Phosphodiesterase-7 inhibition affects accumbal and hypothalamic thyrotropin-releasing hormone expression, feeding and anxiety behavior of rats

Valdés-Moreno, Mariana Isabel; Alcántara-Alonso, Viridiana; Estrada‐Camarena, Erika; Mengod, Guadalupe; Amaya, M.I.; Matamoros-Trejo, Gilberto; Gortari, Patricia de

doi:10.1016/j.bbr.2016.11.027

Cited by 14 publications

(9 citation statements)

References 68 publications

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“…Among these genes, Pde7 encodes phosphodiesterase-7, known for its regulation of T-cell function and association with regulation of immune response, and its inhibitors may help patients with immunological and neuro-inflammatory disorders (51). In rodents, inhibition of Pde7 regulates anxiety behaviors, mediated by increasing levels of hypothalamic thyrotropin-releasing hormone (52). Notably, a dual Pde7 and GSK-3β inhibitor significantly improves episodic and spatial memory and enhances fear memory, as well as facilitating paired-pulse inhibition and latent inhibition, both behaviors that have been found to be impaired in psychosis, suggesting that inhibition of Pde7 and GSK-3β enhances cognition (53).…”

Section: Discussionmentioning

confidence: 99%

Dynamic Patterns of Threat-Associated Gene Expression in the Amygdala and Blood

et al. 2019

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Stress and trauma profoundly influence psychiatric biobehavioral outcomes. The identification of treatment and biomarker targets would be accelerated by a broad understanding of the biological responses to these events. The goal of this study was to determine genes responsive to auditory fear conditioning (FC), a well-characterized amygdala-dependent rodent model of threat-exposure, in the presence or absence of prior stress history, providing insight into the physiological processes underlying response to trauma. RNA-sequencing was performed in blood and amygdala from mice that underwent fear conditioning with (Immo+FC) and without (FC) prior immobilization stress, a paradigm that induces HPA axis, and behavioral stress sensitization. In the amygdala, 607 genes were regulated by FC vs. home-cage (HC) controls, and 516 genes differed in stress-sensitized mice (Immo+FC vs. FC). In the former, we observed an enhancement of specific biological processes involved in learning and synaptic transmission, and in the latter processes associated with cell proliferation and the cellular response to drugs. In the blood of stress-sensitized animals, 468 genes were dynamically regulated when compared to FC, and were enriched for the biological pathways of inflammation and cytokine signaling. This study identified genes and pathways that respond to threat in the amygdala and blood of mice with and without a prior stress history and reveals the impact of stress history on subsequent inflammation. Future studies will be needed to examine the role of these dynamically regulated genes may play in human clinical stress and trauma-related disorders.

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Section: Discussionmentioning

confidence: 99%

Dynamic Patterns of Threat-Associated Gene Expression in the Amygdala and Blood

et al. 2019

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“…Notably, the rescued neurodegenerative disorders were observed in the high-dose BRL-50481-treated group, including prevention of neurodegeneration, improvement in learning and memory, reduction of apoptosis in the hippocampus, restoration of cAMP, and activation of the cAMP/CREB signaling pathway. In agreement with the neuroprotective function of PDE7 inhibitors, Valdes-Moreno et al found that PDE7 inhibitors improved feeding and anxiety behaviors of rats through increasing the accumbal and hypothalamic thyrotropin-releasing hormone expression . Medina-Rodriguez et al revealed that PDE7 inhibitor treatment could accelerate human oligodendrocyte precursor differentiation and survival .…”

Section: Resultsmentioning

confidence: 80%

“…Sevoflurane is a commonly used volatile anesthetic agent due to it exhibiting rapid induction, fast recovery, and less irritation to the airway. , However, accumulative research and clinical data have demonstrated that neonatal administration of sevoflurane may cause widespread neurological disorders. − , Recently, PDE-7 inhibitors have emerged as promising candidates for promoting neuron survival, improving cognitive symptoms, and treating memory deficits. ,− However, little is known about whether PDE-7 inhibitors can attenuate sevoflurane-induced neurodegenerative disorders. Here, we utilized a PDE-7 specific inhibitor, BRL-50481, to demonstrate the preventive effect of PDE-7 inhibitors on sevoflurane-induced neurodegeneration and long-term memory deficits.…”

Section: Resultsmentioning

confidence: 99%

“…The phosphodiesterase 7 (PDE-7) is a cAMP-specific metallophosphohydrolase enzyme, which suppresses the cAMP/CREB signaling pathway though catalyzing cAMP to the inactive form 5′AMP. ,, Accumulating evidence have showed that PDE-7 inhibitors emerge as promising candidates for promoting neuron survival, improving cognitive symptoms, and treating memory deficits. − BRL-50481 is a PDE-7 specific inhibitor, which can decrease animals’ anxiety levels, promote oligodendrocyte precursor differentiation, inhibit neuroinflammation, and protect against spinal cord injury. ,,, However, the roles of BRL-50481 on sevoflurane-induced neurodegenerative disorders remain unknown. In the present study, we demonstrated the neuroprotective effects of PDE7 inhibitor, BRL-50481, against sevoflurane-induced neurodegeneration and long-term memory deficits.…”

Section: Introductionmentioning

confidence: 99%

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PDE-7 Inhibitor BRL-50481 Reduces Neurodegeneration and Long-Term Memory Deficits in Mice Following Sevoflurane Exposure

Chen

Zhong

et al. 2020

ACS Chem. Neurosci.

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Sevoflurane, one of the most commonly used anesthetic agents, has been demonstrated to induce widespread neurodegeneration in the developing brain. We aimed to evaluate the protective effects of a PDE-7 inhibitor (BRL-50481) against the neurotoxic effects of sevoflurane on the developing nervous system. Spatial learning and memory in sevoflurane-treated mice were examined using the Morris water maze test, and neuroprotective effects of PDE-7 inhibitor (BRL-50481) against sevofluraneinduced impairments were evaluated. Our results showed that sevoflurane treatment markedly induced neurodegeneration and impaired long-term memory in neonatal mice. Notably, BRL-50481 coadministration could significantly attenuate sevofluraneinduced learning and memory defects, prevent deterioration of recognition memory, and protect against neuron apoptosis. Mechanistically, BRL-50481 administration suppressed sevoflurane-induced neurodegenerative disorders through restoring cAMP and activating cAMP/CREB signaling in the hippocampus. PDE7 inhibitor may be a potential therapeutic agent for sevofluraneinduced neurodegeneration and long-term memory deficits.

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“…Focusing more globally on the most highly differentially expressed genes (DEGs) in P14 CB (fdr < 0.05, ≥ 1.5 absolute value of FC), up-regulated DEGs were enriched in gene ontology (GO) functional categories related to corticotropin response and transcriptional activation, mostly related to immediate early genes (IEGs), such as Fos , that mark activated neurons (Table 2; Table S3 ) . P14 down-regulated DEGs were not enriched in any functional categories, but included genes associated with AUTS2 -linked neurological disorders such as Hif3a (Zhang et al 2014b), Prodh , Hbegf and Fkbp5 (Yang et al 2015; de Koning et al 2015; Sasaki et al 2015; Valdés-Moreno et al 2017; Shao and Vawter 2008; Fani et al 2013; Menke et al 2013).…”

Section: Resultsmentioning

confidence: 99%

A Mouse Mutation That Dysregulates NeighboringGalnt17andAuts2Genes Is Associated with Phenotypes Related to the Human AUTS2 Syndrome

Weisner

Chen

Sun

et al. 2019

G3 Genes|Genomes|Genetics

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AUTS2 was originally discovered as the gene disrupted by a translocation in human twins with Autism spectrum disorder, intellectual disability, and epilepsy. Since that initial finding, AUTS2-linked mutations and variants have been associated with a very broad array of neuropsychiatric disorders, sugg esting that AUTS2 is required for fundamental steps of neurodevelopment. However, genotype-phenotype correlations in this region are complicated, because most mutations could also involve neighboring genes. Of particular interest is the nearest downstream neighbor of AUTS2, GALNT17, which encodes a brain-expressed N-acetylgalactosaminyltransferase of unknown brain function. Here we describe a mouse (Mus musculus) mutation, T(5G2;8A1)GSO (abbreviated 16Gso), a reciprocal translocation that breaks between Auts2 and Galnt17 and dysregulates both genes. Despite this complex regulatory effect, 16Gso homozygotes model certain human AUTS2-linked phenotypes very well. In addition to abnormalities in growth, craniofacial structure, learning and memory, and behavior, 16Gso homozygotes display distinct pathologies of the cerebellum and hippocampus that are similar to those associated with autism and other types of AUTS2-linked neurological disease. Analyzing mutant cerebellar and hippocampal transcriptomes to explain this pathology, we identified disturbances in pathways related to neuron and synapse maturation, neurotransmitter signaling, and cellular stress, suggesting possible cellular mechanisms. These pathways, coupled with the translocation’s selective effects on Auts2 isoforms and coordinated dysregulation of Galnt17, suggest novel hypotheses regarding the etiology of the human “AUTS2 syndrome” and the wide array of neurodevelopmental disorders linked to variance in this genomic region.

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Phosphodiesterase-7 inhibition affects accumbal and hypothalamic thyrotropin-releasing hormone expression, feeding and anxiety behavior of rats

Cited by 14 publications

References 68 publications

Dynamic Patterns of Threat-Associated Gene Expression in the Amygdala and Blood

Dynamic Patterns of Threat-Associated Gene Expression in the Amygdala and Blood

PDE-7 Inhibitor BRL-50481 Reduces Neurodegeneration and Long-Term Memory Deficits in Mice Following Sevoflurane Exposure

A Mouse Mutation That Dysregulates NeighboringGalnt17andAuts2Genes Is Associated with Phenotypes Related to the Human AUTS2 Syndrome

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