A phosphodiesterase inhibitor, cilomilast, enhances cAMP activity to restore conditioned odor preference memory after serotonergic depletion in the neonate rat

McLean, John H.; Smith, Andrew P.; Rogers, Stacey; Clarke, Kimberley; Darby‐King, Andrea; Harley, Carolyn W.

doi:10.1016/j.nlm.2009.02.003

Cited by 12 publications

(7 citation statements)

References 55 publications

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“…In our earlier work on the cAMP temporal profile associated with early odor preference learning we demonstrated a close link between the timing of a phasic profile of cAMP increases and associative memory (Cui et al 2007;McLean et al 2009). The maximal activation of ERK immediately following pairing of odor and b-adrenoceptor-stimulation is congruent with the phasic peak of cAMP at the same time point (Cui et al 2007).…”

Section: Temporal and Spatial Profiles Of Learning-associated Erk Actmentioning

confidence: 68%

Epac activation initiates associative odor preference memories in the rat pup

et al. 2015

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Here we examine the role of the exchange protein directly activated by cAMP (Epac) in b-adrenergic-dependent associative odor preference learning in rat pups. Bulbar Epac agonist (8-pCPT-2-O-Me-cAMP, or 8-pCPT) infusions, paired with odor, initiated preference learning, which was selective for the paired odor. Interestingly, pairing odor with Epac activation produced both short-term (STM) and long-term (LTM) odor preference memories. Training using b-adrenergic-activation paired with odor recruited rapid and transient ERK phosphorylation consistent with a role for Epac activation in normal learning. An ERK antagonist prevented intermediate-term memory (ITM) and LTM, but not STM. Epac agonist infusions induced ERK phosphorylation in the mitral cell layer, in the inner half of the dendritic external plexiform layer, in the glomeruli and, patchily, among granule cells. Increased CREB phosphorylation in the mitral and granule cell layers was also seen. Simultaneous blockade of both ERK and CREB pathways prevented any long-term b-adrenergic activated odor preference memory, while LTM deficits associated with blocking only one pathway were prevented by stronger b-adrenergic activation. These results suggest that Epac and PKA play parallel and independent, as well as likely synergistic, roles in creating cAMP-dependent associative memory in rat pups. They further implicate a novel ERK-independent pathway in the mediation of STM by Epac.

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Section: Temporal and Spatial Profiles Of Learning-associated Erk Actmentioning

confidence: 68%

Epac activation initiates associative odor preference memories in the rat pup

et al. 2015

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“…Proinflammatory cytokines exacerbate the pathology of neurodegenerative diseases and even deteriorate the processes of many brain injuries, such as traumatic brain injury and stroke. Selective PDE4 inhibitors, such as roflumilast, cilomilast, and apremilast, were reported to curb inflammatory responses both in vitro and in vivo (Buenestado et al, 2012;McLean et al, 2009). In the present study, we sought to investigate the anti-inflammatory effects of the novel PDE4 inhibitor FCPR03 both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of the cAMP/PKA/CREB Signaling Pathway and NF-κB Inhibition

Zou

Chen

Feng

et al. 2017

J Pharmacol Exp Ther

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Overactivation of microglia contributes to the induction of neuroinflammation, which is highly involved in the pathology of many neurodegenerative diseases. Phosphodiesterase 4 (PDE4) represents a promising therapeutic target for anti-inflammation; however, the dose-limiting side effects, such as nausea and emesis, have impeded their clinic application. FCPR03, a novel selective PDE4 inhibitor synthesized in our laboratory, shows little or no emetic potency; however, the anti-inflammatory activities of FCPR03 in vitro and in vivo and the molecular mechanisms are still not clearly understood. This study was undertaken to delineate the anti-inflammatory effects of FCPR03 both in vitro and in vivo and explore whether these effects are regulated by PDE4-mediated signaling pathway. BV-2 microglial cells stimulated by lipopolysaccharide (LPS) and mice injected i.p. with LPS were established as in vitro and in vivo models of inflammation. Our results showed that FCPR03 dose dependently suppressed the production of tumor necrosis factor , interleukin-1, and iinterleukin-6 in BV-2 microglial cells treated with LPS. The role of FCPR03 in the production of proinflammatory factors was reversed by pretreatment with protein kinase A (PKA) inhibitor H89. In addition, FCPR03 reduced the levels of proinflammatory factors in the hippocampus and cortex of mice injected with LPS. Our results further demonstrated that FCPR03 effectively increased the production of cAMP, promoted cAMP response element binding protein (CREB) phosphorylation, and inhibited nuclear factor B (NF-B) activation both in vitro and in vivo. Our findings suggest that FCPR03 inhibits the neuroinflammatory response through the activation of cAMP/PKA/CREB signaling pathway and NF-B inhibition.

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“…This effect was abolished by PKA inhibitors, suggesting the involvement of cAMP-dependent mechanisms (Rozas et al 2012). Serotonin depletion of olfactory bulb impaired conditioned odor preference, which was further restored by 5-HT 2A/2C agonists (Price et al 1998;Yuan et al 2003) or when cAMP levels were increased by adrenergic stimulation (Yuan et al 2000) or cilomilast, PDE inhibitor, in the neonate rats (McLean et al 2009).…”

Section: The Effects Of Serotonin On Intracellular Pathwaysmentioning

confidence: 93%

“…Multiple intracellular pathways are involved in neural plasticity, memory formation and sensitization by 5-HT. A large body of evidence in vertebrates and/or invertebrates indicates that serotonin influences memory through second messengers and effectors including cyclic adenosine monophosphate (cAMP) (Bevilaqua et al 1997;Perez-Garcia and Meneses 2008a;Lee et al 2009;McLean et al 2009), cyclic guanosine monophosphate (cGMP) (van Donkelaar et al 2008), PKC (Byrne and Kandel 1996;Barbas et al 2003), mitogen-activated protein kinases (MAPK) (Cammarota et al 2008;Carlini et al 2012) and glycogen synthase kinase 3 (GSK3) (Polter and Li 2010).…”

Section: The Effects Of Serotonin On Intracellular Pathwaysmentioning

confidence: 99%

The role of serotonin in memory: interactions with neurotransmitters and downstream signaling

et al. 2014

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Serotonin, or 5-hydroxytryptamine (5-HT), is found to be involved in many physiological or pathophysiological processes including cognitive function. Seven distinct receptors (5-HT1-7), each with several subpopulations, have been identified for serotonin, which are different in terms of localization and downstream signaling. Because of the development of selective agonists and antagonists for these receptors as well as transgenic animal models of cognitive disorders, our understanding of the role of serotonergic transmission in learning and memory has improved in recent years. A large body of evidence indicates the interplay between serotonergic transmission and other neurotransmitters including acetylcholine, dopamine, γ-aminobutyric acid (GABA) and glutamate, in the neurobiological control of learning and memory. In addition, there has been an alteration in the density of serotonergic receptors in aging and Alzheimer's disease, and serotonin modulators are found to alter the process of amyloidogenesis and exert cognitive-enhancing properties. Here, we discuss the serotonin-induced modulation of various systems involved in mnesic function including cholinergic, dopaminergic, GABAergic, glutamatergic transmissions as well as amyloidogenesis and intracellular pathways.

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A phosphodiesterase inhibitor, cilomilast, enhances cAMP activity to restore conditioned odor preference memory after serotonergic depletion in the neonate rat

Cited by 12 publications

References 55 publications

Epac activation initiates associative odor preference memories in the rat pup

Epac activation initiates associative odor preference memories in the rat pup

Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of the cAMP/PKA/CREB Signaling Pathway and NF-κB Inhibition

The role of serotonin in memory: interactions with neurotransmitters and downstream signaling

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