Publications by authors named "Cathrin Flauaus"

6 Publications

  • Page 1 of 1

Functional Coupling of Slack Channels and P2X3 Receptors Contributes to Neuropathic Pain Processing.

Int J Mol Sci 2021 Jan 2;22(1). Epub 2021 Jan 2.

Institut für Pharmakologie und Klinische Pharmazie, Goethe-Universität Frankfurt am Main, 60438 Frankfurt am Main, Hessen, Germany.

The sodium-activated potassium channel Slack (K1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (I) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing of neuropathic pain. However, mechanisms underlying the regulation of Slack activity in this context are poorly understood. Using whole-cell patch-clamp recordings we found that Slack-mediated I in sensory neurons of mice is reduced after peripheral nerve injury, thereby contributing to neuropathic pain hypersensitivity. Interestingly, Slack is closely associated with ATP-sensitive P2X3 receptors in a population of sensory neurons. In vitro experiments revealed that Slack-mediated I may be bidirectionally modulated in response to P2X3 activation. Moreover, mice lacking Slack show altered nocifensive responses to P2X3 stimulation. Our study identifies P2X3/Slack signaling as a mechanism contributing to hypersensitivity after peripheral nerve injury and proposes a potential novel strategy for treatment of neuropathic pain.
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http://dx.doi.org/10.3390/ijms22010405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795269PMC
January 2021

Design, Synthesis, and Structure-Activity Relationship Studies of Dual Inhibitors of Soluble Epoxide Hydrolase and 5-Lipoxygenase.

J Med Chem 2020 10 12;63(20):11498-11521. Epub 2020 Oct 12.

Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9 D-60438 Frankfurt a.M., Germany.

Inhibition of multiple enzymes of the arachidonic acid cascade leads to synergistic anti-inflammatory effects. Merging of 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) pharmacophores led to the discovery of a dual 5-LOX/sEH inhibitor, which was subsequently optimized in terms of potency toward both targets and metabolic stability. The optimized lead structure displayed cellular activity in human polymorphonuclear leukocytes, oral bioavailability, and target engagement in vivo and demonstrated profound anti-inflammatory and anti-fibrotic efficiency in a kidney injury model caused by unilateral ureteral obstruction in mice. These results pave the way for investigating the therapeutic potential of dual 5-LOX/sEH inhibitors in other inflammation- and fibrosis-related disease models.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00561DOI Listing
October 2020

Neuropathic and cAMP-induced pain behavior is ameliorated in mice lacking CNGB1.

Neuropharmacology 2020 07 6;171:108087. Epub 2020 Apr 6.

Institute of Pharmacology and Clinical Pharmacy, Goethe University, 60438, Frankfurt am Main, Germany.

Cyclic nucleotide-gated (CNG) channels, which are directly activated by cAMP and cGMP, have long been known to play a key role in retinal and olfactory signal transduction. Emerging evidence indicates that CNG channels are also involved in signaling pathways important for pain processing. Here, we found that the expression of the channel subunits CNGA2, CNGA3, CNGA4 and CNGB1 in dorsal root ganglia, and of CNGA2 in the spinal cord, is transiently altered after peripheral nerve injury in mice. Specifically, we show using in situ hybridization and quantitative real-time RT-PCR that CNG channels containing the CNGB1b subunit are localized to populations of sensory neurons and predominantly excitatory interneurons in the spinal dorsal horn. In CNGB1 knockout (CNGB1) mice, neuropathic pain behavior is considerably attenuated whereas inflammatory pain behavior is normal. Finally, we provide evidence to support CNGB1 as a downstream mediator of cAMP signaling in pain pathways. Altogether, our data suggest that CNGB1-positive CNG channels specifically contribute to neuropathic pain processing after peripheral nerve injury.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108087DOI Listing
July 2020

Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology.

J Med Chem 2018 07 22;61(13):5758-5764. Epub 2018 Jun 22.

Institute of Pharmaceutical Chemistry , Goethe University Frankfurt , Max-von-Laue-Straße 9 , D-60438 Frankfurt , Germany.

Multitarget design offers access to bioactive small molecules with potentially superior efficacy and safety. Particularly multifactorial chronic inflammatory diseases demand multiple pharmacological interventions for stable treatment. By minor structural changes, we have developed a close analogue of the cysteinyl-leukotriene receptor antagonist zafirlukast that simultaneously inhibits soluble epoxide hydrolase and activates peroxisome proliferator-activated receptor γ. The triple modulator exhibits robust anti-inflammatory activity in vivo and highlights the therapeutic potential of designed multitarget agents.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00458DOI Listing
July 2018

K3.1 channels modulate the processing of noxious chemical stimuli in mice.

Neuropharmacology 2017 Oct 18;125:386-395. Epub 2017 Aug 18.

Pharmakologisches Institut für Naturwissenschaftler, Goethe-Universität, Fachbereich Biochemie, Chemie und Pharmazie, 60438 Frankfurt am Main, Germany; Institut für Pharmakologie und Toxikologie, Universität Witten/Herdecke, ZBAF, 58453 Witten, Germany.

Intermediate conductance calcium-activated potassium channels (K3.1) have been recently implicated in pain processing. However, the functional role and localization of K3.1 in the nociceptive system are largely unknown. We here characterized the behavior of mice lacking K3.1 (K3.1) in various pain models and analyzed the expression pattern of K3.1 in dorsal root ganglia (DRG) and the spinal cord. K3.1 mice demonstrated normal behavioral responses in models of acute nociceptive, persistent inflammatory, and persistent neuropathic pain. However, their behavioral responses to noxious chemical stimuli such as formalin and capsaicin were increased. Accordingly, formalin-induced nociceptive behavior was increased in wild-type mice after administration of the K3.1 inhibitor TRAM-34. In situ hybridization experiments detected K3.1 in most DRG satellite glial cells, in a minority of DRG neurons, and in ependymal cells lining the central canal of the spinal cord. Together, our data point to a specific inhibitory role of K3.1 for the processing of noxious chemical stimuli.
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http://dx.doi.org/10.1016/j.neuropharm.2017.08.021DOI Listing
October 2017

Rab7-a novel redox target that modulates inflammatory pain processing.

Pain 2017 07;158(7):1354-1365

Institute of Pharmacology, College of Pharmacy, Goethe University, Frankfurt am Main, Germany.

Chronic pain is accompanied by production of reactive oxygen species (ROS) in various cells that are important for nociceptive processing. Recent data indicate that ROS can trigger specific redox-dependent signaling processes, but the molecular targets of ROS signaling in the nociceptive system remain largely elusive. Here, we performed a proteome screen for pain-dependent redox regulation using an OxICAT approach, thereby identifying the small GTPase Rab7 as a redox-modified target during inflammatory pain in mice. Prevention of Rab7 oxidation by replacement of the redox-sensing thiols modulates its GTPase activity. Immunofluorescence studies revealed Rab7 expression to be enriched in central terminals of sensory neurons. Knockout mice lacking Rab7 in sensory neurons showed normal responses to noxious thermal and mechanical stimuli; however, their pain behavior during inflammatory pain and in response to ROS donors was reduced. The data suggest that redox-dependent changes in Rab7 activity modulate inflammatory pain sensitivity.
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http://dx.doi.org/10.1097/j.pain.0000000000000920DOI Listing
July 2017
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