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Mussen, F.; Van Broeckhoven, J.; Hellings, N.; Schepers, M.; Vanmierlo, T. Role of cAMP-Specific PDE Inhibition in Attenuating Neuroinflammation. Encyclopedia. Available online: https://encyclopedia.pub/entry/44214 (accessed on 10 December 2025).
Mussen F, Van Broeckhoven J, Hellings N, Schepers M, Vanmierlo T. Role of cAMP-Specific PDE Inhibition in Attenuating Neuroinflammation. Encyclopedia. Available at: https://encyclopedia.pub/entry/44214. Accessed December 10, 2025.
Mussen, Femke, Jana Van Broeckhoven, Niels Hellings, Melissa Schepers, Tim Vanmierlo. "Role of cAMP-Specific PDE Inhibition in Attenuating Neuroinflammation" Encyclopedia, https://encyclopedia.pub/entry/44214 (accessed December 10, 2025).
Mussen, F., Van Broeckhoven, J., Hellings, N., Schepers, M., & Vanmierlo, T. (2023, May 12). Role of cAMP-Specific PDE Inhibition in Attenuating Neuroinflammation. In Encyclopedia. https://encyclopedia.pub/entry/44214
Mussen, Femke, et al. "Role of cAMP-Specific PDE Inhibition in Attenuating Neuroinflammation." Encyclopedia. Web. 12 May, 2023.
Role of cAMP-Specific PDE Inhibition in Attenuating Neuroinflammation
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24098135

Cyclic adenosine monophosphate (cAMP) is an important second messenger in the central nervous system (CNS) that modulates these processes. A sustained drop in cAMP levels is observed during SCI, and elevating cAMP is associated with improved functional outcomes in experimental models. cAMP is regulated in a spatiotemporal manner by its hydrolyzing enzyme phosphodiesterase (PDE). Growing evidence suggests that inhibition of cAMP-specific PDEs (PDE4, PDE7, and PDE8) is an important strategy to orchestrate neuroinflammation and regeneration in the CNS.

traumatic spinal cord injury cAMP phosphodiesterases

1. Introduction

Traumatic spinal cord injury (SCI) is a neurological disorder characterized by damage to the spinal cord leading to transient or permanent neurological deficits. The current therapies include surgical decompression, rehabilitation, and in some instances, the administration of the corticosteroid methylprednisolone [1]. Nevertheless, the use of methylprednisolone is under debate because of severe side effects such as wound infections, sepsis, and pulmonary embolism [2]. Hence, there is an urgent need for novel therapies to treat SCI, and modulating the initial neuroinflammation and boosting endogenous repair are considered crucial to improve SCI outcomes.

2. cAMP-Specific PDEs in Neuroinflammation following SCI

2.1. Neutrophils

Cyclic adenosine monophosphate (cAMP) is a pivotal regulator of neutrophil activity, e.g., phagocytosis, neutrophil extracellular trap (NET) formation, and the release of inflammatory products [3][4][5]. Orchestrating cAMP levels upon a bolus intravenous (i.v.) injection of pan phosphodiesterase 4 (PDE4) inhibitor IC486051 2–60 h after a compression SCI reduced neutrophil infiltration and myeloperoxidase (MPO) activity 24 and 72 h post-injury (pi) in rats. Interestingly, these effects were only observed in rats treated with 0.5 mg/kg or 1 mg/kg IC486051, while only limited effects were observed with a high dose of 3 mg/kg [6]. The limited anti-inflammatory effect of 3 mg/kg IC486051 can be due to off-target effects observed at a high dose of PDE4 inhibition [7][8]. PDE4B was revealed to be an especially crucial mediator for neutrophil infiltration in the CNS, since intraperitoneal (i.p.) administration of 3 mg/kg A33, 30 min and 5 h pi reduced neutrophil infiltration in traumatic brain injury [9]. Nevertheless, A33 treatment was not compared to pan PDE4 inhibition, and hence, the contribution of other PDE4 isoforms in regulating neutrophil infiltration cannot be excluded. Indeed, the administration of 3 mg/kg pan PDE4 inhibitor rolipram could further decrease neutrophil infiltration in the lungs of lipopolysaccharide (LPS)-induced chronic obstructive pulmonary disease (COPD) in PDE4B knock-out (KO) mice and, to a lesser extent, in PDE4D KO mice, suggesting a promising role of PDE4D in orchestrating neutrophil infiltration [10]. However, the role of individual PDE4 families in regulating neutrophil infiltration over the blood-spinal cord barrier (BSCB) should be further investigated since the mechanisms of neutrophil infiltration depend on the surrounding tissue barrier. Additionally, PDE4 inhibition can alter the activity of peripheral neutrophils, leading to modified infiltration rather than PDE4 inhibition directly modulating neutrophil–BSCB interaction [11]. In vitro, pan-PDE4 inhibition with 0.01–1000 nM roflumilast suppressed the production of tissue-damaging compounds MPO, elastase, and matrix metallopeptidase 9 (MMP-9) in human neutrophils [12]. The ability of cAMP to cease neutrophil activation is well known and is suggested to be mediated through protein kinase A (PKA) [13]. In conclusion, PDE4 inhibition has the ability to cease neutrophil infiltration and impede the neutrophil-mediated spread of tissue damage by suppressing neutrophil activity.
PDE7 is also expressed in human neutrophils and could, therefore, be involved in regulating specific functions [14]. Research showed that PDE7 inhibition 1, 3, or 6 h pi with 4 mg/kg VP1.15 (i.p.) or 10 mg/kg S14 (i.p.) reduced neutrophil infiltration 24 h pi in mice with compression-induced SCI [15]. Nevertheless, neutrophil infiltration was measured by quantifying MPO activity, and hence, the decrease in MPO activity could be attributed to diminished neutrophil activation rather than reduced infiltration. Indeed, PDE7 was indicated to act in an immunomodulatory way by decreasing tumor necrotic factor α (TNF-α), interleukin 1β (IL-1β), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) levels in the spinal cord tissue 24 h pi as quantified with immunohistochemistry. However, the pro-inflammatory products in the spinal cord lesion did not colocalize with neutrophils. Therefore, the effect of PDE7 inhibition on pro-inflammatory cytokine production can potentially be attributed to influencing other immune cells, such as infiltrated monocytes, microglia, or lymphocytes in the spinal cord lesion [15]. Consequently, PDE7 inhibition is suggested to modulate neuroinflammation in SCI, but the neutrophil-specific influence of PDE7 inhibition in the spinal cord lesion remains largely unknown.

2.2. Phagocytes

The secondary injury in SCI is characterized by the profound activation of CNS phagocytes. Microglia are the resident immune cells of the CNS and rapidly migrate to the spinal cord lesion, adopting a phenotype recognized by the production of TNF-α and IL-1β [16]. Circulating phagocytes, namely, monocyte-derived macrophages (MDMs), are also attracted to the spinal cord lesion. MDMs will contribute to the production of inflammatory cytokines, e.g., TNF-α and IL-1β, along with the resident microglia [17][18][19]. Together, the phagocytes are major mediators of tissue damage by creating an inflammatory environment via the secretion of cytokines and reactive oxygen species. Additionally, infiltrated MDMs contact injured axons and mediate axonal dieback [20][21]. On the other hand, phagocytes can also promote tissue regeneration by clearing anti-regenerative compounds such as cellular debris and producing neurotrophic factors, e.g., brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3), to stimulate neuroregeneration [22][23]. Microglia are the primary phagocytes removing tissue debris in the lesion site in the early stages of SCI, whereas MDMs are the predominant phagocytes in the later stages of SCI [17]. However, MDMs are less capable of processing myelin debris, leading to the formation of inflammatory foamy macrophages [24]. Both repair-promoting and inflammatory phagocytes are observed shortly after the initial injury. The repair-promoting population declines after the first week following the initial injury, while the inflammation-stimulating phagocytes reside until the chronic phases of SCI [17][18]. The persistent inflammatory phagocytes and the decline in regeneration-promoting phagocytes contribute to profound neuroinflammation followed by tissue damage in the spinal cord. Hence, endogenous regeneration in the SCI tissue is diminished, leading to impaired recovery following SCI.
Reducing MDM infiltration and ceasing the production of inflammatory compounds of spinal cord phagocytes has been shown to be promising in promoting functional recovery following SCI [25][26][27]. Monocyte infiltration, quantified by the number of CD68+ cells, was significantly decreased 2 weeks pi upon i.v. administration of 1 mg/kg PDE4 inhibitor rolipram starting 1, 4, or 24 h pi and thereafter once daily for 2 weeks in a thoracic SCI in rats [28]. Elevating cAMP levels stimulated anti-inflammatory cytokine production (Arg1, chitinase-3-like protein 3 (Ym-1), and IL-10) of phagocytes and reduced LPS-induced TNF-α and IL-1β release of the murine microglia BV2 cell line [29][30][31][32]. The anti-inflammatory effect of 10 µM PDE4 inhibitor FCPR03 on BV2 cells was suggested by the activation of the PKA/ cAMP response element-binding protein (CREB) pathway since PKA inhibition counteracted PDE4-induced inhibition of TNF-α and IL-1β production. Additionally, PDE4 inhibition with 10 µM of rolipram in the EOC-2 murine microglia cell line or intragastrical treatment with 0.5–1 mg/kg FCPR03 in vivo lowers Nuclear factor kappa B (NF-κB) p65 phosphorylation and NF-κB activity in the hippocampus of LPS-injected mice, respectively [33][34]. Consequently, PDE4 inhibition is considered to reduce inflammatory responses of phagocytes by promoting anti-inflammatory cytokine production and hampering pro-inflammatory cytokine production through the PKA/CREB pathway and PKA-induced inhibition of NF-κB, which can be beneficial to modulating phagocyte responses in SCI. The immunomodulatory effects of PDE4 inhibition on phagocytes were further observed in SCI animal models. Subcutaneous (s) delivery of 0.5 mg/kg/day pan PDE4 inhibitor rolipram for 1 week reduced the production of pro-inflammatory cytokines TNF-α, 3 and 6 h pi in a contusion rat SCI model [35]. In contrast, 0.5 mg/kg rolipram treatment could not reduce IL-1β levels, suggesting differential regulation in cytokine production in vivo. Additionally, research showed that PDE4 inhibition by i.p. administration of 0.5–1 mg/kg roflumilast 30 min before SCI induction increased the amount of CD163+ microglia and decreased the amount of CD68+ microglia 28 pi. The increase in repair-promoting phagocytes (CD163+ phagocytes) was accompanied by a reduction in pro-inflammatory cytokines TNF-α and IL-1β and enhanced anti-inflammatory cytokine (IL-10) production in rats with a compression-induced SCI [36].
In particular, PDE4B is of interest to modulate phagocyte activity and circumvent emetic side effects. PDE4B deficiency in mouse peritoneal macrophages enhanced the secretion of anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) through a cAMP/PKA but not in an EPAC-dependent manner [37]. PDE4B is acutely upregulated in both microglia and macrophages following SCI in mice with, in particular, high PDE4B2 mRNA expression [38][39]. Moreover, the rise in PDE4B coincided with elevated mRNA expression of TNF-α and IL-1β, which supports PDE4B-mediated regulation of pro-inflammatory cytokine production in SCI [39]. Although the PDE4B inhibitory effect on SCI is unknown, recent data of murine autoimmune encephalomyelitis (EAE) revealed that twice daily subcutaneous (s.c.) treatment with 3 mg/kg PDE4B inhibition shifts the balance to Arg-1+ macrophages but could not reduce monocyte infiltration in the spinal cord (for a comprehensive overview of PDEs in MS, see the review of Schepers et al.) [40][41]. Therefore, phagocyte infiltration in the spinal cord is potentially attributed to other PDE subtypes or the combination of different PDE4 genes, since general PDE4 inhibition could reduce monocyte infiltration in the spinal cord after SCI [42].
PDE7 is expressed to a lesser extent in microglia and macrophages [43]. Nevertheless, i.p. administration of 4 mg/kg VP1.15 or 10 mg/kg S14 1, 3, and 6 h pi and daily for 9 days reduced pro-inflammatory cytokine production potentially by a decreased degradation of IkappaB kinase (IκB-a), Extracellular signal-regulated kinase (ERK), p38, and Jun N-terminal kinase (JNK) in a compression SCI mouse model [15]. Although this was not directly measured in spinal cord phagocytes, the MAPK and ERK1/2 pathway is postulated as key regulator of phagocyte cytokine production [44]. Furthermore, PDE7 inhibition with 10 mg/kg VP3.15 or 20 nmol S14 reduced microgliosis in a murine EAE model or LPS-induced Parkinson’s disease model in rats [45][46]. Therefore, PDE7 can be a key target to modulate cAMP levels in SCI to alter phagocyte activation.

2.3. Lymphocytes

Modulating lymphocyte activation and reducing autoreactivity against spinal cord compounds is considered a promising strategy to influence the neuroinflammatory processes after SCI. Antigen-induced activation of both B and T lymphocytes is modulated by cAMP levels [47]. Additionally, cAMP orchestrates antigen-stimulated proliferation and antibody production in B cells as well as the maintenance of naive T cells and their activation [48]. Furthermore, T-cell activation is hampered upon increasing cAMP levels, and its elevation is crucial in the formation of regulatory T cells. However, prolonged high cAMP levels induce an anergy-like state [49][50][51]. PDE-mediated modulation of lymphocytes in SCI has not been investigated yet, but in vitro works suggest the promising implications of PDE inhibitors to lower lymphocyte activation in SCI. One micromole of PDE4 inhibitor roflumilast and its metabolite roflumilast N-oxide reduced the proliferation of spleen-derived murine CD4+ T cells stimulated with anti-CD3/CD28 antibody. Roflumilast was suggested to block the interaction between inositol triphosphate 3 (IP3) and its receptor, leading to decreased calcium release from the Golgi apparatus and resulting in diminished activation of the nuclear factor of activated T cells (NFAT) and ceased IL-2 transcription, necessary for T-cell proliferation [52]. Furthermore, 1 µM of PDE4 inhibitor RP73401 decreased T-cell proliferation and skewed them to an anti-inflammatory phenotype. Selective PDE4D KO with siRNA showed that the PDE4D subtype is particularly crucial for regulating T-cell proliferation, while PDE4B and PDE4A were less important. However, PDE4A, PDE4B, and PDE4D were all demonstrated to modulate IL-2, IFN-γ, and IL-5 levels in human primary CD4+ T cells [53]. PDE4B2 is suggested to mediate T-cell receptor-induced IL-2 production in Jurkat T cells [54]. IL-2 is a cytokine involved in the proliferation and differentiation of effector T cells and regulatory T cells. Hence, it remains to be elucidated whether the production of IL-2 in response to PDE4B2 upregulation is either detrimental by stimulating the expansion of effector T cells or beneficial to prevent autoimmunity with the production of regulatory T cells. PDE4B upregulation during T-cell receptor (TCR) stimulation in human-isolated CD4+ T lymphocytes has been demonstrated to be the main contributor to reducing cAMP levels. Interestingly, PDE4B mRNA levels decreased after 24 h while PDE4A and PDE4D mRNA levels were upregulated and peaked 120 h after anti-CD3/CD28 stimulation in CD4+ T cells, indicating a time-dependent response [53]. To conclude, different PDE subfamilies are involved in variable processes in the adaptive immune system since PDE4D was shown to be involved in T-cell proliferation while PDE4B was demonstrated to be a major regulator of T-cell activation.
Little is known about the effects of PDE7 and PDE8 inhibition on lymphocytes in SCI. However, PDE7 inhibition was revealed to be beneficial for reducing T-cell proliferation, ceasing IL-17 production, and expanding Foxp3 (T-regulatory) expression in an EAE model of MS [45][55][56]. PDE8 inhibition with 10 mg/kg s.c. PF-04957325 thrice daily for 6–13 days reduced immune cell infiltration of CD4+ T cells 13 days after EAE induction with myelin oligodendrocyte glycoprotein (MOG) [57]. Moreover, PDE8 inhibition with s.c. 2.5 mg/kg of PF-04957325 could not reduce T-cell proliferation in an allergic airway disease mouse model but could regulate T-cell effector interactions with the endothelial cells (for a comprehensive review of the effect of PDE7 and PDE8 inhibition on lymphocytes in MS, please read the review of Schepers et al.) [40][58].

3. cAMP-Specific PDEs in Neuroregeneration following SCI

3.1. Neurons

Important factors in the spinal lesion that inhibit neuronal and axonal regeneration are proteins released from injured oligodendrocytes, including myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp). In addition, Nogo-A is present on axons as well as released from neurons and is considered a major inhibitor for neurite outgrowth [59]. Together, myelin-associated proteins and neuronal inhibitory molecules induce neuronal apoptosis and growth cone collapse by activating the ras homolog family member A (RhoA) / Rho-associated coiled-coil containing kinases (ROCK) pathway [59][60]. Elevating cAMP levels is promising to impede neuronal apoptosis and promote neuronal regeneration through PKA / exchange protein directly activated by cyclic AMP (EPAC)-mediated inhibition of RhoA, which can be indispensable for improving functional recovery for SCI patients.
While MAG inhibits neuronal regeneration in adult neurons, MAG does not inhibit axonal outgrowth during certain embryonal stages. Cai et al. demonstrated that MAG-induced inhibition of axonal regeneration was correlated with cAMP levels in neurons [61]. This concept was reinforced since elevating cAMP in adult neurons could overcome the MAG-induced inhibition of neurite outgrowth suggested by cAMP-mediated activation of the PKA pathway [62][63]. Furthermore, glial-released neurotrophins promote neuronal outgrowth by elevating cAMP-directed activation of ERK signaling [63][64]. More specifically, ERK-induced inhibition of PDE4 led to elevated cAMP levels and proved to be crucial to overcoming MAG-mediated inhibition upon the presence of BDNF [65]. Consequently, modulating PDE activity in SCI could be useful to promote neuronal regeneration and hence improve functional recovery in SCI patients. Treatment with 1 µM roflumilast or s.c. administration of 3 mg/kg roflumilast increased neuronal viability in vitro and in a stroke model, respectively [66][67]. The decrease in neuronal cell death by roflumilast is postulated through decreasing pathways associated with neuronal cell death upon endoplasmic reticulum (ER) stress, such as the inositol-requiring enzyme 1 a (IRE1a)/JNK pathway [68]. Another protective mechanism of roflumilast in neurons could be through inhibition of NF-κB, since 21 days of treatment with 2 mg/kg orally administered roflumilast was neuroprotective against quinolinic acid administration in mice through inhibiting NF-κB and elevating CREB and BDNF expression in the striatum and cortex in rats [69]. Inhibition of PDE4B with i.p. injections of 0.3 mg/kg A33 decreased neuronal loss in traumatic brain injury [9]. Nevertheless, PDE4B is shown to be upregulated in inflammatory cells following traumatic CNS injury, and therefore, the neuroprotective effects of PDE4B inhibition could be achieved indirectly through decreased neuroinflammation. The neuroprotective role of PDE4 inhibition was further confirmed in SCI. First of all, i.v. administration of 1 mg/kg rolipram starting 2 h pi thereafter, continued daily for 2 weeks, promoted neuronal and axonal protection at the end of treatment in a rat thoracic contusion model of SCI [28]. Similar neuroprotective effects were revealed 4 weeks pi upon 0.4 μmol/kg/h s.c. administration of rolipram for 10 days starting 14 dpi in a cervical hemisection model with embryonic tissue transplantation in the lesion site. An embryonic transplant was used to assess axonal growth into the transplant since there is usually no ingrowth in the transplant, but ingrowth was observed during rolipram inhibition [70]. Furthermore, PDE4 inhibition promoted neuronal regeneration in the inhibitory environment of SCI. Here, 0.1, 0.25, 1, or 2 µM of rolipram treatment could overcome MAG-inhibited neurite outgrowth in isolated dorsal root ganglia (DRG) neurons of rats [70]. In addition to the inflammatory environment, chondroitin sulfate proteoglycans (CSPs), produced by glial cells, are pivotal in inhibiting neuronal regeneration in the subacute and chronic phases of SCI. Rolipram alone was unable to promote neuronal survival and outgrowth in a CSP-rich environment in vitro. In addition, it was not potent in protecting neurons against glutamate-induced neuronal toxicity [71]. Hence, PDE4 inhibition can potentially overcome the inhibitory influences of myelin and neuronal released signals. However, current evidence suggests it cannot overcome glutamate and CSP-induced neuronal outgrowth inhibition.
Little is known regarding other cAMP-specific PDEs, including PDE7 and PDE8, in neuronal regeneration. However, research suggests that PDE7 can be promising in stimulating neuronal regeneration. Pretreatment with PDE7 inhibitor TC3.6 was demonstrated to improve the viability of the neuronal cell line PC12 upon glutamate exposure [56]. In addition, the PDE7 inhibitors S14 or BRL50481 reduced 6-hydroxydopamine (OHDA)-induced cellular death of a dopaminergic cell line SH-Sy5Sy 16 h after incubation. The aforementioned PDE7 inhibitors were able to protect neurons in vivo after LPS injection in the substantia nigra [46].

3.2. Myelinating Cells

Mature oligodendrocytes can be replaced in the spinal cord by oligodendrocyte precursor cells (OPCs), which start proliferating shortly after the initial injury and peak in proliferative capacity 2 weeks pi [72]. However, the loss of oligodendrocytes releases inhibitory substances, e.g., MAG and OMgp, which inhibit OPC maturation and hence remyelination [73][74]. The peripheral myelinating cells, namely, Schwann cells (SCs), have been shown to infiltrate the spinal cord lesion. SCs have broad functions in the peripheral nervous system (PNS), including the ensheathment of neurons and the production of neurotrophins and extracellular matrix (ECM) components. These characteristics contribute to the enhanced regenerative capacity of the PNS compared with the CNS. The regenerative stimulating capacity of infiltrated SCs in the spinal cord lesion were shown to be neuroprotective and contribute to remyelinating damaged axons after SCI. Nevertheless, SCs transplantation in the spinal cord lesion appeared to be insufficient to promote functional repair in clinical trials with SCI patients [75][76][77]. Therefore, current research focuses on boosting the regenerative stimulating capacity of SCs in SCI by combining SC transplantation with different modulates, e.g., scaffolds or growth factors. Recently, cAMP modulation by PDE inhibition has been demonstrated to promote the regenerative features of SCs in vitro and improve SCI repair after SC transplantation [35]. As a consequence, orchestrating cAMP levels via PDE inhibition can be considered a promising strategy to impede functional loss following SCI via modulating oligodendrocytes and SCs.
cAMP levels regulate OPC differentiation toward the mature myelinating oligodendrocytes [74]. Although OPC migration and proliferation are observed shortly after the SCI, maturation and differentiation are hindered by myelin products released from dying oligodendrocytes. Oligodendrocyte-derived compounds such as MAG reduce phosphorylation and activation of the ERK1/2/p38/MAPK and CREB pathways in OPCs. Elevating cAMP with 3.21 mM dibutyryl (db)-cAMP or inhibiting PDE4 with 0.5 µM rolipram could oppose this myelin-induced OPC inhibition 48 h after administration in primary rat OPCs. Additionally, OPC differentiation and axonal remyelination were stimulated in focal-induced demyelination upon treatment with 0.5 mg/kg rolipram 14 dpi [74]. Besides the vital role of PDE4 inhibition in OPC differentiation, it has been demonstrated to promote oligodendrocyte protection in the SCI lesion. Whitaker et al. indicated increased oligodendrocyte sparing 24 and 72 h pi in contusive SCI in rats after administering 0.5 mg/kg/day rolipram using a mini-osmotic pump [78]. Additionally, 14 days of s.c. PDE4 inhibition with 0.5 mg/kg/day rolipram improved oligodendrocyte sparing in the white matter of the ventrolateral funiculus in a contusive rat SCI model 5 weeks pi [79]. This was further supported by Schaal et al., who demonstrated oligodendrocyte and white matter sparing upon 2 weeks of i.v. 1 mg/kg rolipram treatment in SCI [28]. PDE4 inhibition is indicated to influence SC functioning and can therefore have the potential to boost SC function in the spinal cord. Six days of treatment with 10 µM roflumilast on rat-derived SCs, followed by co-culturing human iPSC-derived nociceptive neurons demonstrated an increased myelinated area and enhanced neurite outgrowth after 14 days through EPAC and PKA-mediated mechanisms, respectively. Interestingly, the effects of PDE4 inhibition on myelination and axonal outgrowth were not observed after 21 days, indicating that PDE4 inhibition can accelerate the remyelinating and mitogenic activity of SCs [80]. The beneficial effects of boosting SC functioning with PDE4 inhibition were observed in SCI. S.c. administration of 0.5 mg/kg/day rolipram starting immediately after a T8 contusion injury in rats, followed by a SC transplantation 1 week pi improved axonal sparing and the number of SC-myelinated axons in the spinal cord lesion 11 weeks pi. Interestingly, rolipram treatment without SC transplantation was shown to increase peripheral myelin sheaths, suggesting a myelinating boosting effect of PDE4 inhibition on SC. Acute rolipram treatment combined with SC transplantation was not able to improve serotonin+ (5HT) fiber ingrowth in the SC transplant graft. In contrast, the combination of acute rolipram treatment with SC transplantation and db-cAMP administration 1 week pi improved 5HT ingrowth in the graft. It was postulated that the acute and local elevation of cAMP was responsible for the production of neurotrophic factors and modulation of the CNS environment that could not be achieved by the daily PDE4 inhibition [35].
To circumvent the emetic side effects, subtype-specific PDE4 inhibition has shown already promising results. It was shown that PDE4B KO mice had increased white matter sparing and higher levels of oligodendrocytes 42 dpi in a contusion model T9 [39]. However, PDE4B is mainly involved in regulating inflammatory processes. Consequently, the increase in oligodendrocyte sparing can potentially be attributed to decreased neuroinflammation and hence an improved oligodendrocyte sparing and recovery. PDE4D is highly expressed in oligodendrocytes, and pan PDE4 with 1 µM of roflumilast and PDE4D inhibition with 0.5 or 1 µM of GEBR32a, but not PDE4B inhibition with 1 µM of A33, was shown to increase OPC maturation in vitro [41].
PDE7 inhibition with 10 mg/kg VP3.15 could also increase OPC differentiation after 15 days of treatment in Theiler’s murine encephalitis virus-induced demyelinating disease [45]. However, the numbers of OPCs were not increased, indicating that PDE7 inhibition potentially does not induce OPC proliferation but rather stimulates oligodendrocyte recovery. Additionally, PDE7 inhibition in an EAE mouse model of MS showed decreased demyelination, indicating a neuroprotective effect, either direct or indirect by immune modulation, of PDE7 inhibition [56]. These results suggest the promising role of PDE7 inhibition in oligodendrocyte survival, therefore providing prolonged survival of oligodendrocytes in SCI, but this remains to be elucidated.

3.3. Astrocytes

Cytokines released from astrocytes can skew phagocyte polarization and hence influence the inflammatory environment [81]. cAMP levels have proved to be an important regulator of the homeostatic functions of astrocytes since an elevation in cAMP causes an upregulation of genes involved in homeostatic control, metabolic function, and antioxidant mechanisms [82]. Embryonic implanted tissue in the SCI lesions of rats was used to assess the role of PDE4 inhibition on astrocyte activation in the lesion site. S.c. administration of 0.4 µmol/kg rolipram in SCI was demonstrated to reduce astrogliosis in embryonic implanted tissue in the SCI lesion site and surrounding spinal cord tissue, indicating reduced astrocyte activity after SCI upon PDE4 inhibition [70].
PDE7 inhibition reduced astrocyte nitrite, TNF-α, and COX-2 production following LPS stimulation in vitro, and this downregulation of pro-inflammatory cytokines was mediated by the PKA pathway [83]. The astrocyte inhibitory effect of PDE7 in vitro reveals a promising implication of PDE7 inhibition to impede astrocyte activation in SCI. However, in vivo research is demanded to reveal the role of PDE7 inhibition in SCI.
In addition to the inflammatory contribution of astrocytes in SCI, astrocytes exhibit protective properties following SCI by sealing the injury starting 1 dpi to prevent the spread of tissue damage [84][85]. This protective role of astrocytes is further demonstrated since complete ablation results in increased immune cell infiltration and activation, neuronal degeneration, and demyelination, leading to reduced functional recovery in rodents [86]. Although protective, astrocytes adopt a scar-forming phenotype and produce chondroitin sulfate proteoglycans, which are the main inhibitors of OPC growth and differentiation, neuronal outgrowth, and in general, regeneration [84][85][87]. The produced CSPs trigger growth cone collapse mediated through the RhoA/ROCK pathway [88]. Elevating cAMP levels can potentially reduce the glial scar in later phases of SCI since their elevation in astrocytes reduces gene expression for the production of glial scar products, including CSPs [89]. Although little is known about the interaction of PDE inhibition and CSPG, the elevation of cAMP’s downstream molecule EPAC increases neurite outgrowth in postnatal rat cortical neurons in vitro. EPAC agonists were shown to reduce astrocyte activation in vitro during LPS incubation and elongated astrocytes at the lesion border, which guided axonal outgrowth. EPAC agonists overcame CSPG inhibition of neuronal growth in an ex vivo model of SCI [90]. Nevertheless, current evidence indicated that PDE4 inhibition alone was not able to lower CSP production or induce CSP breakdown in an in vivo model of contusive SCI in rats [71]. Both neuroinflammation and neuroregeneration in the spinal cord are predominantly visualized using immunofluorescence.

References

  1. Oldenburger, A.; Roscioni, S.S.; Jansen, E.; Menzen, M.H.; Halayko, A.J.; Timens, W.; Meurs, H.; Maarsingh, H.; Schmidt, M. Anti-inflammatory role of the cAMP effectors Epac and PKA: Implications in chronic obstructive pulmonary disease. PLoS ONE 2012, 7, e31574.
  2. Flack, J.A.; Sharma, K.D.; Xie, J.Y. Delving into the recent advancements of spinal cord injury treatment: A review of recent progress. Neural Regen. Res. 2022, 17, 283–291.
  3. Barletta, K.E.; Ley, K.; Mehrad, B. Regulation of neutrophil function by adenosine. Arter. Thromb. Vasc. Biol. 2012, 32, 856–864.
  4. Eby, J.C.; Gray, M.C.; Hewlett, E.L. Cyclic AMP-mediated suppression of neutrophil extracellular trap formation and apoptosis by the Bordetella pertussis adenylate cyclase toxin. Infect. Immun. 2014, 82, 5256–5269.
  5. Wang, Z.; Wei, X.; Ji, C.; Yu, W.; Song, C.; Wang, C. PGE2 inhibits neutrophil phagocytosis through the EP2R-cAMP-PTEN pathway. Immun. Inflamm. Dis. 2022, 10, e662.
  6. Bao, F.; Fleming, J.C.; Golshani, R.; Pearse, D.D.; Kasabov, L.; Brown, A.; Weaver, L.C. A selective phosphodiesterase-4 inhibitor reduces leukocyte infiltration, oxidative processes, and tissue damage after spinal cord injury. J. Neurotrauma 2011, 28, 1035–1049.
  7. Hertz, A.L.; Bender, A.T.; Smith, K.C.; Gilchrist, M.; Amieux, P.S.; Aderem, A.; Beavo, J.A. Elevated cyclic AMP and PDE4 inhibition induce chemokine expression in human monocyte-derived macrophages. Proc. Natl. Acad. Sci. USA 2009, 106, 21978–21983.
  8. Bryn, T.; Mahic, M.; Enserink, J.M.; Schwede, F.; Aandahl, E.M.; Tasken, K. The cyclic AMP-Epac1-Rap1 pathway is dissociated from regulation of effector functions in monocytes but acquires immunoregulatory function in mature macrophages. J. Immunol. 2006, 176, 7361–7370.
  9. Wilson, N.M.; Gurney, M.E.; Dietrich, W.D.; Atkins, C.M. Therapeutic benefits of phosphodiesterase 4B inhibition after traumatic brain injury. PLoS ONE 2017, 12, e0178013.
  10. Ariga, M.; Neitzert, B.; Nakae, S.; Mottin, G.; Bertrand, C.; Pruniaux, M.P.; Jin, S.L.; Conti, M. Nonredundant function of phosphodiesterases 4D and 4B in neutrophil recruitment to the site of inflammation. J. Immunol. 2004, 173, 7531–7538.
  11. Gane, J.; Stockley, R. Mechanisms of neutrophil transmigration across the vascular endothelium in COPD. Thorax 2012, 67, 553–561.
  12. Jones, N.A.; Boswell-Smith, V.; Lever, R.; Page, C.P. The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro. Pulm. Pharmacol. Ther. 2005, 18, 93–101.
  13. Ernens, I.; Rouy, D.; Velot, E.; Devaux, Y.; Wagner, D.R. Adenosine inhibits matrix metalloproteinase-9 secretion by neutrophils: Implication of A2a receptor and cAMP/PKA/Ca2+ pathway. Circ. Res. 2006, 99, 590–597.
  14. Jones, N.A.; Leport, M.; Holand, T.; Vos, T.; Morgan, M.; Fink, M.; Pruniaux, M.P.; Berthelier, C.; O’Connor, B.J.; Bertrand, C.; et al. Phosphodiesterase (PDE) 7 in inflammatory cells from patients with asthma and COPD. Pulm. Pharmacol. Ther 2007, 20, 60–68.
  15. Paterniti, I.; Mazzon, E.; Gil, C.; Impellizzeri, D.; Palomo, V.; Redondo, M.; Perez, D.I.; Esposito, E.; Martinez, A.; Cuzzocrea, S. PDE 7 inhibitors: New potential drugs for the therapy of spinal cord injury. PLoS ONE 2011, 6, e15937.
  16. Brennan, F.H.; Li, Y.; Wang, C.; Ma, A.; Guo, Q.; Li, Y.; Pukos, N.; Campbell, W.A.; Witcher, K.G.; Guan, Z.; et al. Microglia coordinate cellular interactions during spinal cord repair in mice. Nat. Commun. 2022, 13, 4096.
  17. Zhou, X.; He, X.; Ren, Y. Function of microglia and macrophages in secondary damage after spinal cord injury. Neural Regen. Res. 2014, 9, 1787–1795.
  18. Xu, L.; Wang, J.; Ding, Y.; Wang, L.; Zhu, Y.J. Current Knowledge of Microglia in Traumatic Spinal Cord Injury. Front. Neurol. 2021, 12, 796704.
  19. David, S.; Greenhalgh, A.D.; Kroner, A. Macrophage and microglial plasticity in the injured spinal cord. Neuroscience 2015, 307, 311–318.
  20. Busch, S.A.; Horn, K.P.; Silver, D.J.; Silver, J. Overcoming macrophage-mediated axonal dieback following CNS injury. J. Neurosci. 2009, 29, 9967–9976.
  21. Evans, T.A.; Barkauskas, D.S.; Myers, J.T.; Hare, E.G.; You, J.Q.; Ransohoff, R.M.; Huang, A.Y.; Silver, J. High-resolution intravital imaging reveals that blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury. Exp. Neurol. 2014, 254, 109–120.
  22. Bellver-Landete, V.; Bretheau, F.; Mailhot, B.; Vallieres, N.; Lessard, M.; Janelle, M.E.; Vernoux, N.; Tremblay, M.E.; Fuehrmann, T.; Shoichet, M.S.; et al. Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nat. Commun. 2019, 10, 518.
  23. Fu, H.; Zhao, Y.; Hu, D.; Wang, S.; Yu, T.; Zhang, L. Depletion of microglia exacerbates injury and impairs function recovery after spinal cord injury in mice. Cell Death Dis. 2020, 11, 528.
  24. Ryan, C.B.; Choi, J.S.; Al-Ali, H.; Lee, J.K. Myelin and non-myelin debris contribute to foamy macrophage formation after spinal cord injury. NeuroBiol. Dis. 2022, 163, 105608.
  25. Van Broeckhoven, J.; Sommer, D.; Dooley, D.; Hendrix, S.; Franssen, A. Macrophage phagocytosis after spinal cord injury: When friends become foes. Brain 2021, 144, 2933–2945.
  26. Guo, Y.; Zhang, P.; Zhao, H.; Xu, C.; Lin, S.; Mei, X.; Tian, H. Melatonin promotes microglia toward anti-inflammatory phenotype after spinal cord injury. Int. Immunopharmacol. 2023, 114, 109599.
  27. Papa, S.; Caron, I.; Erba, E.; Panini, N.; De Paola, M.; Mariani, A.; Colombo, C.; Ferrari, R.; Pozzer, D.; Zanier, E.R.; et al. Early modulation of pro-inflammatory microglia by minocycline loaded nanoparticles confers long lasting protection after spinal cord injury. Biomaterials 2016, 75, 13–24.
  28. Schaal, S.M.; Garg, M.S.; Ghosh, M.; Lovera, L.; Lopez, M.; Patel, M.; Louro, J.; Patel, S.; Tuesta, L.; Chan, W.M.; et al. The therapeutic profile of rolipram, PDE target and mechanism of action as a neuroprotectant following spinal cord injury. PLoS ONE 2012, 7, e43634.
  29. Kim, E.J.; Kwon, K.J.; Park, J.Y.; Lee, S.H.; Moon, C.H.; Baik, E.J. Neuroprotective effects of prostaglandin E2 or cAMP against microglial and neuronal free radical mediated toxicity associated with inflammation. J. Neurosci. Res. 2002, 70, 97–107.
  30. Pearse, D.D.; Hughes, Z.A. PDE4B as a microglia target to reduce neuroinflammation. Glia 2016, 64, 1698–1709.
  31. Negreiros-Lima, G.L.; Lima, K.M.; Moreira, I.Z.; Jardim, B.L.O.; Vago, J.P.; Galvao, I.; Teixeira, L.C.R.; Pinho, V.; Teixeira, M.M.; Sugimoto, M.A.; et al. Cyclic AMP Regulates Key Features of Macrophages via PKA: Recruitment, Reprogramming and Efferocytosis. Cells 2020, 9, 128.
  32. Luan, B.; Yoon, Y.S.; Le Lay, J.; Kaestner, K.H.; Hedrick, S.; Montminy, M. CREB pathway links PGE2 signaling with macrophage polarization. Proc. Natl. Acad. Sci. USA 2015, 112, 15642–15647.
  33. Zou, Z.Q.; Chen, J.J.; Feng, H.F.; Cheng, Y.F.; Wang, H.T.; Zhou, Z.Z.; Guo, H.B.; Zheng, W.; Xu, J.P. Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of the cAMP/PKA/CREB Signaling Pathway and NF-kappaB Inhibition. J. Pharmacol. Exp. Ther. 2017, 362, 67–77.
  34. Ghosh, M.; Aguirre, V.; Wai, K.; Felfly, H.; Dietrich, W.D.; Pearse, D.D. The interplay between cyclic AMP, MAPK, and NF-kappaB pathways in response to proinflammatory signals in microglia. BioMed. Res. Int. 2015, 2015, 308461.
  35. Pearse, D.D.; Pereira, F.C.; Marcillo, A.E.; Bates, M.L.; Berrocal, Y.A.; Filbin, M.T.; Bunge, M.B. cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury. Nat. Med. 2004, 10, 610–616.
  36. Moradi, K.; Golbakhsh, M.; Haghighi, F.; Afshari, K.; Nikbakhsh, R.; Khavandi, M.M.; Faghani, S.; Badripour, A.; Etemadi, A.; Ashraf-Ganjouei, A.; et al. Inhibition of phosphodiesterase IV enzyme improves locomotor and sensory complications of spinal cord injury via altering microglial activity: Introduction of Roflumilast as an alternative therapy. Int. Immunopharmacol. 2020, 86, 106743.
  37. Yang, J.X.; Hsieh, K.C.; Chen, Y.L.; Lee, C.K.; Conti, M.; Chuang, T.H.; Wu, C.P.; Jin, S.C. Phosphodiesterase 4B negatively regulates endotoxin-activated interleukin-1 receptor antagonist responses in macrophages. Sci. Rep. 2017, 7, 46165.
  38. Ghosh, M.; Garcia-Castillo, D.; Aguirre, V.; Golshani, R.; Atkins, C.M.; Bramlett, H.M.; Dietrich, W.D.; Pearse, D.D. Proinflammatory cytokine regulation of cyclic AMP-phosphodiesterase 4 signaling in microglia in vitro and following CNS injury. Glia 2012, 60, 1839–1859.
  39. Myers, S.A.; Gobejishvili, L.; Saraswat Ohri, S.; Garrett Wilson, C.; Andres, K.R.; Riegler, A.S.; Donde, H.; Joshi-Barve, S.; Barve, S.; Whittemore, S.R. Following spinal cord injury, PDE4B drives an acute, local inflammatory response and a chronic, systemic response exacerbated by gut dysbiosis and endotoxemia. Neurobiol. Dis. 2019, 124, 353–363.
  40. Schepers, M.; Tiane, A.; Paes, D.; Sanchez, S.; Rombaut, B.; Piccart, E.; Rutten, B.P.F.; Brone, B.; Hellings, N.; Prickaerts, J.; et al. Targeting Phosphodiesterases-Towards a Tailor-Made Approach in Multiple Sclerosis Treatment. Front. Immunol. 2019, 10, 1727.
  41. Schepers, M.; Paes, D.; Tiane, A.; Rombaut, B.; Piccart, E.; van Veggel, L.; Gervois, P.; Wolfs, E.; Lambrichts, I.; Brullo, C.; et al. Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis. Brain Behav. Immun. 2023, 109, 1–22.
  42. Schade, I.; Roth-Eichhorn, S.; Kasper, M.; Kuss, H.; Plotze, K.; Funk, R.H.; Schuler, S. Benefit of phosphodiesterase 4 inhibitors as supplemental therapy after lung transplantation concerning their antiproliferative effects: An experimental study using a heterotopic rodent model. Transplantation 2002, 74, 326–334.
  43. Zhang, Y.; Chen, K.; Sloan, S.A.; Bennett, M.L.; Scholze, A.R.; O’Keeffe, S.; Phatnani, H.P.; Guarnieri, P.; Caneda, C.; Ruderisch, N.; et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 2014, 34, 11929–11947.
  44. Lucas, R.M.; Luo, L.; Stow, J.L. ERK1/2 in immune signalling. BioChem. Soc. Trans. 2022, 50, 1341–1352.
  45. Benitez-Fernandez, R.; Gil, C.; Guaza, C.; Mestre, L.; Martinez, A. The Dual PDE7-GSK3beta Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis. Int. J. Mol. Sci. 2022, 23, 14378.
  46. Morales-Garcia, J.A.; Redondo, M.; Alonso-Gil, S.; Gil, C.; Perez, C.; Martinez, A.; Santos, A.; Perez-Castillo, A. Phosphodiesterase 7 inhibition preserves dopaminergic neurons in cellular and rodent models of Parkinson disease. PLoS ONE 2011, 6, e17240.
  47. Blois, J.T.; Mataraza, J.M.; Mecklenbrauker, I.; Tarakhovsky, A.; Chiles, T.C. B cell receptor-induced cAMP-response element-binding protein activation in B lymphocytes requires novel protein kinase Cdelta. J. Biol. Chem. 2004, 279, 30123–30132.
  48. Raker, V.K.; Becker, C.; Steinbrink, K. The cAMP Pathway as Therapeutic Target in Autoimmune and Inflammatory Diseases. Front. Immunol. 2016, 7, 123.
  49. Kadoshima-Yamaoka, K.; Murakawa, M.; Goto, M.; Tanaka, Y.; Inoue, H.; Murafuji, H.; Hayashi, Y.; Nagahira, K.; Miura, K.; Nakatsuka, T.; et al. Effect of phosphodiesterase 7 inhibitor ASB16165 on development and function of cytotoxic T lymphocyte. Int. Immunopharmacol. 2009, 9, 97–102.
  50. Vang, T.; Torgersen, K.M.; Sundvold, V.; Saxena, M.; Levy, F.O.; Skalhegg, B.S.; Hansson, V.; Mustelin, T.; Tasken, K. Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. J. Exp. Med. 2001, 193, 497–507.
  51. Bopp, T.; Dehzad, N.; Reuter, S.; Klein, M.; Ullrich, N.; Stassen, M.; Schild, H.; Buhl, R.; Schmitt, E.; Taube, C. Inhibition of cAMP degradation improves regulatory T cell-mediated suppression. J. Immunol. 2009, 182, 4017–4024.
  52. Kim, S.Y.; An, T.J.; Rhee, C.K.; Park, C.K.; Kim, J.H.; Yoon, H. The effect and associated mechanism of action of phosphodiesterase 4 (PDE4) inhibitor on CD4+ lymphocyte proliferation. Clin. Exp. Pharmacol. Physiol. 2021, 48, 221–226.
  53. Peter, D.; Jin, S.L.; Conti, M.; Hatzelmann, A.; Zitt, C. Differential expression and function of phosphodiesterase 4 (PDE4) subtypes in human primary CD4+ T cells: Predominant role of PDE4D. J. Immunol. 2007, 178, 4820–4831.
  54. Arp, J.; Kirchhof, M.G.; Baroja, M.L.; Nazarian, S.H.; Chau, T.A.; Strathdee, C.A.; Ball, E.H.; Madrenas, J. Regulation of T-cell activation by phosphodiesterase 4B2 requires its dynamic redistribution during immunological synapse formation. Mol. Cell. Biol. 2003, 23, 8042–8057.
  55. Gonzalez-Garcia, C.; Bravo, B.; Ballester, A.; Gomez-Perez, R.; Eguiluz, C.; Redondo, M.; Martinez, A.; Gil, C.; Ballester, S. Comparative assessment of PDE 4 and 7 inhibitors as therapeutic agents in experimental autoimmune encephalomyelitis. Br. J. Pharmacol. 2013, 170, 602–613.
  56. Mestre, L.; Redondo, M.; Carrillo-Salinas, F.J.; Morales-Garcia, J.A.; Alonso-Gil, S.; Perez-Castillo, A.; Gil, C.; Martinez, A.; Guaza, C. PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis. Br. J. Pharmacol. 2015, 172, 4277–4290.
  57. Basole, C.P.; Nguyen, R.K.; Lamothe, K.; Billis, P.; Fujiwara, M.; Vang, A.G.; Clark, R.B.; Epstein, P.M.; Brocke, S. Treatment of Experimental Autoimmune Encephalomyelitis with an Inhibitor of Phosphodiesterase-8 (PDE8). Cells 2022, 11, 660.
  58. Vang, A.G.; Basole, C.; Dong, H.; Nguyen, R.K.; Housley, W.; Guernsey, L.; Adami, A.J.; Thrall, R.S.; Clark, R.B.; Epstein, P.M.; et al. Differential Expression and Function of PDE8 and PDE4 in Effector T cells: Implications for PDE8 as a Drug Target in Inflammation. Front. Pharmacol. 2016, 7, 259.
  59. Ahuja, C.S.; Nori, S.; Tetreault, L.; Wilson, J.; Kwon, B.; Harrop, J.; Choi, D.; Fehlings, M.G. Traumatic Spinal Cord Injury-Repair and Regeneration. Neurosurgery 2017, 80, S9–S22.
  60. Schmidt, S.I.; Blaabjerg, M.; Freude, K.; Meyer, M. RhoA Signaling in Neurodegenerative Diseases. Cells 2022, 11, 1520.
  61. Cai, D.; Qiu, J.; Cao, Z.; McAtee, M.; Bregman, B.S.; Filbin, M.T. Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate. J. Neurosci. 2001, 21, 4731–4739.
  62. Oishi, A.; Makita, N.; Sato, J.; Iiri, T. Regulation of RhoA signaling by the cAMP-dependent phosphorylation of RhoGDIalpha. J. Biol. Chem. 2012, 287, 38705–38715.
  63. Hannila, S.S.; Filbin, M.T. The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury. Exp. Neurol. 2008, 209, 321–332.
  64. Batty, N.J.; Fenrich, K.K.; Fouad, K. The role of cAMP and its downstream targets in neurite growth in the adult nervous system. Neurosci. Lett. 2017, 652, 56–63.
  65. Gao, Y.; Nikulina, E.; Mellado, W.; Filbin, M.T. Neurotrophins elevate cAMP to reach a threshold required to overcome inhibition by MAG through extracellular signal-regulated kinase-dependent inhibition of phosphodiesterase. J. Neurosci. 2003, 23, 11770–11777.
  66. Xu, B.; Xu, J.; Cai, N.; Li, M.; Liu, L.; Qin, Y.; Li, X.; Wang, H. Roflumilast prevents ischemic stroke-induced neuronal damage by restricting GSK3beta-mediated oxidative stress and IRE1alpha/TRAF2/JNK pathway. Free. Radic. Biol. Med. 2021, 163, 281–296.
  67. Wu, Q.; Qi, L.; Li, H.; Mao, L.; Yang, M.; Xie, R.; Yang, X.; Wang, J.; Zhang, Z.; Kong, J.; et al. Roflumilast Reduces Cerebral Inflammation in a Rat Model of Experimental Subarachnoid Hemorrhage. Inflammation 2017, 40, 1245–1253.
  68. Gomora-Garcia, J.C.; Geronimo-Olvera, C.; Perez-Martinez, X.; Massieu, L. IRE1alpha RIDD activity induced under ER stress drives neuronal death by the degradation of 14-3-3 theta mRNA in cortical neurons during glucose deprivation. Cell Death Discov. 2021, 7, 131.
  69. Saroj, P.; Bansal, Y.; Singh, R.; Akhtar, A.; Sodhi, R.K.; Bishnoi, M.; Sah, S.P.; Kuhad, A. Neuroprotective effects of roflumilast against quinolinic acid-induced rat model of Huntington’s disease through inhibition of NF-kappaB mediated neuroinflammatory markers and activation of cAMP/CREB/BDNF signaling pathway. Inflammopharmacology 2021, 29, 499–511.
  70. Nikulina, E.; Tidwell, J.L.; Dai, H.N.; Bregman, B.S.; Filbin, M.T. The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Proc. Natl. Acad. Sci. USA 2004, 101, 8786–8790.
  71. Yin, Y.; Sun, W.; Li, Z.; Zhang, B.; Cui, H.; Deng, L.; Xie, P.; Xiang, J.; Zou, J. Effects of combining methylprednisolone with rolipram on functional recovery in adult rats following spinal cord injury. Neurochem. Int. 2013, 62, 903–912.
  72. Hassannejad, Z.; Shakouri-Motlagh, A.; Mokhatab, M.; Zadegan, S.A.; Sharif-Alhoseini, M.; Shokraneh, F.; Rahimi-Movaghar, V. Oligodendrogliogenesis and Axon Remyelination after Traumatic Spinal Cord Injuries in Animal Studies: A Systematic Review. Neuroscience 2019, 402, 37–50.
  73. Almad, A.; Sahinkaya, F.R.; McTigue, D.M. Oligodendrocyte fate after spinal cord injury. Neurotherapeutics 2011, 8, 262–273.
  74. Syed, Y.A.; Baer, A.; Hofer, M.P.; Gonzalez, G.A.; Rundle, J.; Myrta, S.; Huang, J.K.; Zhao, C.; Rossner, M.J.; Trotter, M.W.; et al. Inhibition of phosphodiesterase-4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination. EMBO Mol. Med. 2013, 5, 1918–1934.
  75. Kanno, H.; Pearse, D.D.; Ozawa, H.; Itoi, E.; Bunge, M.B. Schwann cell transplantation for spinal cord injury repair: Its significant therapeutic potential and prospectus. Rev. Neurosci. 2015, 26, 121–128.
  76. Zhou, X.H.; Ning, G.Z.; Feng, S.Q.; Kong, X.H.; Chen, J.T.; Zheng, Y.F.; Ban, D.X.; Liu, T.; Li, H.; Wang, P. Transplantation of autologous activated Schwann cells in the treatment of spinal cord injury: Six cases, more than five years of follow-up. Cell Transpl. 2012, 21 (Suppl. S1), S39–S47.
  77. Gant, K.L.; Guest, J.D.; Palermo, A.E.; Vedantam, A.; Jimsheleishvili, G.; Bunge, M.B.; Brooks, A.E.; Anderson, K.D.; Thomas, C.K.; Santamaria, A.J.; et al. Phase 1 Safety Trial of Autologous Human Schwann Cell Transplantation in Chronic Spinal Cord Injury. J. Neurotrauma 2022, 39, 285–299.
  78. Whitaker, C.M.; Beaumont, E.; Wells, M.J.; Magnuson, D.S.; Hetman, M.; Onifer, S.M. Rolipram attenuates acute oligodendrocyte death in the adult rat ventrolateral funiculus following contusive cervical spinal cord injury. Neurosci. Lett. 2008, 438, 200–204.
  79. Beaumont, E.; Whitaker, C.M.; Burke, D.A.; Hetman, M.; Onifer, S.M. Effects of rolipram on adult rat oligodendrocytes and functional recovery after contusive cervical spinal cord injury. Neuroscience 2009, 163, 985–990.
  80. Schepers, M.; Malheiro, A.; Gamardo, A.S.; Hellings, N.; Prickaerts, J.; Moroni, L.; Vanmierlo, T.; Wieringa, P. Phosphodiesterase (PDE) 4 inhibition boosts Schwann cell myelination in a 3D regeneration model. Eur. J. Pharm. Sci. 2023, 185, 106441.
  81. Alizadeh, A.; Dyck, S.M.; Karimi-Abdolrezaee, S. Traumatic Spinal Cord Injury: An Overview of Pathophysiology, Models and Acute Injury Mechanisms. Front. Neurol. 2019, 10, 282.
  82. Zhou, Z.; Ikegaya, Y.; Koyama, R. The Astrocytic cAMP Pathway in Health and Disease. Int. J. Mol. Sci. 2019, 20, 779.
  83. Morales-Garcia, J.A.; Palomo, V.; Redondo, M.; Alonso-Gil, S.; Gil, C.; Martinez, A.; Perez-Castillo, A. Crosstalk between phosphodiesterase 7 and glycogen synthase kinase-3: Two relevant therapeutic targets for neurological disorders. ACS Chem. Neurosci. 2014, 5, 194–204.
  84. Okada, S.; Hara, M.; Kobayakawa, K.; Matsumoto, Y.; Nakashima, Y. Astrocyte reactivity and astrogliosis after spinal cord injury. Neurosci. Res. 2018, 126, 39–43.
  85. Li, X.; Li, M.; Tian, L.; Chen, J.; Liu, R.; Ning, B. Reactive Astrogliosis: Implications in Spinal Cord Injury Progression and Therapy. Oxidative Med. Cell. Longev. 2020, 2020, 9494352.
  86. Faulkner, J.R.; Herrmann, J.E.; Woo, M.J.; Tansey, K.E.; Doan, N.B.; Sofroniew, M.V. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J. Neurosci. 2004, 24, 2143–2155.
  87. Wang, Y.; Cheng, X.; He, Q.; Zheng, Y.; Kim, D.H.; Whittemore, S.R.; Cao, Q.L. Astrocytes from the contused spinal cord inhibit oligodendrocyte differentiation of adult oligodendrocyte precursor cells by increasing the expression of bone morphogenetic proteins. J. Neurosci. 2011, 31, 6053–6058.
  88. Forgione, N.; Fehlings, M.G. Rho-ROCK inhibition in the treatment of spinal cord injury. World Neurosurg. 2014, 82, e535–e539.
  89. Paco, S.; Hummel, M.; Pla, V.; Sumoy, L.; Aguado, F. Cyclic AMP signaling restricts activation and promotes maturation and antioxidant defenses in astrocytes. BMC Genom. 2016, 17, 304.
  90. Guijarro-Belmar, A.; Viskontas, M.; Wei, Y.; Bo, X.; Shewan, D.; Huang, W. Epac2 Elevation Reverses Inhibition by Chondroitin Sulfate Proteoglycans In Vitro and Transforms Postlesion Inhibitory Environment to Promote Axonal Outgrowth in an Ex Vivo Model of Spinal Cord Injury. J. Neurosci. 2019, 39, 8330–8346.
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