In the Brain of Phosphodiesterases: Potential Therapeutic Targets for Schizophrenia
Federica Barbagallo1, Maria Rita Assenza1, Antonino Messina2
1Department of Medicine and Surgery, Kore University of Enna, Enna, Italy
2Department of Mental Health of Enna, Psychiatry Unity, Enna Hospital, Enna, Italy
Correspondence to: Antonino Messina
Department of Mental Health of Enna, Psychiatry Unit “Umberto I” Hospital, Contrada Ferrante, Enna 94100, Italy
E-mail: a.messina@asp.enna.it
ORCID: https://orcid.org/0000-0002-3594-8542
Received: July 25, 2024; Revised: October 19, 2024; Accepted: November 14, 2024; Published online: December 3, 2024.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Intracellular cyclic nucleotides (cyclic adenosine monophosphate and cyclic guanosine monophosphate) and downstream cellular signal transduction are regulated by phosphodiesterases (PDEs). The neuroplasticity, neurotransmitter pathways, and neuroinflammation-controlling functions of PDEs were demonstrated in numerous in vitro and animal model studies. We comprehensively reviewed the literature regarding the expression of PDEs in various brain regions. Subsequently, articles regarding schizophrenia and PDEs were examined. The pathophysiological mechanisms of schizophrenia and PDEs in preclinical and clinical investigations are briefly reviewed. Particularly for those who do not respond to conventional antipsychotics, specific PDE inhibitors may offer innovative therapeutic alternatives. Although the connection between schizophrenia and PDEs is intriguing, additional research is required. Comprehending the brain’s PDE isoforms, their therapeutic potential, and any adverse effects of inhibiting them is essential for progress in this field.
Keywords: Neuroinflammatory diseases; Phosphodiesterase inhibitors; Adenosine cyclic monophosphate; Guanosine cyclic monophosphate; Neuronal plasticity; Schizophrenia
INTRODUCTION

Within the psychotic spectrum disorders, schizophrenia represents a chronic and severe disease that alters the adaptation to reality, leading to changes in behavior, impairing personal, social, and occupational functioning. Individuals with schizophrenia frequently face stigmatization, discrimination, and human rights violations, resulting in social exclusion, limited access to essential services such as healthcare, education, housing, and employment [1]. Worse still, over two-thirds of those worldwide with psychosis, including schizophrenia, do not access specialist mental health services, signaling an immense treatment gap. Schizophrenia affects an estimated 24 million people globally, with a prevalence of 0.5 to 1%, and typically manifests in late adolescence or their 20s [2]. Unfortunately, schizophrenia, besides being a complex disease due to its symptomatologic facets and the difficulty of the treatment, is associated with an increased risk of early mortality, about two to three times higher than in general populations, often due to physical illnesses such as cardiovascular, metabolic, or infectious disorders [1].

The first description of schizophrenia dated to 1887, when Emil Kraepelin identified a clinical entity called “dementia praecox,” characterized by alterations in the flow and content of thought and perception [3]. Eugen Bleuler later (1911) introduced the term schizophrenia, emphasizing aspects of autism, flat affect, ambivalence, and loss in the association of ideas [4].

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition text revision (DSM-5-TR) [5], to meet the criteria for diagnosing schizophrenia, a patient must have experienced at least two of the following symptoms: delusions, hallucinations (positive symptoms), disorganized speech, disorganized or catatonic behavior and flat affect, loss of pleasure in activities, social inhibition, thought barrage (negative symptoms). Continuous signs and symptoms of schizophrenia must have persisted for at least six months, at least one month of active symptoms (or less if successfully treated).

Schizophrenia can be considered a disconnection pathology in the neural circuits of different brain areas [6]. The impairment of neural networks involved in the salience (SN) and the default mode network (DMN) is a hallmark of schizophrenia [7]. SN, activated while attention is focused on a particular object, allowing for appropriate valence to be assigned to stimuli, is disrupted, while the DMN, engaged in brain wandering and not focused on stimuli from the outside, appears hyperactivated in schizophrenia [8]. To current knowledge, the pathogenesis of schizophrenia is complex and not fully understood. The prominent hypothesis is that the underlying mechanisms of schizophrenia are miscommunication between different brain regions, in which abnormalities in dopaminergic, serotonergic, and glutamatergic neurotransmission and related receptor activity play a pivotal role. The pathophysiology of the illness may revolve around the dysregulation of dopamine D2, serotonin 5HT2A, and glutamate NMDA receptors [9-11].

In this regard, as far back a few decades ago, it was hypothesized that cyclic nucleotides (cNs), which are ubiquitous intracellular second messengers involved in many cellular processes, regulate the density of the receptors, as well as their activation state, play a significant role in the pathogenesis of schizophrenia [12].

Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) represent the most common second messengers involved in various intracellular signal transduction processes. Both neurons and glial cells use cAMP or cGMP to activate several signaling pathways [13]. The binding between a neurotransmitter and its specific receptor generates a cascade of events, mediated by cNs, that in turn modulate neuronal homeostasis by activating different intracellular targets such as protein kinases (PKA, PKG), ion channels (Na+, Cl, K+) [14] cytoskeleton proteins (microtubule-associated proteins and actin-binding protein cofilin [15,16], and transcription factors (i.e., cAMP-response element binding protein [CREB]) [17]. Through cNs-mediated phosphorylation of the transcription factor CREB, genes synthesizing neurotransmitters, receptors, cytoskeleton proteins, cell adhesion molecules (CAMs), and growth factors (i.e., BDNF, NGF) are expressed [18,19]. These proteins are associated with survival processes, neuronal homeostasis maintenance, and neurotransmission.

cAMP/cGMP local and temporal regulation is fine-tuned by their generation by cyclase enzymes, adenylate cyclase-ACs and guanylate cyclase-GCs, and by their hydrolysis that is in charge of enzymes named phosphodiesterases (PDEs).

Since schizophrenia is related to alterations in the processes that control neuronal survival, functioning, and remodeling, the intracellular level of cNs and its regulation, represents an aspect of paramount relevance in the pathogenetic process leading to schizophrenia and any changes of PDEs activity or expression could contribute to abnormalities observed in this disease [20].

Given the widespread presence of PDEs in the brain this review will summarize studies that have assessed the potential implication of PDEs in schizophrenia pathogenesis. The function of PDEs in patients with schizophrenia could elucidate the pathogenetic factors underlying schizophrenia and explore new pharmacological approaches to the disease. This literature review followed the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. Two authors independently screened the databases MEDLINE and SCOPUS and through Mendeley for the following entries: schizophrenia or patients with schizophrenia and PDEs. Only articles written in English were considered.

THE FAMILY OF PHOSPHODIESTERASES

cNs are mediators required in calcium signaling, cardiac contraction, sexual reproduction, vision, neurogenesis, inflammatory processes, and synaptic neuroplasticity. Given the delicate function in different vital cell homeostasis processes, it appears necessary for cAMP and cGMP levels to be subtly regulated. Therefore, the levels of cNs within the cell are controlled by enzymes that hydrolyze cAMP and cGMP into their inactive form 5’AMP and 5’GMP, respectively. PDEs are a class of enzymes encoded by 24 genes that are grouped into 11 different gene families (PDE1-11) according to their kinetic properties, mechanisms of activation, and sensitivity to inhibitors (Table 1) [21-39]. An additional level of variety is guaranteed by alternative splicing or alternative promoters, that produce more than 100 gene products that display specificity in their tissue, cellular and subcellular distribution. According to their different affinities for cAMP and cGMP, they can be classified as cAMP-specific (PDE4, 7, and 8), cGMP-specific (PDE5, 6, and 9), and dual substrate (PDE1, 2, 3, 10, and 11) [21].

ROLE OF CYCLIC NUCLEOTIDES AND PHOSPHODIESTERASES IN NEURONAL HOMEOSTASIS AND SIGNALING

Neurotransmitter receptors have long been linked to either cAMP or cGMP signaling pathways (Table 2), and PDEs prevent the cNs signal from being over-amplified [40]. It is worth noting that different areas of the brain specifically express only certain members of PDEs families (Fig. 1 and Tables 3, 4) [41-59].

PDE1 family comprises the isoforms PDE1A, PDE1B, and PDE1C. The PDE1 class is a calcium/calmodulin-dependent enzyme able to hydrolyze cAMP and cGMP with different affinities according to the isoform. The expression of PDE1 isoforms has been revealed in hippocampus, frontal cortex, temporal cortex, parietal cortex, and striatum associating their function with synaptic plasticity and memory processes [60].

PDE2A is the sole isoform in the PDE2 class and breaks down both cNs with higher affinity for cGMP. It has the peculiar feature of being stimulated by cGMP, indeed the binding of cGMP to its allosteric domain causes a conformational change that promotes cAMP hydrolysis. It is expressed in the cingulate cortex, orbital frontal cortex, superior temporal gyrus, hippocampus, parahippocampal cortex, amygdala, and striatum [41,61]. PDE2A upregulation is associated to neurological disease such depression and anxiety [62,63].

PDE3 class of enzymes comprises two isoforms, PDE3A and PDE3B acting on cAMP and cGMP with higher affinity for cAMP, interestingly, cGMP binding to the allosteric domain inhibits cAMP hydrolysis. They are expressed in the brain but within peripheral tissue. Both PDE3 hydrolyze cAMP, which is implicated in neuronal differentiation, neurotransmitter release, and brain microvascular endothelial functions [64,65].

PDE4 enzymes represent the majority of cAMP-selective PDEs. They are widely expressed throughout neurons, microglia, and astrocytes of the brain, where it plays a crucial role in synaptic plasticity processes such as learning, memory formation, and neuroinflammation processes [66] attributable to PDE4B and PDE4D activity, since they are the most expressed in the brain [42,66]. Interestingly, PDE4B plays a prominent role in learning and long-term memory processes, particularly within the hippocampus, where it acts on long-term potentiation [61,67].

PDE5A, acting on the hydrolysis of cGMP, regulates NO/cGMP/PKG/CREB pathway whose activation is impaired is during aging and neurodegenerative disease like Alzheimer’s disease [61,68].

PDE6 expression is restricted in rod and cone where it regulates the intracellular level of cGMP, given that its role is confined to these photoreceptors [22].

PDE7A and PDE7B, belonging to PDE7 class, fine tune cAMP intracellular level. PDE7A is mainly expressed in the cerebral cortex, striatum, thalamus, hypothalamus, and hippocampus; whereas PDE7B is expressed mostly in the caudate nucleus, the cortex, thalamus, hypothalamus, hippocampus and spinal cord [69,70]. PDE7 is involved in a variety of neurodegenerative disease and autoim-mune neurodegenerative disease including multiple sclerosis, Parkinson’s and Alzheimer’s disease, in addition to other neuropsychiatric disorders [70,71]. Recent and preliminary findings suggest a potential link between PDE7A polymorphisms and depression [72].

Among PDE8, belonging to cAMP-specific PDEs, PDE8B is the one found abundant in different neuronal populations; in particular in the cerebral cortex, in the basal ganglia, putamen, hippocampus and cerebellum [43,70]. A frameshift mutation in PDE8B that leads to loss of activity, causes an autosomal-dominant striatal degeneration [73] indicating that it could play an important role in the regulation of neuronal function, especially in the striatum.

PDE9A is widely expressed throughout the brain, particularly in the hippocampus and cortex regions [62]. This enzyme hydrolyzes cGMP to modulate signaling pathways involved in synaptic plasticity and memory processes [74].

PDE10A is highly expressed in various cortical and subcortical regions. Specifically, PDE10A is engaged in signal transduction of the striatum’s medium spine neurons (MSNs) [75,76]. It regulates cAMP and cGMP signaling pathways while playing an essential role in dopaminergic neurotransmission, motor control, reward-related behaviors, memory, and learning [20,41,77].

PDE11 class hydrolyzes cAMP and cGMP in equal manner and its expression is restricted in hippocampal formation [78]. It is required for consolidation of social memories in mice and in human studies PDE11A dysfunction is correlated with mood disorders and several single nucleotide polymorphisms (SNPs) with major depressive disorder [79].

PHOSPHODIESTERASES AND NEUROINFLAMMATION

Excessive neuroinflammation has been linked to various neurological conditions, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, depressive disorder, and schizophrenia [80,81].

In schizophrenia, activating the innate immune system and the secretion of pro-inflammatory cytokines, impact the neurotransmission of dopaminergic, serotonergic, and glutamatergic circuits [82]. Various harmful agents such as infectious agents, trauma, maternal immune activation (MIA), or psychological stressors occurred during childhood may act as factors in activating microglia and neuroinflammation, resulting in altered synaptic plasticity and pruning [6,83]. The innate immune system activation noticed in schizophrenia results in the triggering of an immune-inflammatory cascade, mediated by the nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome, responsible for the production of pro-inflammatory cytokines [84]. Activation of microglia and secretion of pro-inflammatory cytokines makes the brain-blood barrier (BBB) more permeable. Consequently, immune cells enter the central nervous system (CNS) with further immune-mediated damage [83,85]. The progression of neuroinflammation leads, if persistent, to the loss of synaptic plasticity, neuronal death, and white matter lesions, which collectively define neurodegeneration [83].

A high expression of some PDEs is associated with the activation of microglia and neuroinflammation [86]. By modulating cAMP and cGMP level, PDEs can regulate immune cell activity and release pro-inflammatory mediators into circulation [87]. The reduction of the PDEs activity has a beneficial function by decreasing pro-inflamma-tory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) [88,89]. For instance, it has been observed that cGMP reduces the production of pro-inflammatory cytokines, oxidative stress, and the expression of nuclear factor-kappa B (NF-κB), which contribute to amplifying neuroinflammation [90]. Further-more, cAMP plays a role in immunomodulation by suppressing T-lymphocyte activity and cAMP-PKA pathway is involved in neuronal survival by activating cAMP-responsive element binding protein CREB [91]. Thus, low cAMP levels are ultimately responsible for the pathway activation that, through NF-κB-pro-inflammatory cytokines, induces the microglia to switch from a restrained (M2) to an activated (M1) state. Activation of microglia leads to further amplification of neuroinflammation with other cytokine secretion, recruitment of immune cells, and, in the long term, neuronal loss resulting in neurodegeneration (Fig. 2).

Evidence on the role of PDEs in modulating neuroinflammation arise, primarily, from preclinical and clinical studies where their activity was blocked by using specific inhibitors.

Preclinical evidence has shown that ibudilast, a non-selective PDE inhibitor (acting preferentially on PDE3, PDE4, PDE10, and PDE11), displays anti-inflammatory and neuroprotective properties suppressing the activation of microglia and the release of pro-inflammatory cytokines, including IL-1β, TNF-α, IL-6, and IL-10 in several neurodegenerative and neurodevelopmental disease [92,93]. Recently, PDE1 inhibitors in in vitro and in vivo model revealed promising results indeed they suppress NF-κB transcription and activate cAMP/CREB pathway hampering neuroinflammation [94]. Moreover, it has been proven that PDE3 inhibition ameliorates the neuroinflammatory in aged mice and in processes involved in the development of post-traumatic stress disorder symptoms reducing microglia and astrocytes number by limiting IL-1β expression [95]. Similar effect where attributed to PDE4 inhibition, which significantly reduces the production of pro-inflammatory cytokines by immune cells in the CNS, such as TNF-α and interleukin-6 (IL-6), and suppressing microglial cell activation and the conversion to pro-inflammatory M1-type cells [96]. Recently, roflumilast has been shown to ameliorate motor dysfunction and depression symptoms in rodents where autoimmune encephalomyelitis was induced by reducing inflammation. Same anti-inflammatory results were obtained in the LPS-induced neuroinflammation mouse model [97]. This anti-inflammatory effect is achieved by increasing intracellular cAMP levels, activating PKA and CREB, leading to downregulation of pro-inflammatory gene expression [98]. Unfortunately, due to the high drug concentration required to pass BBB, and given the ubiquitous expression of PDE4, its inhibition coincides with severe side effects, such as nausea and vomiting [99]. New strategies should be implemented to minimize side effects while retaining potential therapeutic effects. For example, a specific PDE4B isoform inhibitor could be applied, given that this isoform is an essential factor in the NLRP3 inflammasome activation [100] and that its inhibition has been proven to diminish neuroinflammation [101]. PDE5A and PDE7A inhibitors modulate neuroinflammatory responses by increasing cNs levels and suppressing pro-inflammatory cytokines and immune cell activation [101,102]. Finally, in different animal models, the inhibition of PDE4 activates the cAMP/PKA pathway and downregulates the expression of NRLP3 or activates NF-κB exerting neuroprotection by inhibiting apoptosis and inflammation by decreasing microglia activation [103].

PHOSPHODIESTERASES AND NEUROPROTECTION

PDEs inhibitors have shown great promise in providing neuroprotection and repair by modulating cNs signaling pathways in the CNS [87,104,105].

Studies have demonstrated how PDE1 inhibitors, such as Vinpocetine, can reduce cerebral inflammation, modulate oxidative stress levels, and enhance cognitive performance [106]. PDE1 inhibitors also exhibited advantageous results when applied to animal models recapitulating neurodegenerative diseases with regards to motor function, memory retention, and neuronal survival, supporting their potential use as therapeutic agents against conditions like Parkinson’s, Huntington’s, or Alzheimer’s diseases [104].

PDE2 inhibition showed documented neuroprotective and reparative properties by increasing neuronal nitric oxide synthase (nNOS) activity and increasing cGMP levels. PDE2 inhibitors improve memory and cognitive performance and reduce secondary injury post-stroke/traumatic brain injury, evidencing their therapeutic value as potential interventions against such conditions [107]. PDE3 inhibitors, such as cilostazol, have been found to have neuroreparative properties. When tested on animal models of neuronal loss and depression-like symptoms, PDE3 inhibitors were shown to promote neuronal proliferation, enhance synaptic plasticity and behavioral outcomes and even help treat depression symptoms [108]. Furthermore, clinical trials on PDE3 inhibition for neurodegenerative diseases such as Alzheimer’s have yielded encouraging results in improving cognitive function in mild cognitive impairment (MCI) and in reducing the risk of progression from MCI to Alzheimer’s disease [109].

PDE4 inhibitors, such as rolipram and etazolate, have long been recognized for their neuroprotective benefits and thoroughly examined across various neuropsychiatric diseases. By increasing cAMP levels, PDE4 inhibitors promote neuronal survival, sweeten synaptic plasticity, and reduce oxidative stress/neurotoxicity, and neuroinflam-mation, with animal models of spinal cord injury benefitting significantly in terms of functional recovery, axonal growth, and myelination [110]. Preclinical studies found that the use of PDE5 inhibitors, like sildenafil, by activating the NO-cGMP pathway, have been shown to be effective in diminishing neuronal death, microgliosis, and astrocytosis [111]. It also boosts myelination and regeneration of neuronal progenitors [111].

The modulation of PDE7 signaling is involved in neuroinflammation and CNS disorders, such as Parkinson’s disease, Alzheimer’s disease, or Huntington’s disease. Indeed, interfering with PDE7 by RNA silencing, the authors were able to attenuates neurodegeneration and motor deficits in hemiparkinsonian mice; its inhibition was sufficient to rescue cognitive decline by improving hippocampal neurogenesis in an Alzheimer’s and preserves dopaminergic neurons in Parkinson’s disease rodent model likely by the direct activation of cAMP/PKA/CREB or the indirect inhibition of glycogen synthase kinase 3β (GSK3β) [112,113].

Little is known regarding PDE8 involvement in neuroprotection, but it has been shown that PDE8 increases in specific brain regions in aged mice and in cortical areas and parts of the hippocampal formation in AD patients proposing PDE8 as a novel pharmacological target in these pathologies [46,70].

PDE9 inhibitors may contribute to fostering remyelination and synaptogenesis [114], while PDE10 inhibitors benefit neuronal survival and reduce the formation of neuronal nuclear inclusion and microgliosis [115]. Few years ago, in early-onset AD (EOAD) patients two missense mutations were identified in the PDE11A gene. These variants were classified as pathogenic given that they have been predicted to alter the protein conformation able to induce Tau phosphorylation [116]. Interestingly the same authors found decreased PDE11A level in brain samples of AD patients reporting it as a novel risk gene.

PHOSPHODIESTERASES AND SCHIZOPHRENIA

Analyzing the data from the literature, we found few studies focusing on the pathogenetic mechanisms of schizophrenia related to PDEs compared to pharmacology studies aimed to treat schizophrenia with PDE inhibitors. One of the reasons might be the fact that there has been a lack of appropriate techniques to investigate PDEs function, localization, activation, in living brains. For the sake of notice, recently, several tracers have been successfully developed and have been tested to target PDE4, PDE7 and PDE10 in living human brains [74,117,118] that could change, hopefully, the current situation in the near future.

Confirming the importance of PDEs in the pathogenesis of schizophrenia, various data in the literature have accumulated. Starting with the discovery of disrupted in schizophrenia 1 (DISC-1), a gene involved in susceptibility to develop schizophrenia and encoding for a multifunctional protein engaged in neurodevelopment and cell signaling. Authors found that DISC-1, interacting with PDE4, forms a DISC1-PDE4 complex influencing cNs-mediated signal transduction. A mutated DISC-1 is unable to regulate PDE4, which could underlie some dysfunction of organelles in neurons, such as mitochondria, centrosomes, and the nucleus, and altered synapse activity [119].

Some studies have focused on neuroimaging and investigated the presence of PDEs in specific brain areas of patients with schizophrenia. A positron emission tomography (PET)-study did not evidence any difference in the availability of PDE10A in basal ganglia and thalamus between patients with schizophrenia and healthy controls [120]. However, the study was performed on chronic patients, in which antipsychotic treatment and the long duration of illness could have modified the presence of PDE10A. Other PET studies revealed that the potential binding of the ligand to PDE10 is lower in the striatum of patients with schizophrenia than in controls [121], and levels of PDE10 in the striatum are correlated with cognitive impairment observed in schizophrenia [122].

So, how can we explain the role of PDEs in schizophrenia? PDEs come into play in several cellular mechanisms, such as intracellular signaling, neurotransmission, neuroinflammation, and neuroplasticity, since these elements play a substantial role in schizophrenia. Therefore, it can be inferred that PDEs could be implied in the pathogenesis of schizophrenia.

Based on numerous preclinical and clinical studies on genes, mRNA transcript, and protein expression, the most entangled candidates in schizophrenia are PDE4 and PDE10 [123]. Moreover, it has been demonstrated that PDE2A is reduced in the amygdala, cingulate cortex, and orbital frontal cortex of patients with schizophrenia [41]. The decrease in PDE2A expression was explained as a compensatory mechanism to cope with the reduced levels of cAMP [41]. Other PDE families, such as PDE1, PDE3, and PDE7, have also been linked with schizophrenia [44,124]. PDE7 is widespread in the striatum and prefrontal cortex, which are associated with schizophrenia, and in addition, the gene for PDE7 is located on 6q23-24, which is a region strongly linked with schizophrenia [44]. Impaired cognitive function observed in schizophrenia, such as memory, appears to be related instead to the activity of PDE1 and PDE3 [125].

Furthermore, interactions between PDEs and neurotransmitter systems are critical in understanding the therapeutic effects of PDE inhibitors in schizophrenia. As already discussed, dopamine, glutamate, and serotonin are neurotransmitters linked to schizophrenia pathophysiology. PDEs, regulating levels of cAMP and cGMP, modulate signaling pathways from these neurotransmitters. Dopamine dysregulation is a central feature of schizophrenia, and PDE1, PDE4, and PDE10A are overexpressed in brain sites rich with dopaminergic neurons [126]. PDEs modulate the dopaminergic neurotransmission of the frontostriatal circuits, which have a crucial role in motor, associative, and limbic pathways and are misconnected in schizophrenia [126].

PDE10A regulates signal pathway transduction of D1 and D2 receptors of MSNs of the striatum, and it undergoes relevant genetic drug-induced regulation [127]. So, PDE10A modulation is essential in the neurogenesis of the striatum, dependent more on dopamine neurotransmission [127]. Interestingly, in mouse the depletion/inhibition of PDE10A in the striatum is related to an aberrant SN attribution [128,129], which is the characteristic of patients with schizophrenia to an inducement SN to irrelevant stimuli [7]. Cognitive impairment and positive symptoms of schizophrenia are correlated with dysfunctional D1 receptors in the prefrontal cortex. The hypofunction of D1 receptors in cortical pyramidal neurons of the VI layer is conditioned by PDE4. In the dopaminergic receptors of prefrontal pyramidal neurons, elevation of cAMP levels induces phosphorylation of DARPP-32 (dopamine- and -cAMP-regulated phosphoprotein), which increases neuroplasticity and synaptogenesis between the prefrontal cortex and hippocampus (Fig. 3) [130].

Inhibition of PDE4 results in increased activity and strengthening of neural pathways between the hippocampus and prefrontal cortex, resulting in implementation of cognitive function [130].

Thus, levels of the PDEs in the striatum and the frontal cortex could explain the pathophysiology base of subcortical dopaminergic hyper tone, responsible for positive symptoms, and cortical dopaminergic hypotonia, associated with negative and cognitive symptoms.

Glutamate is the brain’s excitatory neurotransmitter, indispensable in cognitive processes. PDE4, PDE9, PDE10, and PDE11 regulate dopaminergic and glutamatergic neurotransmission [77,131,132], representing a relevant element of cognitive deficits in schizophrenia. The regulation of the metabotropic glutamate receptors is conditioned by the levels of cAMP, regulated by DISC-1 [133], encoding for a scaffolding protein that acts on the PDE4 [134].

In patients with schizophrenia, PDE2A mRNA analysis detected variable levels in different cerebral areas. In a case-control study, the PDE2A mRNA expression was lower than controls at the amygdala, cingulate, and orbitofrontal cortex regions. Nevertheless, the levels reduction of PDE2A would result from the negative feedback exerted by the sustained low levels of cAMP [41]. On the other hand, PDE2A mRNA resulted higher in the hippocampus [41]. This variability is still unclear and could be related to molecular downregulation of the PDEs, use of antipsychotics, and stage of illness.

Moreover, epigenetic research demonstrated that chronic stress could cause hippocampal damage by inducing PDE4A expression [135]. Several studies, including a meta-analysis, reported that the polymorphism of the PDE4B gene is associated with an increased risk of developing schizophrenia [136-138]. Since neurogenesis and hippocampus-related learning processes are linked to PDE4B it can have a detrimental effect on long-term potentiation, an essential function in memory and learning [139].

Recently, a two-sample Mendelian randomization study, investigate the relationship between PDEs and nine psychiatric disorders. Interestingly, the analysis of genome-wide association studies (GWASs), revealed that PDE4D was associated with higher odds with schizophrenia while PDE2A was negative associated offering PDEs as potential therapeutic drug target [140].

PHOSPHODIESTERASES AS POTENTIAL TARGET FOR SCHIZOPHRENIA TREATMENT

In a recent review, the authors reported that in the coming years the treatment of schizophrenia will undergo a revolution with new molecules with different action mechanisms that will be used to manage the course of schizophrenia [20,132,141-144]. The pharmacodynamics of the antipsychotic drug is classically based on the antagonism of the D2 receptor associated with an inhibitory G protein. Thus, the modulation of intracellular cAMP may be considered a second-level target in the treatment of schizophrenia indeed many trials have investigated the efficacy of PDEs inhibitors [87,145].

Several preclinical and clinical studies have shown that inhibition of PDE10A and PDE4 would potentially emerge as the most effective in the clinical setting on the control of both positive and negative psychotic symptomatology as well as on the improvement of cognitive function [143,146]. Furthermore, by acting downstream from post-synaptic D2 receptor blockade, all adverse effects related to D2 receptor antagonisms, such as extrapyramidal syndrome and hyperprolactinemia, could be avoided.

The inhibition of PDE10A, modulating mesolimbic do-paminergic transmission, could improve positive symptoms of schizophrenia [147]. Specifically, PDE10A, expressed in the striatum of basal ganglia, is relevant in regulating MSNs of the striatum [148]. The antipsychotic-like effect of the inhibition of PDE10A results in the activation of the indirect MSNs pathway, in which dopamine D2 receptors are involved. In contrast, activation of the direct MSNs pathway, which involves D1 receptors, explains the pro-cognitive action of PDE10A inhibitors [123,125,149].

Similarly, dual inhibition of PDE10A and PDE1/PDE4 in the prefrontal cortex could also enhance cognitive function in patients with schizophrenia [125]. Some phase 1 studies and another study in the 2b clinical phase have demonstrated the tolerability, safety, and pro-cognitive effect of a selective PDE10A inhibitor in patients with schizophrenia [150,151]. Underlying the effectiveness of PDEs modulation would be the effect that PDE inhibitors have on saliency regulation. Particularly, a PDE4 inhibitor, roflumilast, would act by restoring the sensory gating process, which is essential in filtering stimuli from outside, preventing overstimulation and aberrant SN. Inhibition of PDE4 obtained by roflumilast ameliorates cognitive patterns in schizophrenia, demonstrated by the electroencephalogram cognitive markers impaired in schizophrenia (auditory steady-state response, mismatch negativity and theta, and P300) [152]. In addition, PDE4 inhibitors have been demonstrated to enhance GABAergic neurotransmission and improve cognitive performance both in animal models and human studies, possibly thanks to the modulation of GABAergic signaling by PDE inhibitors which could explain their cognitive-enhancing properties for schizophrenia patients [153]. PDE1 and PDE4 inhibitors appear to improve cognitive function and memory enhancement for both animal models and human subjects [144].

A randomized phase 2 trial tested on 300 patients, at the first psychotic episode, the efficacy of an inhibitor of PDE9. The authors observed improved cognitive ability and global function [154]. Other randomized, placebo-controlled, double-blind studies on the inhibition of PDE10A showed significant improvements in both positive and negative symptoms, as well as global function, with no significant adverse effects [155,156]. Some evidence derived from a blind double randomized clinical trial showed that the combined treatment of sildenafil and risperidone was helpful in the reduction of negative symptoms of schizophrenia [157].

However, not all studies agreed that PDEs inhibitors are effective, likely the failure of this different therapeutic approach is to be found in both pharmacokinetic and pharmacodynamic aspects such as absorption, elimination, selectivity of the molecule, reversibility of inhibition, and dosage [158,159].

CONCLUSION

Studies have established that PDEs, specifically PDE4 and PDE10A, play a key role in the pathophysiology of schizophrenia. PDE inhibitors have demonstrated promise in improving cognitive symptoms associated with this disorder by modulating intracellular levels of cAMP and cGMP, increasing synaptic plasticity and neurotrans-mission, and potentially interfering with dopamine systems to relieve symptoms.

PDE inhibitors have also been investigated as potential solutions to reduce neuroinflammation associated with schizophrenia. Specifically, PDE4 inhibitors possess an anti-inflammatory effect by decreasing the production of pro-inflammatory cytokines within the CNS and targeting PDEs for therapeutic benefit in mitigating neuroinflammatory processes associated with this disorder. In addition, the use of PDEs inhibitors by modulating receptor transduction pathways ultimately act on neuronal survival, improving synaptic plasticity, and decreasing oxidative stress levels in neurons. Further investigation is required to better understand PDE inhibitors’ mechanisms of action, optimize their pharmacokinetic properties, and evaluate their efficacy and safety in clinical settings. Exploring the role of PDEs in schizophrenia provides insight into its complex neurobiology while opening doors for novel treatments targeting specific PDE isoforms. Research in this field could significantly enhance the quality of life among those with schizophrenia by targeting cognitive deficits, decreasing neuroinflammation, and increasing neuroprotection.

The determining issues that summarize the data that emerged in this study are as follows:

∙ PDEs are pivotal in neuroinflammation, a pathogenic process associated with schizophrenia, and regulate the life and survival of neurons.

∙ PDEs represent a bridge between neurotransmitter receptor and the nucleus, thus regulating the expression of specific genes involved in neurogenesis and neuroplasticity and, ultimately, in the cytoarchitecture of neural networks.

∙ Some genes, such as DISC-1, are strongly associated with schizophrenia and encode a scaffold protein that regulates PDE4.

∙ PDE4 and PDE10A emerge to be the isoforms most involved in schizophrenia.

∙ The use of PDE inhibitors in clinical practice brings significant benefits in managing positive, negative, and cognitive symptoms of schizophrenia.

THE FAMILY OF PHOSPHODIESTERASES

cNs are mediators required in calcium signaling, cardiac contraction, sexual reproduction, vision, neurogenesis, inflammatory processes, and synaptic neuroplasticity. Given the delicate function in different vital cell homeostasis processes, it appears necessary for cAMP and cGMP levels to be subtly regulated. Therefore, the levels of cNs within the cell are controlled by enzymes that hydrolyze cAMP and cGMP into their inactive form 5’AMP and 5’GMP, respectively. PDEs are a class of enzymes encoded by 24 genes that are grouped into 11 different gene families (PDE1-11) according to their kinetic properties, mechanisms of activation, and sensitivity to inhibitors (Table 1) [21-39]. An additional level of variety is guaranteed by alternative splicing or alternative promoters, that produce more than 100 gene products that display specificity in their tissue, cellular and subcellular distribution. According to their different affinities for cAMP and cGMP, they can be classified as cAMP-specific (PDE4, 7, and 8), cGMP-specific (PDE5, 6, and 9), and dual substrate (PDE1, 2, 3, 10, and 11) [21].

Funding

None.

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Author Contributions

Conceptualization: Federica Barbagallo, Antonino Messina. Data acquisition: Federica Barbagallo, Maria Rita Assenza, Antonino Messina. Supervision: Federica Barbagallo. Draft writing: Federica Barbagallo, Maria Rita Assenza, Antonino Messina. Final revision: Federica Barbagallo, Antonino Messina. Images and tables elaboration: Federica Barbagallo, Maria Rita Assenza.

Figures
Fig. 1. PDEs expression in the various brain structures. Each color corresponds to a different brain region. The longitudinal plane is shown in the panel (A) and coronal plane in the panel (B) to highlight the striatum.
PDEs, phosphodiesterases.
Fig. 2. cAMP pathway in microglia activation.
The reduction of cAMP, induced by increased activity of PDEs, promotes the expression of proinflammatory cytokines that in turn activates microglia.
PDEs, phosphodiesterases; cAMP, cyclic adenosine monophosphate; NF-κB, nuclear factor-kappa B; IL-6, interleukin-6; TNF-α, tumor necrosis factor-alpha; IL-1β, interleukin-1 beta.
Fig. 3. D1R signaling pathway in prefrontal cortex and neuroplasticity.
D1R, dopamine receptor 1; cAMP, cyclic adenosine monopho-sphate; PKA, protein kinase A; DARPP-32, dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa.
Tables

PDE family classification

PDE family Gene Substrate Property Tissue expression
PDE1 PDE1A cGMP > cAMP Ca2+/calmodulin (CaM)-dependent Broadly expressed [23]
Brain [24]
Heart, testis, kidney, liver, and pancreas [21,25]
PDE1B cGMP > cAMP
PDE1C cGMP ≈ cAMP
PDE2 PDE2A cGMP ≈ cAMP cGMP stimulated Heart, liver, adrenal gland, platelets, brain, endothelial cells, neurons and macrophages [26,27]
PDE3 PDE3A cGMP ≈ cAMP cGMP inhibited Heart, vascular smooth muscle, platelets, oocyte and kidney [29]
Vascular smooth muscle, adipocytes, hepatocytes, kidney, b cells, T lymphocytes and macrophages [30]
PDE3B
PDE4 PDE4A cAMP cAMP specific Ubiquitous with variant-specific tissue distribution [29]
PDE4B
PDE4C
PDE4D
PDE5 PDE5A cGMP cGMP specific Digestive system, lung, platelets, cerebellum, kidney, vascular smooth muscle cells, skeletal and cardiac muscle, endocrine glands, including testis [31-33]
PDE6 PDE6A cGMP Retina [22]
PDE6B
PDE6C
PDE6D
PDE6G
PDE6H
PDE7 PDE7A cAMP Skeletal muscle, immune cells, brain [34]
PDE7B
PDE8 PDE8A cAMP IBMX-insensitive Liver, kidney, testis, thyroid, heart [35,36]
PDE8B
PDE9 PDE9A cGMP Spleen, brain and cerebellum [37]
PDE10 PDE10A cGMP ≈ cAMP Thyroid, pituitary glands and brain [38]
PDE11 PDE11A cGMP ≈ cAMP Skeletal muscle and prostate testis, pituitary and thyroid glands [39]

PDE isoforms, substrate specificity, properties and tissue expression are reported. The table does not provide information with respect to the level of expression (mRNA levels or protein levels) of the different isoforms.

PDE, phosphodiesterase; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate.

Neurotransmitters and relative receptors associated with cyclic nucleotides transduction pathway

Neurotrasmitter Receptors
Acetylcholine M1-M3/M5
Dopamine D1-like-, D2 like
Serotonin 5-HT1, 5-HT4, 5-HT6, 5-HT7
Noradrenaline a1-, a2-
Glutamate mGlu2, mGlu3, mGlu4, mGlu6, mGlu7, mGlu8
GABA GABAB

PDEs expressed in the key regions of the brain (references referred to Fig. 1)

PDEs Brain regions

FL PL OL TL CCo CC St Th Hypo Hip Po MO SC Cer
1A [45] [46]
1B [46-48]
1C [46] [25,46]
2A [41] [41,46,49] [46] [41] [49]
3A [50] [50] [50] [50] [46]
3B [50] [50] [46]
4A [42] [42] [46] [42] [42] [51] [42]
4B [42] [42] [46] [42] [42,51] [42]
4D [42] [42] [46] [42] [42] [42,52]
5A [53] [46]
7A [54] [54] [54] [54] [54] [54] [54] [54] [54] [46,54]
7B [46]
8A [46] [46] [46] [46] [46]
8B [55] [55] [46,55] [55] [55] [55] [55] [55]
9A [56] [46] [53,56,57] [46,56,57]
10A [46] [41] [41]
11A [46] [46]

The table does not provide information with respect to the level of expression (mRNA levels or protein levels) of the different isoforms.

PDEs, phosphodiesterases; FL, frontal lobe; PL, parietal lobe; OL, occipital lobe; TL, temporal lobe; CCo, cingulate cortex; CC, corpus callosum; St, striatum; Th, thalamus; Hypo, hypothalamus; Hip, hippocampus; Po, pons; MO, medulla oblongata; SC, spinal cord; Cer, cerebellum.

PDEs mainly expressed in the key regions of human brain

PDEs Brain regions

FL PL OL TL CCo St Th Hypo Hip Po MO SC Cer
PDE1A ++
PDE1B ++ ++ ++
PDE1C +++ +++ ++
PDE2A +++ +++ +++ +++ ++ +++
PDE3A ++
PDE3B ++
PDE4A ++ ++ ++ ++ ++ ++ +++
PDE4B +++ ++ ++ +++ +++ ++ ++ +++ +++ +++
PDE4D ++ ++ +++
PDE5A ++ +++
PDE7A +++ ++ ++ ++ ++ ++
PDE7B +++ ++ ++ ++ ++
PDE8A ++ ++
PDE8B ++ ++ ++ ++ ++ ++ ++
PDE9A ++ ++ ++ ++ +++
PDE10A ++ ++ +++
PDE11A ++ ++

++, mild expression; +++, high expression; FL, frontal lobe; PL, parietal lobe; OL, occipital lobe; TL, temporal lobe; CCo, cingulate cortex; St, striatum; Th, thalamus; Hypo, hypothalamus; Hip, hippocampus; Po, pons; MO, medulla oblongata; SC, spinal cord; Cer, cerebellum [41-44,58,59].

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