiesterase inhibitors roflumilast and vardenafil prevent sleep deprivation-induced deficits in spatial pattern separation.

Sleep deprivation (SD) is known to impair hippocampus-dependent memory processes, in part by stimulating the phosphodiesterase (PDE) activity. In the present study, we assessed in mice whether SD also affects spatial pattern separation, a cognitive process that specifically requires the dentate gyrus (DG) subregion of the hippocampus. Adult male mice were trained in an object pattern separation (OPS) task in the middle of the light phase and then tested 24 hr thereafter. In total, we conducted three studies using the OPS task. In the first study, we validated the occurrence of pattern separation and tested the effects of SD. We found that 6 hr of SD during the first half of the light phase directly preceding the test trial impaired the spatial pattern separation performance. As a next step, we assessed in two consecutive studies whether the observed SD-induced performance deficits could be prevented by the systemic application of two different PDE inhibitors that are approved for human use. Both the PDE4 inhibitor roflumilast and PDE5 inhibitor vardenafil successfully prevented SD-induced deficits in spatial pattern separation. As a result, these PDE inhibitors have clinical potential for the prevention of memory deficits associated with loss of sleep.

Sleep deprivation-induced impairment of memory consolidation is not mediated by glucocorticoid stress hormones.

The general consensus is that sleep promotes neuronal recovery and plasticity, whereas sleep deprivation (SD) impairs brain function, including cognitive processes. Indeed, a wealth of data has shown a negative impact of SD on learning and memory processes, particularly those that involve the hippocampus. The mechanisms underlying these negative effects of sleep loss are only partly understood, but a reoccurring question is whether they are in part caused by stress hormones that may be released during SD. The purpose of the present study is therefore to examine the role of glucocorticoid stress hormones in SD-induced memory impairment. Male C57BL/6J mice were trained in an object-location memory paradigm, followed by 6 hr of SD by mild stimulation. At the beginning of the SD mice were injected with the corticosterone synthesis inhibitor metyrapone. Memory was tested 24 hr after training. Blood samples taken in a separate group of mice showed that SD resulted in a mild but significant increase in plasma corticosterone levels, which was prevented by metyrapone. However, the SD-induced impairment in object-location memory was not prevented by metyrapone treatment. This indicates that glucocorticoids play no role in causing the memory impairments seen after a short period of SD.

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.

Treatment with the selective PDE4B inhibitor A-33 or PDE4D inhibitor zatolmilast prevents sleep deprivation-induced deficits in spatial pattern separation.

Sleep deprivation (SD) disrupts hippocampus-dependent memory, particularly in the dentate gyrus (DG) region, an area crucial for pattern separation. Previous research showed that non-selective phosphodiesterase type 4 (PDE4) inhibitors like roflumilast can alleviate these deficits. However, it remains unclear whether these outcomes are specific to a particular subfamily of PDE4. Hence, this study examined the specific impact of PDE4B inhibitor (A-33) and PDE4D inhibitor (zatolmilast) on spatial pattern separation in sleep deprived mice. Results demonstrated that SD impairs pattern separation, but both zatolmilast and A-33 alleviate these effects. However, A-33 impaired pattern separation in non-sleep deprived animals. The cognitive benefits of these inhibitors after SD may arise from alterations in relevant signaling pathways in the DG. This study provides initial evidence that inhibiting PDE4B or PDE4D holds promise for mitigating memory deficits due to SD.

Recovering object-location memories after sleep deprivation-induced amnesia.

It is well established that sleep deprivation after learning impairs hippocampal memory processes and can cause amnesia. It is unknown, however, whether sleep deprivation leads to the loss of information or merely the suboptimal storage of information that is difficult to retrieve. Here, we show that hippocampal object-location memories formed under sleep deprivation conditions can be successfully retrieved multiple days following training, using optogenetic dentate gyrus (DG) memory engram activation or treatment with the clinically approved phosphodiesterase 4 (PDE4) inhibitor roflumilast. Moreover, the combination of optogenetic DG memory engram activation and roflumilast treatment, 2 days following training and sleep deprivation, made the memory more persistently accessible for retrieval even several days later (i.e., without further optogenetic or pharmacological manipulation). Altogether, our studies in mice demonstrate that sleep deprivation does not necessarily cause memory loss but instead leads to the suboptimal storage of information that cannot be retrieved without drug treatment or optogenetic stimulation. Furthermore, our findings suggest that object-location memories, consolidated under sleep deprivation conditions and thought to be lost, can be made accessible again several days after the learning and sleep deprivation episode, using the clinically approved PDE4 inhibitor roflumilast.

Soluble guanylate cyclase stimulator riociguat improves spatial memory in mice via peripheral mechanisms.

Soluble guanylate cyclase (sGC) - cyclic guanosine monophosphate (cGMP) signalling is important for healthy memory function and a healthy vascular system. Targeting sGC-cGMP signalling can therefore be a potential strategy to enhance memory processes. sGC can be targeted by using agonists, such as sGC stimulator riociguat. Therefore, this study aimed to target sGC using riociguat to investigate its acute effects on memory function and neuronal plasticity in mice. The effects of riociguat on long-term memory and a biperiden-induced memory deficit model for assessing short-term memory were tested in the object location task, and working memory was tested in the Y-maze continuous alternation task. Pharmacokinetic measurements were performed within brain tissue of mice, and hippocampal plasticity measures were assessed using western blotting. Acute oral administration with a low dose of 0.03 mg/kg riociguat was able to enhance working-, short-, and long-term spatial memory. Under cerebral vasoconstriction higher doses of riociguat were still effective on memory. Pharmacokinetic measurements revealed poor brain penetration of riociguat and its metabolite M-1. Increased activation of VASP was found, while no effects were found on other memory-related hippocampal plasticity measures. Memory enhancing effects of riociguat are most likely regulated by vascular peripheral effects on cGMP signalling. Yet, further research is needed to investigate the possible contribution of hemodynamic or metabolic effects of sGC stimulators on memory performance.

Genetic manipulation of cyclic nucleotide signaling during hippocampal neuroplasticity and memory formation.

Decades of research have underscored the importance of cyclic nucleotide signaling in memory formation and synaptic plasticity. In recent years, several new genetic techniques have expanded the neuroscience toolbox, allowing researchers to measure and modulate cyclic nucleotide gradients with high spatiotemporal resolution. Here, we will provide an overview of studies using genetic approaches to interrogate the role cyclic nucleotide signaling plays in hippocampus-dependent memory processes and synaptic plasticity. Particular attention is given to genetic techniques that measure real-time changes in cyclic nucleotide levels as well as newly-developed genetic strategies to transiently manipulate cyclic nucleotide signaling in a subcellular compartment-specific manner with high temporal resolution.

Role of cyclic nucleotides and their downstream signaling cascades in memory function: Being at the right time at the right spot.

A plethora of studies indicate the important role of cAMP and cGMP cascades in neuronal plasticity and memory function. As a result, altered cyclic nucleotide signaling has been implicated in the pathophysiology of mnemonic dysfunction encountered in several diseases. In the present review we provide a wide overview of studies regarding the involvement of cyclic nucleotides, as well as their upstream and downstream molecules, in physiological and pathological mnemonic processes. Next, we discuss the regulation of the intracellular concentration of cyclic nucleotides via phosphodiesterases, the enzymes that degrade cAMP and/or cGMP, and via A-kinase-anchoring proteins that refine signal compartmentalization of cAMP signaling. We also provide an overview of the available data pointing to the existence of specific time windows in cyclic nucleotide signaling during neuroplasticity and memory formation and the significance to target these specific time phases for improving memory formation. Finally, we highlight the importance of emerging imaging tools like Förster resonance energy transfer imaging and optogenetics in detecting, measuring and manipulating the action of cyclic nucleotide signaling cascades.

Alzheimer's disease pathogenesis: The role of disturbed sleep in attenuated brain plasticity and neurodegenerative processes.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairments. The classical symptoms of the disease include gradual deterioration of memory and language. Epidemiological studies indicate that around 25-40% of AD patients have sleep-wake cycle disturbances. Importantly, a series of studies suggested that the relationship between AD and sleep disturbance may be complex and bidirectional. Indeed, accumulation of the extracellular neuronal protein amyloid-beta (Aß) leads to altered sleep-wake behavior in both mice and humans. At the same time, disturbances of the normal sleep-wake cycle may facilitate AD pathogenesis. This paper will review the mechanisms underlying this potential interrelated connection including locus coeruleus damage, reductions in orexin neurotransmission, alterations in melatonin levels, and elevated cytokine levels. In addition, we will also highlight how both the development of AD and sleep disturbances lead to changes in intracellular signaling pathways involved in regulating neuronal plasticity and connectivity, particularly extremes in cofilin phosphorylation. Finally, current pharmacological and nonpharmacological therapeutic approaches will be discussed.

Acute treatment with the PDE4 inhibitor roflumilast improves verbal word memory in healthy old individuals: a double-blind placebo-controlled study.

There is ample evidence that phosphodiesterase 4 (PDE4) inhibition can improve memory performance in animal studies. In the present study, we examined the acute effects of the PDE4 inhibitor roflumilast on memory performance in healthy individuals (60-80 years of age). We tested the effects of acute roflumilast administration (100, 250, 1000 µg) in a double-blind, placebo-controlled, 4-way crossover design. Participants were first screened for their verbal word memory performance to ensure normal memory performance (within 0.5 standard deviation from norm score; n = 20) Drug effects on memory performance were tested in a verbal memory test and a spatial memory test. Reported side effects of drug treatment were registered. Roflumilast (100 µg) improved the delayed recall performance of the participants (Cohen's d, 0.69). No effects were observed in the spatial memory task. Roflumilast was well tolerated at this low dose. Although no clear adverse side effects were reported at the low dose, mild adverse events (including headache, dizziness, insomnia, and diarrhea) were reported after the 1000 µg dose. The present study provides first evidence that the PDE4 inhibitor roflumilast improves verbal memory performance in old participants. The current data encourage further development of PDE4 inhibitors for improving memory.

Validation of the xylazine/ketamine anesthesia test as a predictor of the emetic potential of pharmacological compounds in rats.

The xylazine/ketamine anesthesia test is widely used as a predictor of the emetic potential of pharmacological compounds in rats. An emetic reflex is usually triggered by the emetic center, which is populated with many different chemoreceptors. Inhibition of the α2 adrenergic receptor (α2 receptor) is involved in the initiation of the emetic reflex, and this is the key mechanism behind the xylazine/ketamine anesthesia test. In this study, we attempt to validate this test as a predictor of the emetic potential of pharmacological compounds. Furthermore, it was investigated whether an anti-emetic potential of pharmacological compounds could be assessed within this test as well. Rats were anesthetized with a combination of low doses of ketamine and xylazine, and subsequently treated with PDE4 inhibitor rolipram, α2 receptor antagonist yohimbine, α2 receptor agonist clonidine, tricyclic antidepressant imipramine, D2-receptor antagonist haloperidol, or 5-HT3 receptor antagonist (and anti-emetic drug) ondansetron. We were able to successfully reproduce the reduction in anesthesia time after rolipram or yohimbine treatment, as found in previous studies and has been suggested to be indicative of emetic properties of these treatments is humans. Furthermore, clonidine shortened anesthesia duration whereas imipramine and haloperidol lengthened anesthesia duration. Ondansetron was unable to rescue the reduction in duration of anesthesia induced by either rolipram or yohimbine. Altogether, the xylazine/ketamine anesthesia test is a reliable measure for α2 receptor antagonism. However, it may not be appropriate to assess emesis independent of this mechanism.

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

INTRODUCTION: Sensory 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. METHODS: The 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). RESULTS: Results 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. CONCLUSION: The 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.

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

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.

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 Alzheimer's 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.