FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects

Guo, Haibiao; Cheng, Yufang; Wang, Canmao; Wu, Jingang; Zou, Zhengqiang; Niu, Bo; Yu, Hui; Wang, Haitao; Xu, Jiang

doi:10.1016/j.neuropharm.2017.01.004

Cited by 108 publications

(84 citation statements)

References 49 publications

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“…The most important posttranscriptional modification is the phosphorylation of the amino acid residue Ser133 in the KID domain (Guo et al, 2017). This domain contains multiple phosphorylation sites for many canonical signaling pathways, such as Ras/Raf/MAPK/p90RSK, Ca 2+ /CaMK, PI3K/Akt/GSK3β, and cAMP/PKA pathways (Tang et al, 2014; Cheng et al, 2016; Xi et al, 2016; Zeng et al, 2016; Heckman et al, 2018), which, upon activation, lead to CREB’s antagonistic effects ( Figure 1 ).…”

Section: Molecular Structure Of Crebmentioning

confidence: 99%

“…Cells treated with phosphodiesterase inhibitors will also prevent the degradation and increase of the endogenous level of cAMP (Guo et al, 2017). The activated PKA enters into the nucleus and promotes the binding of phosphorylated CREB to a CRE region (5′-TGACGTCA-3′).…”

Section: Molecular Structure Of Crebmentioning

confidence: 99%

“…On the contrary, the expression of BDNF is regulated by CREB (Tao et al, 1998). The PKA enhances the phosphorylation of CREB at Ser133, which leads to the nuclear localization and activation of CREB (Guo et al, 2017). The promoter region of BDNF contains CRE; activated CREB binds to CRE and promotes the transcription of BDNF (Tao et al, 1998).…”

Section: Molecular Structure Of Crebmentioning

confidence: 99%

“…The promoter region of BDNF contains CRE; activated CREB binds to CRE and promotes the transcription of BDNF (Tao et al, 1998). Upregulation of BDNF mRNA expression is parallel to increased phosphorylated CREB expression (Guo et al, 2017), and inhibition of PKA/CREB pathway attenuates the level of BDNF in neurons (Xue et al, 2016). …”

Section: Molecular Structure Of Crebmentioning

confidence: 99%

“…However, increasing CREB function in the CA1 region of dorsal hippocampus rescued the spatial memory deficits (Yiu et al, 2011). In recent experiments, it has been demonstrated that CREB represents an important target for drug development in the therapy of AD (Guo et al, 2017). …”

Section: Molecular Structure Of Crebmentioning

confidence: 99%

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cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia

Wang

Lazarovici

et al. 2018

Front. Mol. Neurosci.

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Dopamine is a brain neurotransmitter involved in the pathology of schizophrenia. The dopamine hypothesis states that, in schizophrenia, dopaminergic signal transduction is hyperactive. The cAMP-response element binding protein (CREB) is an intracellular protein that regulates the expression of genes that are important in dopaminergic neurons. Dopamine affects the phosphorylation of CREB via G protein-coupled receptors. Neurotrophins, such as brain derived growth factor (BDNF), are critical regulators during neurodevelopment and synaptic plasticity. The CREB is one of the major regulators of neurotrophin responses since phosphorylated CREB binds to a specific sequence in the promoter of BDNF and regulates its transcription. Moreover, susceptibility genes associated with schizophrenia also target and stimulate the activity of CREB. Abnormalities of CREB expression is observed in the brain of individuals suffering from schizophrenia, and two variants (-933T to C and -413G to A) were found only in schizophrenic patients. The CREB was also involved in the therapy of animal models of schizophrenia. Collectively, these findings suggest a link between CREB and the pathophysiology of schizophrenia. This review provides an overview of CREB structure, expression, and biological functions in the brain and its interaction with dopamine signaling, neurotrophins, and susceptibility genes for schizophrenia. Animal models in which CREB function is modulated, by either overexpression of the protein or knocked down through gene deletion/mutation, implicating CREB in schizophrenia and antipsychotic drugs efficacy are also discussed. Targeting research and drug development on CREB could potentially accelerate the development of novel medications against schizophrenia.

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Section: Molecular Structure Of Crebmentioning

confidence: 99%

Section: Molecular Structure Of Crebmentioning

confidence: 99%

Section: Molecular Structure Of Crebmentioning

confidence: 99%

Section: Molecular Structure Of Crebmentioning

confidence: 99%

Section: Molecular Structure Of Crebmentioning

confidence: 99%

See 3 more Smart Citations

cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia

Wang

Lazarovici

et al. 2018

Front. Mol. Neurosci.

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316

204

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Vinpocetine amended prenatal valproic acid induced features of ASD possibly by altering markers of neuronal function, inflammation, and oxidative stress

Luhach

Kulkarni²,

Singh

et al. 2021

Autism Research

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology and phenotypes. Phosphodiesterase-1 (PDE1) inhibitors are known to provide benefits in various brain conditions manifesting similar behavioral phenotypes. The pharmacological consequences of vinpocetine administration a PDE1 inhibitor in prenatal-valproic acid (pre-VPA) induced ASD related behavioral phenotypes (social behavior deficits, repetitive behavior, anxiety, hyperlocomotion, and nociception) was assessed. Also, effects on important biochemical markers of neuronal function (DCX-neurogenesis, BDNF-neuronal survival, synapsin-IIa-synaptic transmission, pCREB-neuronal transcription factor), inflammation (interleukin [IL]-6, IL-10, and TNF-α) and oxidative stress (thiobarbituric acid reactive substance [TBARS] and glutathione (GSH) were studied in important brain areas (frontal cortex, cerebral cortex, hippocampus, and striatum). Further, neuronal cell viability was determined in dentate gyrus using Nissl staining. Pre-VPA administration resulted into impaired behavior, brain biochemistry, and neuronal cell viability. Administration of vinpocetine resulted in improvements of pre-VPA impaired social behavior, repetitive behavior, anxiety, locomotion, and nociception. Also, vinpocetine resulted in a significant increase in the levels of BDNF, synapsin-IIa, DCX, pCREB/CREB, IL-10, and GSH along with significant decrease in TNF-α, IL-6, TBARS, number of pyknotic and chromatolytic cells in different brain areas of pre-VPA group. Finally, high association between behavioral parameters and biochemical parameters was observed upon Pearson's correlation analysis. Vinpocetine, a PDE1 inhibitor rectified important behavioral phenotypes related with ASD, possibly by improving neuronal function, brain inflammation and brain oxidative stress. Thus, PDE1 may be a possible target for further understanding ASD. Lay SummaryASD is a brain developmental disorder with a wide array of genetic and environmental factors. Many targets have been identified till date, but a clinical treatment is still afar. The results of this study indicate that vinpocetine administration resulted in amelioration of ASD associated symptomatology in rats, prenatally exposed to VPA. Our research adds a widely expressed brain enzyme PDE1, as a possible novel pharmacological target and opens-up a new line of enquiry for ASD treatment.

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Pivotal role of cAMP‐PKA‐CREB signaling pathway in manganese‐induced neurotoxicity in PC12 cells

Yang

Ma²,

Wei

et al. 2019

Environmental Toxicology

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Manganese (Mn) plays a critical role in individual growth and development, yet excessive exposure can result in neurotoxicity, especially cognitive impairment. Neuronal apoptosis is considered as one of the mechanisms of Mn‐induced neurotoxicity. Recent evidence suggests that cAMP‐PKA‐CREB signaling regulates apoptosis and is associated with cognitive function. However, whether this pathway participates in Mn‐induced neurotoxicity is not completely understood. To fill this gap, in vitro cultures of PC12 cells were exposed to 0, 400, 500, and 600 μmol/L Mn for 24 hours, respectively. Another group of cells were pretreated with 10.0 μmol/L rolipram (a phosphodiesterase‐4 [PDE4] inhibitor) for 1 hour followed by 500 μmol/L Mn exposure for 24 hours. Flow cytometry, immunofluorescence staining, enzyme‐linked immunosorbent assay, and Western blot analysis were used to detect the apoptosis rate, protein levels of PDE4, cAMP signaling, and apoptosis‐associated proteins, respectively. We found that Mn exposure significantly inhibited cAMP signaling and protein expression of Bcl‐2, while increasing apoptosis rate, protein levels of PDE4, Bax, activated caspase‐3, and activated caspase‐8 in PC12 cells. Pretreatment of rolipram ameliorated Mn‐induced deficits in cAMP signaling and apoptosis. These findings demonstrate that cAMP‐PKA‐CREB signaling pathway‐induced apoptosis is involved in Mn‐induced neurotoxicity.

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FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects

Cited by 108 publications

References 49 publications

cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia

cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia

Vinpocetine amended prenatal valproic acid induced features of ASD possibly by altering markers of neuronal function, inflammation, and oxidative stress

Pivotal role of cAMP‐PKA‐CREB signaling pathway in manganese‐induced neurotoxicity in PC12 cells

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