Modulation of Second Messenger Signaling in the Brain Through PDE4 and PDE5 Inhibition: Therapeutic Implications for Neurological Disorders

Abstract

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.

Full text

Academic Editors: Paul M. Epstein,
Michy P. Kelly, Stefan Brocke and
Leila Gobejishvili
Received: 11 December 2024
Revised: 7 January 2025
Accepted: 7 January 2025
Published: 9 January 2025
Citation: Park, M.K.; Yang, H.W.;
Woo, S.Y.; Kim, D.Y.; Son, D.-S.; Choi,
B.Y.; Suh, S.W. Modulation of Second
Messenger Signaling in the Brain
Through PDE4 and PDE5 Inhibition:
Therapeutic Implications for
Neurological Disorders. Cells 2025,14,
86. https://doi.org/10.3390/
cells14020086
Copyright: © 2025 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license
(https://creativecommons.org/
licenses/by/4.0/).
Review
Modulation of Second Messenger Signaling in the Brain
Through PDE4 and PDE5 Inhibition: Therapeutic Implications
for Neurological Disorders
Min Kyu Park 1, Hyun Wook Yang 1, Seo Young Woo 1, Dong Yeon Kim 1, Dae-Soon Son 2, Bo Young Choi 3,4
and Sang Won Suh 1,*
1Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea;
bagmingyu50@gmail.com (M.K.P.); akqjqtj5@hallym.ac.kr (H.W.Y.); 1wsy@naver.com (S.Y.W.);
roy8596@naver.com (D.Y.K.)
2Division of Data Science, Data Science Convergence Research Center, Hallym University,
Chuncheon 24252, Republic of Korea; biostat@hallym.ac.kr
3Institute of Sport Science, Hallym University, Chuncheon 24252, Republic of Korea; bychoi@hallym.ac.kr
4Department of Physical Education, Hallym University, Chuncheon 24252, Republic of Korea
*Correspondence: swsuh@hallym.ac.kr
Abstract: 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 regula-
tion 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 neurologi-
cal 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, Parkin-
son’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.
Keywords: phosphodiesterase (PDE); phosphodiesterase 4 (PDE4); phosphodiesterase
5 (PDE5); protein kinase A (PKA); protein kinase G (PKG)
1. Introduction
Phosphodiesterases (PDEs) are enzymes essential for cellular signaling, responsible
for breaking down cyclic nucleotides like cyclic adenosine monophosphate (cAMP) and
cyclic guanosine monophosphate (cGMP) [
1
]. These cyclic nucleotides act as key second
messengers in numerous physiological processes, including metabolism, vascular regula-
tion, and neuronal signaling [
1
]. The PDE family is diverse, consisting of 11 subfamilies
(PDE1–PDE11), each with distinct tissue distribution, substrate specificity, and regulatory
mechanisms, reflecting their specialized roles in various biological systems [1].
Cells 2025,14, 86 https://doi.org/10.3390/cells14020086

Cells 2025,14, 86 2 of 14
Among the PDE family, PDE4 and PDE5 have garnered particular interest due to their
involvement in brain function and neurological disorders [
2
,
3
]. PDE4 primarily regulates
cAMP levels in neurons, influencing intracellular signaling pathways that govern synaptic
plasticity, neuronal survival, and memory formation [4–7].
Dysregulation of PDE4 and PDE5 activity has been implicated in the pathology of
several neurodegenerative and neuropsychiatric disorders, including Alzheimer’s disease,
stroke, and cognitive impairments [
3
,
8
–
12
]. As a result, pharmacological inhibitors tar-
geting these enzymes have emerged as promising therapeutic strategies. PDE4 inhibitors
enhance cAMP signaling, promoting neuroprotection and cognitive improvements, while
PDE5 inhibitors restore cGMP signaling, supporting cerebral blood flow, reducing oxidative
stress, and mitigating neuronal damage [3,8–12].
This review focuses on the roles of PDE4 and PDE5 in neurological health and disease,
highlighting their mechanisms of action, therapeutic potential, and the latest advancements
in pharmacological modulation.
2. Distribution and Functional Roles of PDE4 and PDE5 Isoforms in the
Central Nervous System and Peripheral Tissues
2.1. PDE4 Isoforms in the CNS and Peripheral Tissues
The PDE4 family includes four isoforms PDE4A, PDE4B, PDE4C, and PDE4D each
exhibiting distinct expression patterns and physiological roles [
13
,
14
]. 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 neurodegener-
ation [
15
,
16
]. Among these, PDE4B is the most widely distributed, with high expression
in brain regions such as the cortex, hippocampus, and cerebellum [
17
–
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. Conversely, PDE4C is minimally expressed in the brain, indicating a
limited or specialized role [17] (Figure 1).
Cells 2025, 14, x FOR PEER REVIEW 2 of 15
PDE11), each with distinct tissue distribution, substrate specificity, and regulatory mecha-
nisms, reflecting their specialized roles in various biological systems [1].
Among the PDE family, PDE4 and PDE5 have garnered particular interest due to their
involvement in brain function and neurological disorders [2,3]. PDE4 primarily regulates
cAMP levels in neurons, influencing intracellular signaling pathways that govern synaptic
plasticity, neuronal survival, and memory formation [4–7].
Dysregulation of PDE4 and PDE5 activity has been implicated in the pathology of sev-
eral neurodegenerative and neuropsychiatric disorders, including Alzheimer’s disease,
stroke, and cognitive impairments [3,8–12]. As a result, pharmacological inhibitors targeting
these enzymes have emerged as promising therapeutic strategies. PDE4 inhibitors enhance
cAMP signaling, promoting neuroprotection and cognitive improvements, while PDE5 in-
hibitors restore cGMP signaling, supporting cerebral blood flow, reducing oxidative stress,
and mitigating neuronal damage [3,8–12].
This review focuses on the roles of PDE4 and PDE5 in neurological health and disease,
highlighting their mechanisms of action, therapeutic potential, and the latest advancements
in pharmacological modulation.
2. Distribution and Functional Roles of PDE4 and PDE5 Isoforms in the
Central Nervous System and Peripheral Tissues
2.1. PDE4 Isoforms in the CNS and Peripheral Tissues
The PDE4 family includes four isoforms PDE4A, PDE4B, PDE4C, and PDE4D each ex-
hibiting distinct expression patterns and physiological roles [13,14]. 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 [17–19]. 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. Conversely, PDE4C is minimally expressed in the brain, indicating a limited or spe-
cialized role [17] (Figure 1).
Figure 1. The chemical structures of cyclic adenosine monophosphate (cAMP) and adenosine mono-
phosphate (AMP) [20]. Phosphodiesterase type 4 (PDE4) catalyzes the hydrolysis of cAMP into AMP
[20]. In cAMP, the 3′ and 5′ hydroxyl groups of the adenosine ribose are connected by a phosphodiester
bond, forming its characteristic cyclic structure [20]. PDE4 cleaves the phosphodiester bond at the 3′
position, disrupting the cyclic structure and resulting in the formation of a linear AMP molecule [20].
Figure 1. The chemical structures of cyclic adenosine monophosphate (cAMP) and adenosine
monophosphate (AMP) [
20
]. Phosphodiesterase type 4 (PDE4) catalyzes the hydrolysis of cAMP
into AMP [
20
]. In cAMP, the 3
′
and 5
′
hydroxyl groups of the adenosine ribose are connected by a
phosphodiester bond, forming its characteristic cyclic structure [
20
]. PDE4 cleaves the phosphodiester
bond at the 3
′
position, disrupting the cyclic structure and resulting in the formation of a linear AMP
molecule [
20
]. This hydrolysis reaction involves the addition of water, yielding AMP and inorganic
phosphate (Pi) as final products [20].

Cells 2025,14, 86 3 of 14
In peripheral tissues, PDE4B and PDE4D are predominant, contributing to immune
regulation, inflammation, and vascular function. Dysregulation of PDE4 activity has been
associated with psychiatric conditions, including depression and schizophrenia, due to its
influence on cAMP signaling pathways [
17
–
19
]. PDE4 also regulates ion channels involved
in neuronal excitability, underscoring its importance in maintaining neural communication
and preventing hyperactivity [17–19].
2.2. PDE5 Isoforms in the CNS and Peripheral Tissues
Unlike PDE4, PDE5 primarily exists as a single isoform. Its expression is robust in
peripheral tissues, including vascular smooth muscle, platelets, and the gastrointesti-
nal tract, where it regulates vascular tone, platelet aggregation, and smooth muscle
contraction [3,21–23]
. In the CNS, PDE5 expression is relatively limited but regionally
specific [
3
,
21
–
23
]. It is prominently expressed in the hippocampus, cerebellum, and cortex,
regions critical for cognitive functions and synaptic plasticity [
3
,
21
–
23
]. In the hippocampus,
PDE5 is involved in processes such as memory formation and long-term potentiation (LTP),
mediated by the cGMP-dependent nitric oxide (NO)-cGMP signaling pathway [
3
,
21
–
23
].
Moderate expression in the cerebellum suggests a role in motor coordination, while cortical
distribution varies based on localized cGMP signaling demands [3,21–23] (Figure 2).
Figure 2. The chemical structures of cyclic guanosine monophosphate (cGMP) and guanosine
monophosphate (GMP) [
24
]. Phosphodiesterase type 5 (PDE5) catalyzes the hydrolysis of cGMP
into GMP. In cGMP, a phosphodiester bond links the 3
′
and 5
′
hydroxyl groups of the guanosine
ribose, creating its cyclic structure [
24
]. In cGMP, a phosphodiester bond links the 3
′
and 5
′
hydroxyl
groups of the guanosine ribose, forming a cyclic structure [
24
]. PDE5 cleaves this bond at the 3
′
position, breaking the cyclic structure and converting cGMP into its linear form, GMP [
24
]. This
hydrolysis reaction involves the addition of water, producing GMP and inorganic phosphate (Pi) as
final products [24].
2.3. Integration of Roles in Signaling and Pathophysiology
PDE4 and PDE5 regulate complementary but distinct pathways, with PDE4 focusing
on cAMP and PDE5 on cGMP. Both enzymes ensure the balance of second messengers
critical for neuronal signaling and plasticity [
25
,
26
]. PDE4 activity governs PKA-mediated
phosphorylation of targets like CREB, influencing gene expression essential for learning,
memory, and neuronal survival [
25
,
26
]. Similarly, PDE5 modulates PKG activation through
NO-cGMP signaling, affecting synaptic transmission and neurovascular coupling [25,26].
The dysregulation of these pathways has significant pathological implications. In the
CNS, altered PDE4 activity has been linked to neuropsychiatric disorders, while PDE5
dysfunction is implicated in neurodegenerative conditions such as Alzheimer’s disease and

Cells 2025,14, 86 4 of 14
cerebrovascular disorders like stroke [
3
,
27
,
28
]. Notably, PDE5 regulates cerebral blood flow
by modulating vascular tone, playing a crucial role in brain homeostasis and protection
against ischemic injury [28].
2.4. Therapeutic Implications
The distinct and region-specific roles of PDE4 and PDE5 in the CNS present unique
opportunities for therapeutic targeting. PDE4B and PDE4D, due to their prominence in
synaptic function, may be viable targets for treating psychiatric and neurodegenerative
disorders [
25
–
28
]. Similarly, PDE5’s targeted expression in cognitive-related brain regions
highlights its potential for interventions aimed at memory enhancement and neuroprotec-
tion. By selectively modulating these isoforms, therapies can address disorders linked to
dysregulated cAMP or cGMP signaling while minimizing off-target effects [25–28].
3. Therapeutic Potential of PDE4 and PDE5 in Neurological Disorders
Among the diverse phosphodiesterase subtypes, PDE4 and PDE5 have garnered sig-
nificant attention due to their crucial involvement in the pathophysiology of several brain
disorders. Inhibition of these enzymes shows promising therapeutic potential, particularly
in managing traumatic brain injury (TBI), ischemic stroke, and epilepsy [
1
,
26
]. By modu-
lating intracellular cAMP and cGMP levels, targeted interventions involving PDE4 and
PDE5 may provide therapeutic advantages for both acute and progressive neurological
conditions [29].
PKA and PKG pathways, activated by cAMP and cGMP respectively, play essential
roles in cellular processes associated with brain repair and neuroprotection [
30
]. PKA
activity contributes to synaptic repair, reduces neuronal apoptosis, attenuates neuroinflam-
mation, and helps preserve the integrity of the blood-brain barrier, all of which are essential
for recovery following brain injury [
31
,
32
]. In parallel, PKG signaling mitigates oxidative
stress and combats mitochondrial dysfunction, key pathological features observed in TBI
and other neurodegenerative conditions [
33
]. This dual modulation of PKA and PKG
pathways offers a promising framework for developing therapeutic strategies targeting
PDE4 and PDE5 to mitigate brain injury, restore neural function, and protect against future
degeneration (Figure 3).
Cells 2025, 14, x FOR PEER REVIEW 5 of 15
Figure 3. The diagram highlights the roles of PDE4 and PDE5 in regulating second messenger systems
and their therapeutic relevance in neurological disorders [16,23]. (A) PDE4 controls cAMP levels, with
its inhibition activating PKA and phosphorylating CREB, promoting neuronal survival, synaptic plas-
ticity, cognitive function, and anti-inflammatory responses [9]. Elevated cAMP also reduces reactive
oxygen species (ROS), alleviating oxidative stress [28]. (B) PDE5 inhibition prevents cGMP degrada-
tion, activating PKG, which enhances vasodilation, neuroprotection, and antioxidant defenses [34,35].
PKG also mitigates ROS production, reducing oxidative damage [34,35]. In traumatic brain injury
(TBI), PDE4 and PDE5 inhibitors improve neuronal repair, reduce inflammation, and protect against
oxidative stress [18,36,37]. In ischemic stroke, these inhibitors lower ROS, support neurogenesis, and
facilitate recovery through CREB and PKG pathways [18,36–38]. In epilepsy, PDE4 inhibition regulates
synaptic plasticity, while PDE5 inhibition stabilizes neuronal function by improving blood flow and
reducing excitotoxicity [34,35]. In Alzheimer’s disease, combined PDE4 and PDE5 inhibition improves
Figure 3. Cont.

Cells 2025,14, 86 5 of 14
Cells 2025, 14, x FOR PEER REVIEW 5 of 15
Figure 3. The diagram highlights the roles of PDE4 and PDE5 in regulating second messenger systems
and their therapeutic relevance in neurological disorders [16,23]. (A) PDE4 controls cAMP levels, with
its inhibition activating PKA and phosphorylating CREB, promoting neuronal survival, synaptic plas-
ticity, cognitive function, and anti-inflammatory responses [9]. Elevated cAMP also reduces reactive
oxygen species (ROS), alleviating oxidative stress [28]. (B) PDE5 inhibition prevents cGMP degrada-
tion, activating PKG, which enhances vasodilation, neuroprotection, and antioxidant defenses [34,35].
PKG also mitigates ROS production, reducing oxidative damage [34,35]. In traumatic brain injury
(TBI), PDE4 and PDE5 inhibitors improve neuronal repair, reduce inflammation, and protect against
oxidative stress [18,36,37]. In ischemic stroke, these inhibitors lower ROS, support neurogenesis, and
facilitate recovery through CREB and PKG pathways [18,36–38]. In epilepsy, PDE4 inhibition regulates
synaptic plasticity, while PDE5 inhibition stabilizes neuronal function by improving blood flow and
reducing excitotoxicity [34,35]. In Alzheimer’s disease, combined PDE4 and PDE5 inhibition improves
Figure 3. The diagram highlights the roles of PDE4 and PDE5 in regulating second messenger
systems and their therapeutic relevance in neurological disorders [
16
,
23
]. (A) PDE4 controls cAMP
levels, with its inhibition activating PKA and phosphorylating CREB, promoting neuronal survival,
synaptic plasticity, cognitive function, and anti-inflammatory responses [
9
]. Elevated cAMP also
reduces reactive oxygen species (ROS), alleviating oxidative stress [
28
]. (B) PDE5 inhibition prevents
cGMP degradation, activating PKG, which enhances vasodilation, neuroprotection, and antioxidant
defenses [
34
,
35
]. PKG also mitigates ROS production, reducing oxidative damage [
34
,
35
]. In traumatic
brain injury (TBI), PDE4 and PDE5 inhibitors improve neuronal repair, reduce inflammation, and
protect against oxidative stress [
18
,
36
,
37
]. In ischemic stroke, these inhibitors lower ROS, support
neurogenesis, and facilitate recovery through CREB and PKG pathways [
18
,
36
–
38
]. In epilepsy,
PDE4 inhibition regulates synaptic plasticity, while PDE5 inhibition stabilizes neuronal function by
improving blood flow and reducing excitotoxicity [
34
,
35
]. In Alzheimer ’s disease, combined PDE4
and PDE5 inhibition improves cognition, reduces amyloid-beta accumulation, and protects against
oxidative stress [
18
,
36
–
38
]. (A,B) Together, PDE4 and PDE5 inhibitors strengthen the cAMP/CREB
and cGMP/PKG pathways, offering broad neuroprotective benefits, reducing inflammation, and
enhancing cognitive and synaptic function across multiple neurological conditions [
2
,
3
,
9
,
28
,
39
,
40
].
“Created with BioRender.com”.
3.1. Seizure and Epilepsy
Seizures result from abnormal electrical activity in the brain, manifesting as a spectrum
of neurological symptoms ranging from brief lapses in attention to severe convulsions [
41
].
Epilepsy, a chronic condition characterized by recurrent seizures, significantly affects
quality of life [
42
]. The PKA and PKG pathways, which regulate neuronal excitability and
synaptic function, play pivotal roles in the development and control of seizure activity and
epilepsy [34,43–46] (Figure 4).
Several phosphodiesterases (PDEs), including PDE1, PDE2, PDE3, and particularly
PDE4, contribute to cAMP degradation within neurons [
47
,
48
]. PDE4 is highly expressed in
the central nervous system (CNS) and is crucial for maintaining appropriate cAMP levels,
preventing excessive neuronal excitability driven by increased PKA activation [
43
,
47
,
48
].
Dysregulated cAMP signaling can lead to abnormal neuronal firing, contributing to the on-
set and persistence of seizures. PDE4 inhibitors reduce cAMP breakdown, modulating PKA
activity to stabilize synaptic function and potentially prevent seizure
progression [43,44]
.
These inhibitors have also demonstrated protective effects in models of pilocarpine-induced
seizures, reducing neuronal cell death, oxidative stress, and inflammation while promoting

Cells 2025,14, 86 6 of 14
lysosomal function and autophagy [
26
,
43
,
44
]. The PKG pathway, regulated by cGMP, offers
neuroprotective benefits through the modulation of nitric oxide (NO) signaling, reduction
of oxidative stress, and prevention of mitochondrial dysfunction, all of which are associated
with seizures [
26
,
43
,
44
]. PKG activation also influences ion channel function, stabilizing
neuronal excitability [
34
,
35
,
45
,
46
]. PDE5 inhibitors, which enhance PKG activity, have
shown potential to reduce seizure frequency and severity by improving neuronal resilience
and mitigating oxidative damage [34,45,46].
Cells 2025, 14, x FOR PEER REVIEW 6 of 15
cognition, reduces amyloid-beta accumulation, and protects against oxidative stress [18,36–38]. (A,B)
Together, PDE4 and PDE5 inhibitors strengthen the cAMP/CREB and cGMP/PKG pathways, offering
broad neuroprotective benefits, reducing inflammation, and enhancing cognitive and synaptic func-
tion across multiple neurological conditions [2,3,9,28,39,40]. “Created with BioRender.com”.
3.1. Seizure and Epilepsy
Seizures result from abnormal electrical activity in the brain, manifesting as a spectrum
of neurological symptoms ranging from brief lapses in attention to severe convulsions [41].
Epilepsy, a chronic condition characterized by recurrent seizures, significantly affects qual-
ity of life [42]. The PKA and PKG pathways, which regulate neuronal excitability and syn-
aptic function, play pivotal roles in the development and control of seizure activity and ep-
ilepsy [34,43–46] (Figure 4).
Several phosphodiesterases (PDEs), including PDE1, PDE2, PDE3, and particularly
PDE4, contribute to cAMP degradation within neurons [47,48]. PDE4 is highly expressed in
the central nervous system (CNS) and is crucial for maintaining appropriate cAMP levels,
preventing excessive neuronal excitability driven by increased PKA activation [43,47,48].
Dysregulated cAMP signaling can lead to abnormal neuronal firing, contributing to the on-
set and persistence of seizures. PDE4 inhibitors reduce cAMP breakdown, modulating PKA
activity to stabilize synaptic function and potentially prevent seizure progression [43,44].
These inhibitors have also demonstrated protective effects in models of pilocarpine-induced
seizures, reducing neuronal cell death, oxidative stress, and inflammation while promoting
lysosomal function and autophagy [26,43,44]. The PKG pathway, regulated by cGMP, offers
neuroprotective benefits through the modulation of nitric oxide (NO) signaling, reduction
of oxidative stress, and prevention of mitochondrial dysfunction, all of which are associated
with seizures [26,43,44]. PKG activation also influences ion channel function, stabilizing
neuronal excitability [34,35,45,46]. PDE5 inhibitors, which enhance PKG activity, have
shown potential to reduce seizure frequency and severity by improving neuronal resilience
and mitigating oxidative damage [34,45,46].
Figure 4. One week after epilepsy induction, brains were harvested to evaluate the effects of the PDE4
inhibitor amlexanox. NeuN staining demonstrates preserved neuronal populations in the CA1 region
of the hippocampus in the amlexanox-treated group, indicating a neuroprotective effect [26]. (A) Im-
munofluorescence images show overexpression of PDE4B within neurons in the hippocampal CA1
region 1 week after epilepsy, detected using PDE4B immunohistochemistry with specific antibodies
Figure 4. One week after epilepsy induction, brains were harvested to evaluate the effects of
the PDE4 inhibitor amlexanox. NeuN staining demonstrates preserved neuronal populations in
the CA1 region of the hippocampus in the amlexanox-treated group, indicating a neuroprotective
effect [
26
]. (A) Immunofluorescence images show overexpression of PDE4B within neurons in the
hippocampal CA1 region 1 week after epilepsy, detected using PDE4B immunohistochemistry with
specific antibodies PDE4B [
26
]. PDE4 staining indirectly verifies the efficacy of the PDE4 inhibitor by
detecting a decrease in the intensity of PDE4 expression (PDE4B, red) [
26
]. (B) Immunofluorescence
images show overexpression of PDE4B within neurons in the hippocampal CA1 region 1 week
after epilepsy, detected using IL-6 and TNF-
α
immunohistochemistry with specific antibodies IL-6,
TNF-
α
[
26
]. IL-6 and TNF-
α
staining indirectly verifies the efficacy of the PDE4 inhibitor by detecting
a decrease in the intensity of inflammation expression (TNF-
α
, red) (IL-6, green) [
26
]. (C) COX-2,
the final inflammatory marker, was confirmed to have a decreased protein expression level by PDE4
inhibitors through Western blot [
26
]. (D) Immunofluorescence images show live neurons in the
hippocampal CA1 region 1 week after epilepsy, detected using NeuN [
26
]. It was confirmed that
more neurons survived when PDE4 inhibitors were administered after epilepsy was induced [
26
].
COX-2 Western blot, along with TNF-
α
and IL-6 immunofluorescence, reveals decreased levels of
pro-inflammatory markers, suggesting anti-inflammatory effects [
26
]. These findings underscore the
potential of amlexanox to mitigate neuronal damage and inflammation in epilepsy [26].
3.2. Ischemia and Stroke
Ischemia, particularly in the context of stroke, results from reduced cerebral blood
flow and oxygen supply, causing widespread neuronal damage [
28
,
49
]. The PKA and
PKG pathways play essential roles in the brain’s response to ischemia, promoting neuronal
survival and supporting recovery processes [28,49,50].
During ischemic events, activation of the PKA pathway facilitates neural repair by
enhancing synaptic plasticity, crucial for the restoration of damaged networks [
51
,
52
].
PKA also reduces neuronal apoptosis and neuroinflammation, helping to maintain the

Cells 2025,14, 86 7 of 14
integrity of the blood-brain barrier and preventing further damage from inflammatory
infiltration [51,52]
. PDE4 inhibitors, by elevating cAMP levels and activating PKA, offer
neuroprotective effects by promoting these recovery processes and improving outcomes in
stroke [
2
]. Additionally, PKA activation triggers the Nrf-2/HO-1 pathway, reducing oxida-
tive stress and improving cell viability, which highlights its therapeutic potential in both
ischemia and neurodegenerative diseases [
53
]. Increased AMP, SIRT1, and phosphorylated
AMPK have also been linked to protection against brain edema and blood-brain barrier
dysfunction, further supporting PKA’s protective role [2].
Similarly, the PKG pathway, activated by cGMP, mitigates oxidative stress and mi-
tochondrial dysfunction—two key contributors to neuronal death in stroke [
27
,
50
]. PKG
enhances the expression of antioxidant enzymes and supports mitochondrial health, en-
suring neurons maintain energy production and resist apoptosis [
27
,
50
]. Furthermore,
PKG modulates cerebral blood flow and reduces inflammation, preserving the viability of
ischemic brain tissue [
27
,
50
]. Although PDE4 inhibitors generally have fewer side effects,
such as emesis, higher doses needed for antidepressant effects may increase the risk of ad-
verse reactions, necessitating further research into optimal dosing strategies [
27
,
50
]. PDE5
inhibitors, which prevent cGMP degradation, boost PKG activity and offer neuroprotection
by enhancing mitochondrial function and reducing reactive oxygen species (ROS) [
27
].
By stimulating both the PKG and PI3K/Akt pathways, PDE5 inhibitors present a syner-
gistic therapeutic strategy to protect neurons, minimize cell death, and improve recovery
outcomes in stroke [28].
3.3. Traumatic Brain Injury (TBI)
Following traumatic brain injury (TBI), elevated expression of PDE4B2 and PDE4D2
in the hippocampus leads to reduced cAMP levels, impacting neuronal and immune cell
function [
18
,
36
]. Inhibiting PDE4 has been shown to restore long-term potentiation (LTP) in
the hippocampus and improve basal synaptic transmission by modulating AMPA receptor
transport [
18
,
36
]. PDE4D, which is predominantly expressed in microglia and immune cells,
suggests that PDE4 inhibition also helps regulate the inflammatory response following TBI.
Collectively, PDE4 inhibitors hold potential to enhance cognitive and synaptic function
post-TBI by promoting synaptic plasticity and reducing inflammation [18,36].
PDE5 inhibitors offer additional neuroprotection in TBI by targeting the NO-cGMP
pathway, mitigating vasospasm, and preventing ischemia—two key contributors to poor
outcomes in events such as subarachnoid hemorrhage (SAH) [
37
,
38
]. Research shows that
PDE5 inhibition reduces neuronal death following SAH without increasing intracranial
pressure, confirming its safety and efficacy [
37
,
38
]. These inhibitors also improve cerebral
blood flow regulation in injured brain tissue without elevating intracranial pressure, even
under conditions of reduced mean arterial pressure, which is essential for preserving
brain function and preventing further damage [
37
,
38
]. Furthermore, PDE5 inhibition
reduces levels of endothelin-1, a potent vasoconstrictor implicated in early brain injury,
thus enhancing cerebral perfusion during the acute phase of TBI [
37
,
38
]. By improving
blood flow to damaged areas, PDE5 inhibitors limit ischemic injury, reduce neuronal
death, and support recovery. As such, PDE5 inhibition presents a promising therapeutic
strategy for TBI management by maintaining vascular function and protecting neurons
from ischemic damage and cell death [37,38].
3.4. Alzheimer’s Disease
PDE4 inhibitors hold promise for treating Alzheimer’s disease (AD) with comorbid de-
pression by targeting the PDE4B and PDE4D subtypes, which regulate mood and memory,
respectively [
9
]. By inhibiting PDE4, these compounds elevate cAMP levels, activating the

Cells 2025,14, 86 8 of 14
cAMP/CREB/BDNF signaling pathway, which supports neuroprotection, anti-apoptotic
effects, and cognitive enhancement [
9
,
39
]. Studies in APP/PS1 transgenic mice—a model
for AD—have demonstrated that PDE4 inhibitors improve cognitive function, reduce de-
pressive behaviors, and decrease neuronal apoptosis by increasing the Bcl-2/Bax ratio [
9
,
39
].
Additionally, PDE4 inhibition restores cAMP and pCREB levels, which are associated with
cognitive improvements [9,39].
PDE5 inhibitors also exhibit potential in AD treatment through multiple mechanisms.
They reduce amyloid-beta (A
β
) and phosphorylated tau levels, enhancing cognitive func-
tion in animal models of AD [
3
,
40
]. PDE5 inhibition activates the cGMP/PKG/CREB
pathway, increasing neurotrophic factors such as BDNF and NGF, preserving mitochondrial
function, and preventing apoptosis [
3
,
40
]. These inhibitors also counteract A
β
-induced
dysregulation by modulating glucocorticoid receptor activity and restoring Wnt/
β
-catenin
signaling, promoting neuroprotection [
3
,
40
]. Furthermore, PDE5 inhibitors facilitate A
β
clearance by activating the autophagy-lysosome and ubiquitin-proteasome systems, reduc-
ing toxic protein accumulation [
3
]. Their impact on reducing intracellular calcium levels in
pericytes may further enhance cerebral blood flow and improve vascular function [3,40].
3.5. Summary of Effects of PDE4 and PDE5 Inhibitors in Neurological Disorders
The regulation of PDE4 and PDE5 highlights the critical role of second messenger sys-
tems in brain health, making them promising targets for neurological disorders. Modulating
these pathways offers therapeutic potential across a range of conditions, including traumatic
brain injury, ischemic stroke, epilepsy, and neurodegenerative diseases
(Tables 1and 2).
Further research on PDE inhibitors may pave the way for innovative strategies to treat these
debilitating conditions by enhancing cognitive function, preventing neurodegeneration,
and promoting recovery [3,9,39,40].
Table 1. Observed effects of PDE4 inhibitors in neurological disorders.
PDE4 Inhibitor Neurological
Disorder Animal Model Observed Effects
References
Amlexanox Seizures and
Epilepsy
Sprague Dawley rats
(6–8 weeks old)
▼Neuronal cell death
▲Lysosomal function
▲Autophagy
▼Neuroinflammation
▼Reactive oxygen species (ROS)
[26]
Rolipram
FCPR03
Ischemia and
Stroke
Adult male C57BL/6 mice
(6–8 weeks old)
Sprague Dawley rats
(6–8 weeks old)
▼Neuronal cell death
▼Neuroinflammation
▲Blood-brain barrier integrity
▼ROS production
▲SIRT1 and p-AMPK
▲AKT/GSK3β/β-catenin
[2,54]
A33
Rolipram
Traumatic Brain
Injury (TBI)
Sprague Dawley rats
(6–8 weeks old)
▼Neuronal cell death
▲Cognitive function
▲Synaptic function
▲Synaptic plasticity
▼Neuroinflammation
[18,36]
Roflumilast Alzheimer’s
Disease (AD)
APP/PS1 double
transgenic mice
▼Neuronal cell death
▲cAMP/CREB/BDNF signaling
▲Bcl-2/Bax ratio
▲Cognitive function
▼Depressive-like behavior
[9]

Cells 2025,14, 86 9 of 14
Table 2. Observed effects of PDE5 inhibitors in neurological disorders.
PDE5
Inhibitor
Neurological
Disorder Animal Model Observed Effects
References
Sildenafil Seizures and
Epilepsy
Male Swiss mice
Wistar rats
▲Neuroprotection via NO-cGMP-PKG
pathway
▼ROS production
▼Neuronal excitability
[34,35]
Sildenafil Ischemia and
Stroke
10-day-old (P10) male
Long–Evans rat
▼Neuronal death
▲Neuroprotection via PKG pathway
▼ROS production
▲PI3K/Akt/mTOR pathway activation
▲Mitochondrial function
[28]
Sildenafil Traumatic Brain
Injury (TBI)
Twenty-eight
Wistar-derived albino
strain female rats
▼Neuronal death
▲
Cerebral blood flow without increasing
intracranial pressure
▼Endothelin-1 levels
▲Cerebral perfusion
[37]
Mirodenafil Alzheimer’s
Disease (AD) APP-C105 AD mouse
▼Amyloid-beta (Aβ) and tau levels
▲Cognitive function
▲Aβclearance via autophagy-lysosome
pathway
▲
cGMP/PKG/CREB signaling pathway
▲Mitochondrial function
[3]
This table highlights the therapeutic potential of various PDE4 inhibitors across a
range of neurological disorders, as demonstrated in preclinical animal models. Amlex-
anox, in a seizure and epilepsy model using Sprague Dawley rats, showed neuroprotective
effects, including reduced neuronal cell death, decreased neuroinflammation, and oxida-
tive stress, as well as enhanced lysosomal function and autophagy [
26
]. Rolipram and
FCPR03, in ischemia and stroke models using adult male C57BL/6 mice and Sprague
Dawley rats, reduced neuronal cell death, neuroinflammation, and reactive oxygen species
(ROS) production while preserving blood-brain barrier integrity and promoting SIRT1,
p-AMPK, and AKT/GSK3
β
/
β
-catenin signaling pathways [
2
,
54
]. A33 and Rolipram, in
traumatic brain injury (TBI) models with Sprague Dawley rats, demonstrated significant
neuroprotective effects, including reduced neuronal death, enhanced cognitive and synap-
tic function, and increased synaptic plasticity while mitigating neuroinflammation [
18
,
36
].
Roflumilast, in an Alzheimer’s disease (AD) model using APP/PS1 double transgenic mice,
showed reduced neuronal death, increased cAMP/CREB/BDNF signaling, and improved
Bcl-2/Bax ratios [
9
]. These effects contributed to enhanced cognitive function and alle-
viation of depressive-like behavior. These results underscore the broad neuroprotective
and therapeutic potential of PDE4 inhibitors in addressing key pathological processes in
neurological disorders.
This figure illustrates the therapeutic potential of PDE5 inhibitors across various
neurological disorders, as evidenced in preclinical animal studies. Sildenafil, in seizure
and epilepsy models using Male Swiss mice and Wistar rats, exhibited neuroprotective
effects via the NO-cGMP-PKG pathway, reducing ROS production and neuronal excitabil-
ity [
34
,
35
]. In ischemia and stroke models using 10-day-old male Long–Evans rats, Sildenafil
significantly reduced neuronal death, enhanced neuroprotection through the PKG pathway,
decreased ROS production, and activated the PI3K/Akt/mTOR pathway while improving
mitochondrial function [
28
]. In traumatic brain injury (TBI) models with twenty-eight
Wistar-derived albino strain female rats, Sildenafil reduced neuronal death, improved

Cells 2025,14, 86 10 of 14
cerebral blood flow without increasing intracranial pressure, decreased endothelin-1 lev-
els, and enhanced cerebral perfusion [
37
]. Mirodenafil, in an Alzheimer ’s disease (AD)
model using APP-C105 AD mice, decreased amyloid-beta (A
β
) and tau levels, improved
cognitive function, facilitated A
β
clearance through the autophagy-lysosome pathway,
enhanced cGMP/PKG/CREB signaling, and supported mitochondrial function [
3
]. These
findings underscore the diverse and significant neuroprotective benefits of PDE5 inhibitors,
highlighting their potential as therapeutic agents in neurological disorders.
4. Discussion
Phosphodiesterase (PDE) enzymes play an essential role in hydrolyzing phospho-
diester bonds, contributing to brain development and the pathogenesis of neurological
diseases [
1
]. Among the 11 PDE subtypes, PDE4 and PDE5 are particularly significant for
brain function due to their roles in regulating cAMP and cGMP signaling pathways [
1
,
55
]
(Table 3).
Table 3. Focused roadmap for advancing PDE inhibitor research in neurological disorders.
Focus Area Key Objectives Specific Actions Expected Outcomes
Mechanisms of
Action
1.1 Disease-Specific Pathways: Study PDE4
and PDE5 roles in Alzheimer’s, TBI, stroke,
and epilepsy.
1.2 Crosstalk Analysis: Investigate
interactions between PDE4 and PDE5 in
overlapping conditions.
- Use single-cell RNA sequencing to
identify PDE expression patterns.
- Perform proteomic studies in
disease-specific animal models.
- Analyze effects of selective PDE
inhibition in vitro and in vivo.
- Clear understanding of
PDE pathways for
specific diseases.
- Identification of potential
targets for dual PDE
modulation.
Enhancing
PDE Inhibitors
2.1 Improve Selectivity: Design
isoform-specific inhibitors (e.g.,
PDE4D, PDE5A).
2.2 Improve Bioavailability: Ensure BBB
penetration and target engagement.
2.3 Safety Testing: Examine chronic dosing
impacts (e.g., emesis, cardiovascular
side effects).
- Conduct structure-activity
relationship (SAR) studies to refine
drug candidates.
- Test nanoparticles for
enhanced delivery.
-
Perform 6–12 month chronic toxicity
studies in rodents.
- Highly selective inhibitors
with reduced
off-target effects.
- Drugs optimized for safety
and efficacy in neurological
conditions.
Preclinical to
Clinical
3.1 Validate in Human Models: Use
iPSC-derived neurons and 3D brain
organoids to test PDE inhibitors.
3.2 Initiate Clinical Trials: Prioritize stroke
and epilepsy for Phase 1 studies.
- Generate organoids to mimic
Alzheimer’s and ischemia
environments.
- Develop protocols for multicenter
trials focusing on safety and efficacy
in humans.
- Accelerated clinical
translation of
PDE inhibitors.
- Identification of optimal
dosing regimens and
therapeutic windows.
Combination
Therapies
4.1 Dual PDE Inhibition: Explore combined
PDE4 and PDE5 targeting.
4.2 Synergistic Approaches: Pair PDE
inhibitors with anti-inflammatory or
antioxidant agents.
- Conduct combinatory drug testing
in animal models of TBI
and epilepsy.
- Perform synergy analysis using
isobologram techniques.
- Enhanced efficacy through
synergistic mechanisms.
- Broader therapeutic
applications for complex
neurological disorders.
Phosphodiesterase (PDE) enzymes play a crucial role in hydrolyzing phosphodiester
bonds, influencing brain development and the pathogenesis of neurological diseases [
1
].
Among the 11 PDE subtypes, PDE4 and PDE5 are particularly important for brain function
due to their regulation of cAMP and cGMP signaling pathways [
1
]. PDE4 specifically
hydrolyzes cAMP, a second messenger critical for cognitive functions [
56
]. Increased PDE4
activity lowers cAMP levels, impairing PKA activity and disrupting synaptic plasticity,
which is essential for memory and learning [
26
,
56
]. Proper regulation of PDE4 is necessary
to prevent cognitive disorders such as Alzheimer’s disease and epilepsy [
9
]. Similarly,
PDE5 controls cGMP degradation, and its dysregulation affects vascular function and
neuronal survival, contributing to neurological diseases [1,50].
PDE4 inhibitors offer therapeutic benefits by stabilizing cAMP levels, enhancing PKA
activity, and improving synaptic plasticity [
9
,
26
]. They also reduce neuroinflammation and

Cells 2025,14, 86 11 of 14
oxidative stress, which may mitigate seizure severity and slow progression of epilepsy.
PDE5 inhibitors enhance the cGMP-PKG pathway, modulate nitric oxide (NO) signal-
ing, and reduce oxidative stress, showing potential in decreasing seizure frequency and
severity [34,35].
Both PDE4 and PDE5 inhibitors contribute to neuroprotection during ischemic strokes.
PDE4 inhibitors increase cAMP levels, activating PKA to reduce neuronal apoptosis, neu-
roinflammation, and oxidative stress, while maintaining blood-brain barrier integrity [
2
,
54
].
Activation of the Nrf-2/HO-1 pathway further reduces reactive oxygen species (ROS),
aiding recovery [
2
,
54
]. PDE5 inhibitors, through PKG activation, protect against mito-
chondrial dysfunction and promote neuronal survival by activating the PI3K/Akt/mTOR
pathway [28].
In traumatic brain injury (TBI), PDE4 inhibition improves cognitive outcomes by rais-
ing cAMP levels and reducing neuroinflammation through decreased microglia activation
and inflammatory cytokine production [
18
,
36
]. PDE5 inhibitors enhance cerebral blood
flow, reduce neuronal death, and improve perfusion in damaged brain tissue, suggesting
that PDE inhibitors could significantly enhance clinical outcomes [18,36].
In Alzheimer’s disease (AD) models, PDE4 inhibitors improve cognitive function and
alleviate depression-like behavior by activating the cAMP/CREB/BDNF pathway, promot-
ing neuroprotection and reducing apoptosis [
3
,
9
]. PDE5 inhibitors reduce amyloid-beta
(A
β
) and phosphorylated tau levels, prevent neuronal death, and support mitochondrial in-
tegrity via the cGMP/PKG/CREB signaling pathway [
3
,
9
]. They also promote A
β
clearance
and improve vascular function, making PDE5 a promising target for AD therapy [3,9].
5. Conclusions
PDE4 and PDE5 inhibitors show great promise as therapeutic agents for neurological
disorders like epilepsy, ischemia, TBI, and Alzheimer’s disease. By modulating cAMP
and cGMP signaling pathways, they enhance neuroprotection, reduce inflammation, and
improve cognitive and vascular functions. While preclinical and clinical studies are encour-
aging, further research is needed to confirm their long-term efficacy and safety, potentially
advancing treatment options for these conditions.
Author Contributions: M.K.P. performed the data analysis and reviewed and edited the manuscript.
H.W.Y., S.Y.W., D.Y.K., D.-S.S. and B.Y.C. reviewed and edited the manuscript. S.W.S. contributed
to the discussion and wrote, reviewed, and edited the manuscript. S.W.S. takes full responsibility
for the manuscript and its originality. All authors have read and agreed to the published version of
the manuscript.
Funding: Hallym University Research Fund (grant number: MHC-202402-003), National Research
Foundation of Korea (NRF) (grant number: NRF-2021R1C1C2012889), Ministry of Education and
National Research Foundation of Korea (grant number: GLOCAL-202406240001).
Data Availability Statement: Not applicable.
Acknowledgments: This research was supported by a grant received from the Hallym University
Research Fund (grant number: MHC-202402-003). This research was supported by funding from
the National Research Foundation of Korea (NRF) (NRF-2021R1C1C2012889) to Bo Young Choi.
“Created with BioRender.com”. Following are results of a study on the "Glocal University” Project
(GLOCAL-202406240001), supported by the Ministry of Education and National Research Foundation
of Korea to Dae-Soon Son.
Conflicts of Interest: The authors declare no conflict of interest in this study.

Cells 2025,14, 86 12 of 14
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