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Introduction:
The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning, and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs.
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Context 1
... their cognition-and memory-enhancing effects are now well established, the mechanism of action of PDE4 inhibitors and the downstream targets that mediate their procognitive effects are less well defined. There is strong evidence that PDE4 inactivation stimulates and/or reverses deficits in PKA/p-CREB signaling induced by pharmacological agents, aging or disease [8,34,48,49,51,52,54,55] but may also act via regulation of neurotransmitter release [44,56] (Figure 2). Mechanistically, PDE4 inactivation serves to enhance LTP as well as promote synaptic plasticity [30,49,50,57,58]. ...
Context 2
... addition to affecting active cognitive mechanisms, PDE4 inhibition may prevent disruption of brain homeostasis that results in cognitive dysfunction. This includes promoting neurogenesis and exerting neuroprotective and regenerative as well as anti-inflammatory effects (Figure 2). In one of the earliest studies revealing a neuroprotective effect of PDE4 inhibition, Yamashita et. ...
Context 3
... their cognition-and memory-enhancing effects are now well established, the mechanism of action of PDE4 inhibitors and the downstream targets that mediate their procognitive effects are less well defined. There is strong evidence that PDE4 inactivation stimulates and/or reverses deficits in PKA/p-CREB signaling induced by pharmacological agents, aging or disease [8,34,48,49,51,52,54,55] but may also act via regulation of neurotransmitter release [44,56] (Figure 2). Mechanistically, PDE4 inactivation serves to enhance LTP as well as promote synaptic plasticity [30,49,50,57,58]. ...
Context 4
... addition to affecting active cognitive mechanisms, PDE4 inhibition may prevent disruption of brain homeostasis that results in cognitive dysfunction. This includes promoting neurogenesis and exerting neuroprotective and regenerative as well as anti-inflammatory effects (Figure 2). In one of the earliest studies revealing a neuroprotective effect of PDE4 inhibition, Yamashita et. ...
Citations
... In the CNS, PDE4 is highly expressed in regions such as the hippocampus and striatum, where it regulates cognitive processes, memory consolidation, and synaptic plasticity [22]. Dysregulation of PDE4 activity has been linked to neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), primarily through the disruption of cAMP/PKA/CREB signaling [23]. ...
... The four subfamilies of PDE4 possess an upstream conserved region (UCR) that plays a key role in controlling intracellular signaling [22] (Figure 3). Based on the presence of UCRs, PDE4 isoforms are further categorized into subclasses, namely, long, short, super-short, and dead-short variants [37]. ...
... The four subfamilies of PDE4 possess an upstream conserved region (UCR) that plays a key role in controlling intracellular signaling [22] (Figure 3). Based on the presence of UCRs, PDE4 isoforms are further categorized into subclasses, namely, long, short, supershort, and dead-short variants [37]. ...
Phosphodiesterase 4 (PDE4) catalyzes cyclic adenosine monophosphate (cAMP) hydrolysis, playing a crucial role in the cAMP signaling pathway. cAMP is a secondary messenger involved in numerous physiological functions, such as inflammatory responses, immune responses, neural activity, learning, and memory. PDE4 inhibition is important for controlling anti-inflammatory and neuroprotective effects. In this review, we provide a comprehensive overview of the molecular functions and properties of human PDE4s. The study presents detailed sequence information for the PDE4 isoforms and the structural properties of the catalytic domain in members of the PDE4 family. We also review the inhibitory effects of the PDE4 inhibitors roflumilast and cilomilast related to respiratory diseases in PDE4. The crystal structures of PDE4 in complex with roflumilast and cilomilast are also analyzed. This review provides useful information for the future design of novel PDE4 inhibitors.
... In the CNS, PDE4 isoforms are broadly expressed in neurons and glial cells and are notably persistent in aged and Alzheimer's disease-affected brains, suggesting potential roles in neurodegeneration [15,16]. Among these, PDE4B is the most widely distributed, with high expression in brain regions such as the cortex, hippocampus, and cerebellum [17][18][19]. PDE4A is also abundant in the cortex but is expressed at two to four times lower levels in other areas [17]. PDE4D is prominent in the frontal cortex but is generally less abundant than PDE4B in most CNS regions. ...
... Among these, PDE4B is the most widely distributed, with high expression in brain regions such as the cortex, hippocampus, and cerebellum [17][18][19]. PDE4A is also abundant in the cortex but is expressed at two to four times lower levels in other areas [17]. PDE4D is prominent in the frontal cortex but is generally less abundant than PDE4B in most CNS regions. ...
... PDE4D is prominent in the frontal cortex but is generally less abundant than PDE4B in most CNS regions. Conversely, PDE4C is minimally expressed in the brain, indicating a limited or specialized role [17] (Figure 1). [20]. ...
Phosphodiesterase (PDE) enzymes regulate intracellular signaling pathways crucial for brain development and the pathophysiology of neurological disorders. Among the 11 PDE subtypes, PDE4 and PDE5 are particularly significant due to their regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling, respectively, which are vital for learning, memory, and neuroprotection. This review synthesizes current evidence on the roles of PDE4 and PDE5 in neurological health and disease, focusing on their regulation of second messenger pathways and their implications for brain function. Elevated PDE4 activity impairs synaptic plasticity by reducing cAMP levels and protein kinase A (PKA) activity, contributing to cognitive decline, acute brain injuries, and neuropsychiatric conditions such as bipolar disorder and schizophrenia. Similarly, PDE5 dysregulation disrupts nitric oxide (NO) signaling and protein kinase G (PKG) pathways, which are involved in cerebrovascular homeostasis, recovery after ischemic events, and neurodegenerative processes in Alzheimer’s, Parkinson’s, and Huntington’s diseases. PDE4 and PDE5 are promising therapeutic targets for neurological disorders. Pharmacological modulation of these enzymes offers potential to enhance cognitive function and mitigate pathological mechanisms underlying brain injuries, neurodegenerative diseases, and psychiatric disorders. Further research into the regulation of PDE4 and PDE5 will advance therapeutic strategies for these conditions.
... The mammalian genome contains a total of 11 PDE families (PDE 1-11) with cAMP-selective PDEs belonging to the PDE 4, 7 and 8 families, cGMP-selective PDEs belonging to the PDE 5, 6 and 9 families, while PDEs belonging to the PDE 1, 2, 3, 10 and 11 families lack selectivity and degrade both cAMP and cGMP (Keravis & Lugnier, 2012). The PDE4 family of phosphodiesterases accounts for a significant proportion of cAMP phosphodiesterase activity in the brain, and the importance of PDE4 activity in the brain is also reflected in the efforts to develop PDE4 inhibitors as cognitive enhancers to treat Alzheimer's disease (Richter et al., 2013;Tibbo et al., 2019) and fragile X syndrome (Berry-Kravis et al., 2021). ...
cAMP signalling is critical for memory consolidation and certain forms of long‐term potentiation (LTP). Phosphodiesterases (PDEs), enzymes that degrade the second messengers cAMP and cGMP, are highly conserved during evolution and represent a unique set of drug targets, given the involvement of these enzymes in several pathophysiological states including brain disorders. The PDE4 family of cAMP‐selective PDEs exert regulatory roles in memory and synaptic plasticity, but the specific roles of distinct PDE4 isoforms in these processes are poorly understood. Building on our previous work demonstrating that spatial and contextual memory deficits were caused by expressing selectively the long isoform of the PDE4A subfamily, PDE4A5, in hippocampal excitatory neurons, we now investigate the effects of PDE4A isoforms on different cAMP‐dependent forms of LTP. We found that PDE4A5 impairs long‐lasting LTP induced by theta burst stimulation (TBS) while sparing long‐lasting LTP induced by spaced four‐train stimulation (4 × 100 Hz). This effect requires the unique N‐terminus of PDE4A5 and is specific to this long isoform. Targeted overexpression of PDE4A5 in area CA1 is sufficient to impair TBS‐LTP, suggesting that cAMP levels in the postsynaptic neuron are critical for TBS‐LTP. Our results shed light on the inherent differences among the PDE4A subfamily isoforms, emphasizing the importance of the long isoforms, which have a unique N‐terminal region. Advancing our understanding of the function of specific PDE isoforms will pave the way for developing isoform‐selective approaches to treat the cognitive deficits that are debilitating aspects of psychiatric, neurodevelopmental and neurodegenerative disorders. image
Key points
Hippocampal overexpression of PDE4A5, but not PDE4A1 or the N‐terminus‐truncated PDE4A5 (PDE4A5Δ4), selectively impairs long‐term potentiation (LTP) induced by theta burst stimulation (TBS‐LTP).
Expression of PDE4A5 in area CA1 is sufficient to cause deficits in TBS‐LTP.
Hippocampal overexpression of the PDE4A isoforms PDE4A1 and PDE4A5 does not impair LTP induced by repeated tetanic stimulation at the CA3–CA1 synapses.
These results suggest that PDE4A5, through its N‐terminus, regulates cAMP pools that are critical for memory consolidation and expression of specific forms of long‐lasting synaptic plasticity at CA3–CA1 synapses.
... The novel PDE4B-preferring radioligand [ 18 F]PF-06445974 was recently evaluated in rodents, monkeys, and humans [17]. This radioligand demonstrates widespread distribution in the brain and can quantify PDE4B in the human brain [18]. Building on this work, this study sought to use PET imaging with [ 18 F]PF-06445974 to assess the effects of both acute and chronic alcohol exposure on PDE4B radioligand binding in rat brains in vivo. ...
The cyclic adenosine monophosphate (cAMP) cascade is thought to play an important role in regulating alcohol-dependent behaviors, with potentially opposite effects following acute versus chronic administration. Phosphodiesterase 4 (PDE4) is the primary brain enzyme that metabolizes cAMP, thereby terminating its signal. Radioligand binding to PDE4 serves as an indirect biomarker of cAMP activity, as cAMP-protein kinase A (PKA)-mediated phosphorylation of PDE4 increases its affinity for radioligand binding ~10-fold. Of the four PDE4 subtypes, PDE4B polymorphisms are known to be strongly associated with alcohol and substance use disorders. This study imaged rats with the PDE4B-preferring positron emission tomography (PET) radioligand [ ¹⁸ F]PF-06445974 following acute and chronic ethanol administration, aiming to explore the potential of PDE4B PET imaging for future human studies. Compared to the control group treated with saline, acute alcohol administration (i.p. ethanol 0.5 g/kg) significantly increased whole brain uptake of [ ¹⁸ F]PF-06445974 as early as 30 minutes post-exposure. This effect persisted at 2 hours, peaked at 4 hours, and diminished at 6 hours and 24 hours post-exposure. In contrast, in a rat model of alcohol dependence, [ ¹⁸ F]PF-06445974 brain uptake was significantly reduced at 5 hours post-exposure and was normalized by 3 days. This reduction may reflect long-term adaptation to repeated alcohol-induced activation of cAMP signaling with chronic exposure. Taken together, the results suggest that PET imaging of PDE4B in individuals with alcohol use disorder (AUD) should be considered in conjunction with ongoing trials of PDE4 inhibitors to treat alcohol withdrawal and reduce alcohol consumption.
... PDEs play an important role in regulating the functions of the central nervous system (CNS), as well as PDE inhibitors have anti-inflammatory, antioxidant, vasodilator, antidepressant, and memory-enhancing effects (Sadeghi et al., 2023). In addition, many studies have expanded the correlation between PDE4 and the pathogenesis of CNS diseases, demonstrating the beneficial effects of PDE4 inhibitors on CNS diseases such as stroke, Alzheimer's disease, and depression (Richter et al., 2013;Blokland et al., 2019). Nevertheless, the side effects induced by PDE4 inhibitors (notably nausea and vomiting) greatly limit their clinical utility (Schick and Schlegel, 2022). ...
Background
Phosphodiesterase 7 (PDE7) plays a role in neurological function. Increased expression and activity of PDE7 has been detected in several central nervous system diseases. However, the role of PDE7 in regulating stress levels remains unclear. Thus, this study aimed to determine whether and how PDE7 involved in the stress-induced behavioral and neuron morphological changes.
Methods
The single prolonged stress (SPS) was used to build a stress exposure model in C57BL/6 J mice and detected PDE7 activity in hippocampus, amygdala, prefrontal cortex and striatum. Next, three doses (0.2, 1, and 5 mg/kg) of the PDE7 inhibitor BRL-50481 were intraperitoneally administered for 10 days, then behavioral, biochemical, and morphological tests were conducted.
Results
PDE7 activity in hippocampus of mice significantly increased at all times after SPS. BRL-50481 significantly attenuated SPS induced anxiety-like behavior and fear response in both context and cue. In addition, BRL-50481 increased the levels of key molecules in the cAMP signaling pathway which were impaired by SPS. Immunofluorescent staining and Sholl analysis demonstrated that BRL-50481 also restored the nucleus/cytoplasm ratio of hippocampal neurons and improved neuronal plasticity. These effects of BRL-50481 were partially blocked by the TrkB inhibitor ANA-12.
Conclusion
PDE7 inhibitors attenuate stress-induced behavioral changes by protecting the neuron cytoarchitecture and the neuronal plasticity in hippocampus, which is mediated at least partly through the activation of BDNF/TrkB signaling pathway. These results proved that PDE7 is a potential target for treating stress-induced behavioral and physiological abnormalities.
... The main question is whether and how PDE4B downregulation contributes to the development of schizophrenia and affects LTP and memory formation processes in a subset of the patients. Several studies employing various techniques, such as mutated PDE4B genes and pharmacological inhibition of PDE4B protein products, support this notion [24,63,64]. First, PDE4B-related SNPs were associated with schizophrenia, supporting PDE4B involvement in disease development. ...
... Looking at the mechanism, appropriate cellular responses in LTP require a transient increase in cAMP levels. Counterintuitively, sustained elevation in cAMP levels could directly or indirectly induce cognitive and memory impairments [63,64] as demonstrated in a mice model treated chronically with Rolipram, a PDE4 inhibitor, which led to PKA upregulation and subsequent memory and learning deficits [66]. Consistent with that, mutant mice with a decreased catalytic ability of PDE4B have shown reduced contextual fear memory after seven days of fear conditioning [24]. ...
Schizophrenia symptomatology includes negative symptoms and cognitive impairment. Several studies have linked schizophrenia with the PDE4 family of enzymes due to their genetic association and function in cognitive processes such as long-term potentiation. We conducted a systematic gene expression meta-analysis of four PDE4 genes (PDE4A-D) in 10 brain sample datasets (437 samples) and three blood sample datasets (300 samples). Subsequently, we measured mRNA levels in iPSC-derived hippocampal dentate gyrus neurons generated from fibroblasts of three groups: healthy controls, healthy monozygotic twins (MZ), and their MZ siblings with schizophrenia. We found downregulation of PDE4B in brain tissues, further validated by independent data of the CommonMind consortium (515 samples). Interestingly, the downregulation signal was present in a subgroup of the patients, while the others showed no differential expression or even upregulation. Notably, PDE4A, PDE4B, and PDE4D exhibited upregulation in iPSC-derived neurons compared to healthy controls, whereas in blood samples, PDE4B was found to be upregulated while PDE4A was downregulated. While the precise mechanism and direction of altered PDE4 expression necessitate further investigation, the observed multilevel differential expression across the brain, blood, and iPSC-derived neurons compellingly suggests the involvement of PDE4 genes in the pathophysiology of schizophrenia.
... We confirm that the second-generation PDE4 inhibitor roflumilast promoted SCI recovery, as demonstrated previously [34]. This second-generation PDE4 inhibitor is accompanied with less emetic side effects compared to first-generation pan-PDE4 inhibitors (e.g., rolipram) [35,36]. Noteworthy, the second-generation PDE3, PDE4, and PDE5 inhibitor Ibudilast is currently being evaluated for degenerative cervical myelopathy, a non-traumatic SCI [37]. ...
Spinal cord injury (SCI) is a life-changing event that severely impacts the patient's quality of life. Modulating neuroinflammation, which exacerbates the primary injury, and stimulating neuro-regenerative repair mechanisms are key strategies to improve functional recovery. Cyclic adenosine monophosphate (cAMP) is a second messenger crucially involved in both processes. Following SCI, intracellular levels of cAMP are known to decrease over time. Therefore, preventing cAMP degradation represents a promising strategy to suppress inflammation while stimulating regeneration. Intracellular cAMP levels are controlled by its hydrolyzing enzymes phosphodiesterases (PDEs). The PDE4 family is most abundantly expressed in the central nervous system (CNS) and its inhibition has been shown to be therapeutically relevant for managing SCI pathology. Unfortunately, the use of full PDE4 inhibitors at therapeutic doses is associated with severe emetic side effects, hampering their translation toward clinical applications. Therefore, in this study, we evaluated the effect of inhibiting specific PDE4 subtypes (PDE4B and PDE4D) on inflammatory and regenerative processes following SCI, as inhibitors selective for these subtypes have been demonstrated to be well-tolerated. We reveal that administration of the PDE4D inhibitor Gebr32a, even when starting 2 dpi, but not the PDE4B inhibitor A33, improved functional as well as histopathological outcomes after SCI, comparable to results obtained with the full PDE4 inhibitor roflumilast. Furthermore, using a luminescent human iPSC-derived neurospheroid model, we show that PDE4D inhibition stabilizes neural viability by preventing apoptosis and stimulating neuronal differentiation. These findings strongly suggest that specific PDE4D inhibition offers a novel therapeutic approach for SCI.
... The PDE4 inhibitor rolipram (1 mg/kg, i.p.): PDE4 inhibitors prevent metabolism of second messengers such as cAMP and increase their tissue levels. They have procognitive and antidepressant properties [96]. The emetic effect of some PDE4 inhibitors is thought to be a consequence of inhibition of PDE4 and the subsequent increase in cAMP levels in the brainstem DVC [30,42]. ...
In contrast to cats and dogs, here we report that the α2-adrenergic receptor antagonist yohimbine is emetic and corresponding agonists clonidine and dexmedetomidine behave as antiemetics in the least shrew model of vomiting. Yohimbine (0, 0.5, 0.75, 1, 1.5, 2, and 3 mg/kg, i.p.) caused vomiting in shrews in a bell-shaped and dose-dependent manner, with a maximum frequency (0.85 ± 0.22) at 1 mg/kg, which was accompanied by a key central contribution as indicated by increased expression of c-fos, serotonin and substance P release in the shrew brainstem emetic nuclei. Our comparative study in shrews demonstrates that clonidine (0, 0.1, 1, 5, and 10 mg/kg, i.p.) and dexmedetomidine (0, 0.01, 0.05, and 0.1 mg/kg, i.p.) not only suppress yohimbine (1 mg/kg, i.p.)-evoked vomiting in a dose-dependent manner, but also display broad-spectrum antiemetic effects against diverse well-known emetogens, including 2-Methyl-5-HT, GR73632, McN-A-343, quinpirole, FPL64176, SR141716A, thapsigargin, rolipram, and ZD7288. The antiemetic inhibitory ID50 values of dexmedetomidine against the evoked emetogens are much lower than those of clonidine. At its antiemetic doses, clonidine decreased shrews’ locomotor activity parameters (distance moved and rearing), whereas dexmedetomidine did not do so. The results suggest that dexmedetomidine represents a better candidate for antiemetic potential with advantages over clonidine.
... BDNF promotes synaptic plasticity, a fundamental process that underlies learning and memory [30,31]. PDE4s are of particular interest due to their widespread expression in the brain and reported role in cognition, oxidative stress, autophagy, apoptosis, and inflammation [36]. Researchers have focused on PDE4s because of their possible role in reducing neurodegenerative illnesses due to their ability to regulate cAMP/cGMP concentration in neurons. ...
Phosphodiesterases (PDEs) have become a promising therapeutic target for various disorders. PDEs are a vast and diversified family of enzymes that degrade cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which have several biochemical and physiological functions. Phosphodiesterase 4 (PDE4) is the most abundant PDE in the central nervous system (CNS) and is extensively expressed in the mammalian brain, where it catalyzes the hydrolysis of intracellular cAMP. An alteration in the balance of PDE4 and cAMP results in the dysregulation of different biological mechanisms involved in neurodegenerative diseases. By inhibiting PDE4 with drugs, the levels of cAMP inside the cells could be stabilized, which may improve the symptoms of mental and neurological disorders such as memory loss, depression, and Parkinson’s disease (PD). Though numerous studies have shown that phosphodiesterase 4 inhibitors (PDE4Is) are beneficial in PD, there are presently no approved PDE4I drugs for PD. This review presents an overview of PDE4Is and their effects on PD, their possible underlying mechanism in the restoration/protection of dopaminergic cell death, which holds promise for developing PDE4Is as a treatment strategy for PD. Methods on how these drugs could be effectively delivered to develop as a promising treatment for PD have been suggested.
... Upregulating the cAMP signaling pathway is thus a promising drug target for ameliorating memory impairments. In support of this idea, rolipram, a phosphodiesterase 4 (PDE4) inhibitor, has pro-cognitive effects in several animal models via activation of the cAMP pathway Richter et al. 2013;Rutten et al. 2006Rutten et al. , 2008bRutten et al. , 2009Sutcliffe et al. 2014;Vecsey et al. 2009;Wang et al. 2012;Peters et al. 2014). However, the gastrointestinal side effects of PDE4 inhibitors, such as nausea and vomiting, have strictly limited its doses in clinical trials (Hebenstreit et al. 1989;Robichaud et al. 2002a;Simpson et al. 2019). ...
Rationale
Phosphodiesterase 4D negative allosteric modulators (PDE4D NAMs) enhance memory and cognitive function in animal models without emetic-like side effects. However, the relationship between increased cyclic adenosine monophosphate (cAMP) signaling and the effects of PDE4D NAM remains elusive.
Objective
To investigate the roles of hippocampal cAMP metabolism and synaptic activation in the effects of D159687, a PDE4D NAM, under baseline and learning-stimulated conditions.
Results
At 3 mg/kg, D159687 enhanced memory formation and consolidation in contextual fear conditioning; however, neither lower (0.3 mg/kg) nor higher (30 mg/kg) doses induced memory-enhancing effects. A biphasic (bell-shaped) dose–response effect was also observed in a scopolamine-induced model of amnesia in the Y-maze, whereas D159687 dose-dependently caused an emetic-like effect in the xylazine/ketamine anesthesia test. At 3 mg/kg, D159687 increased cAMP levels in the hippocampal CA1 region after conditioning in the fear conditioning test, but not in the home-cage or conditioning cage (i.e., context only). By contrast, 30 mg/kg of D159687 increased hippocampal cAMP levels under all conditions. Although both 3 and 30 mg/kg of D159687 upregulated learning-induced Fos expression in the hippocampal CA1 30 min after conditioning, 3 mg/kg, but not 30 mg/kg, of D159687 induced phosphorylation of synaptic plasticity-related proteins such as cAMP-responsive element-binding protein, synaptosomal-associated protein 25 kDa, and the N-methyl-D-aspartate receptor subunit NR2A.
Conclusions
Our findings suggest that learning-stimulated conditions can alter the effects of a PDE4D NAM on hippocampal cAMP levels and imply that a PDE4D NAM exerts biphasic memory-enhancing effects associated with synaptic plasticity-related signaling activation.
