Publications by authors named "Sandra Heine"

9 Publications

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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

CNGA3: a target of spinal nitric oxide/cGMP signaling and modulator of inflammatory pain hypersensitivity.

J Neurosci 2011 Aug;31(31):11184-92

Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, 60590 Frankfurt am Main, Germany.

A large body of evidence indicates that nitric oxide (NO) and cGMP contribute to central sensitization of pain pathways during inflammatory pain. Here, we investigated the distribution of cyclic nucleotide-gated (CNG) channels in the spinal cord, and identified the CNG channel subunit CNGA3 as a putative cGMP target in nociceptive processing. In situ hybridization revealed that CNGA3 is localized to inhibitory neurons of the dorsal horn of the spinal cord, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. CNGA3 expression is upregulated in the superficial dorsal horn of the mouse spinal cord and in dorsal root ganglia following hindpaw inflammation evoked by zymosan. Mice lacking CNGA3 (CNGA3(-/-) mice) exhibited an increased nociceptive behavior in models of inflammatory pain, whereas their behavior in models of acute or neuropathic pain was normal. Moreover, CNGA3(-/-) mice developed an exaggerated pain hypersensitivity induced by intrathecal administration of cGMP analogs or NO donors. Our results provide evidence that CNGA3 contributes in an inhibitory manner to the central sensitization of pain pathways during inflammatory pain as a target of NO/cGMP signaling.
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http://dx.doi.org/10.1523/JNEUROSCI.6159-10.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6623383PMC
August 2011

cGMP produced by NO-sensitive guanylyl cyclase essentially contributes to inflammatory and neuropathic pain by using targets different from cGMP-dependent protein kinase I.

J Neurosci 2008 Aug;28(34):8568-76

Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, 60590 Frankfurt am Main, Germany.

A large body of evidence indicates that the release of nitric oxide (NO) is crucial for the central sensitization of pain pathways during both inflammatory and neuropathic pain. Here, we investigated the distribution of NO-sensitive guanylyl cyclase (NO-GC) in the spinal cord and in dorsal root ganglia, and we characterized the nociceptive behavior of mice deficient in NO-GC (GC-KO mice). We show that NO-GC is distinctly expressed in neurons of the mouse dorsal horn, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. GC-KO mice exhibited a considerably reduced nociceptive behavior in models of inflammatory or neuropathic pain, but their responses to acute pain were not impaired. Moreover, GC-KO mice failed to develop pain sensitization induced by intrathecal administration of drugs releasing NO or carbon monoxide. Surprisingly, during spinal nociceptive processing, cGMP produced by NO-GC may activate signaling pathways different from cGMP-dependent protein kinase I (cGKI), whereas cGKI can be activated by natriuretic peptide receptor-B dependent cGMP production. Together, our results provide evidence that NO-GC is crucially involved in the central sensitization of pain pathways during inflammatory and neuropathic pain.
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http://dx.doi.org/10.1523/JNEUROSCI.2128-08.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671070PMC
August 2008

The chemokine receptor CXCR2 is differentially regulated on glial cells in vivo but is not required for successful remyelination after cuprizone-induced demyelination.

Glia 2008 Aug;56(10):1104-13

Department of Neurology, Medical School Hannover, Hannover, Germany.

Unravelling the factors that can positively influence remyelination is one of the major challenges in multiple sclerosis research. Expression of the chemokine receptor CXCR2 on oligodendrocytes both in vitro and in MS lesions has suggested a possible role for CXCR2 in the recruitment of oligodendrocyte precursor cells (OPC). To investigate the function of CXCR2 during remyelination in vivo, we studied this receptor in cuprizone-induced demyelination and subsequent remyelination. We found that CXCR2 is constitutively expressed on OPC, whereas on macrophages/microglia CXCR2 is upregulated upon activation during demyelination. Hence, the expression of CXCR2 is differentially regulated in oligodendrocytes and macrophages/microglia. Furthermore, we subjected CXCR2-/- mice to the cuprizone model demonstrating that remyelination was not altered in comparison to wildtype controls. In addition, the number of OPC and the amount of microglial accumulation were similar in both CXCR2-/- and wildtype animals during the whole demyelination and remyelination process. These results suggest that despite expression on OPC and microglia CXCR2 plays only a minor role during remyelination.
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http://dx.doi.org/10.1002/glia.20682DOI Listing
August 2008

Lack of interferon-beta leads to accelerated remyelination in a toxic model of central nervous system demyelination.

Acta Neuropathol 2007 Dec 17;114(6):587-96. Epub 2007 Oct 17.

Department of Neurology, Medical School Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Interferon-beta (IFN-beta) is a pleiotropic cytokine that is known to modulate the immune response in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). Spontaneous remyelination and repair mechanisms in MS are mostly insufficient and contribute to clinical disability. Here, we investigated whether IFN-beta has a potential in modifying the extent of de- and remyelination in a toxic model of CNS demyelination induced by the copper chelator cuprizone. IFN-beta deficient (k/o) mice showed an accelerated spontaneous remyelination. However, the amount of remyelination after 6 weeks did not differ between the two groups. Demyelination in IFN-beta k/o mice was paralleled by a diminished astrocytic and microglia response as compared with wildtype controls, whereas the accelerated remyelination was paralleled by an increased number of oligodendrocyte precursor cells (OPC) within the demyelinated lesion at the beginning of the remyelination phase. We hypothesize that the absence of IFN-beta leads to more efficient recruitment and proliferation of OPC already during demyelination, thus allowing early remyelination. These results demonstrate that IFN-beta is able to alter remyelination in the absence of an immune-mediated demyelination.
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http://dx.doi.org/10.1007/s00401-007-0300-zDOI Listing
December 2007

Modulation of rat oligodendrocyte precursor cells by the chemokine CXCL12.

Neuroreport 2006 Jul;17(11):1187-90

Department of Neurology, Medical School Hannover, Hannover, Germany.

Migration, proliferation, and differentiation of oligodendrocyte precursor cells are essential for the assembly of myelin in the central nervous system. Knowledge on the regulation of these precursor cells is therefore of great importance for the understanding of developmental myelination and remyelination in demyelinating diseases. Here, we show that primary rat oligodendrocyte precursor cells express the chemokine receptor CXCR4. Stimulation with the ligand CXCL12 (SDF-1 alpha) leads to intracellular Ca elevation. Furthermore, 10 ng/ml CXCL12 augmented differentiation of precursors into mature oligodendrocytes. Migration toward growth factor conditioned medium was inhibited by CXCL12, while proliferation was only slightly modulated. The effect of CXCL12 on both migration and differentiation was blocked using a G protein antagonist. These data suggest a role for CXCL12 and oligodendroglial CXCR4 receptors during developmental myelination and repair in demyelinating diseases of the central nervous system.
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http://dx.doi.org/10.1097/01.wnr.0000227985.92551.9aDOI Listing
July 2006

Oligodendrocyte precursor cells express a functional chemokine receptor CCR3: implications for myelination.

J Neuroimmunol 2006 Sep 10;178(1-2):17-23. Epub 2006 Jul 10.

Department of Neurology, Medical School Hannover, Hannover, Germany.

Myelination in the central nervous system requires an accurate interplay between oligodendrocyte precursor cells (OPC) and axons. By as yet not fully understood mechanisms, OPC proliferate, migrate to the axon to be myelinated and finally differentiate into mature oligodendrocytes. The recent finding that OPC express CXC chemokine receptors led us to the investigation of the expression and functional importance of CC chemokine receptors. Using RT-PCR, we show that primary OPC from neonatal rats express CCR3, while CCR1, CCR2, CCR4, CCR5, and CCR7 are not expressed. Immunofluorescence staining of OPC could further demonstrate protein expression of CCR3. A rise of intracellular Ca2+ upon stimulation with the appropriate ligand CCL11 showed that this receptor is functional. Moreover, CCL11 led to a concentration specific increase in proliferation, inhibition of migration, and augmentation of differentiation in primary OPC. Thus, CCR3 may influence the process of myelination. This is of general importance for both developmental tissue patterning and for repair processes in demyelinating diseases like multiple sclerosis.
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http://dx.doi.org/10.1016/j.jneuroim.2006.05.021DOI Listing
September 2006

Effects of interferon-beta on oligodendroglial cells.

J Neuroimmunol 2006 Aug 5;177(1-2):173-80. Epub 2006 Jun 5.

Department of Neurology, Medical School Hannover, Germany.

The effect of interferon-beta (IFN-beta) for the treatment of multiple sclerosis (MS) is thought to be mediated by the modulation of immune cells. In addition, it has been shown that glial cells may be influenced by IFN-beta and a role during remyelination has been suggested. However, the mechanism is not yet clear and there are conflicting data. We have therefore systematically investigated proliferation, differentiation, toxicity, and cytoprotection of IFN-beta on oligodendroglia, both as a direct effect and mediated indirectly via other glial cells. Differentiation of oligodendrocyte progenitor cells (OPC) was significantly (p<0.01) inhibited by IFN-beta only when cultured in the presence with astrocytes and microglia. Proliferation was not changed, neither was IFN-beta toxic. There was no cytoprotective effect of IFN-beta on oligodendroglia injury induced by H2O2, NO, complement, or glutamate. Similarly, there was no cytoprotective effect mediated via treatment of astrocytes with IFN-beta. These data demonstrate that IFN-beta is neither toxic nor cytoprotective for oligodendrocytes. In summary, the only effect of IFN-beta was the inhibition of differentiation of OPC mediated indirectly via other glial cells. In vivo experiments will show how this effect may influence remyelination.
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http://dx.doi.org/10.1016/j.jneuroim.2006.04.016DOI Listing
August 2006

Inhibition of mitochondrial respiration elevates oxygen concentration but leaves regulation of hypoxia-inducible factor (HIF) intact.

Blood 2005 Oct 9;106(7):2311-7. Epub 2005 Jun 9.

Institute of Physiology, University of Lübeck, Lübeck, Germany.

The transcription factor hypoxia-inducible factor-1 (HIF-1) is critical for erythropoietin and other factors involved in the adaptation of the organism to hypoxic stress. Conflicting results have been published regarding the role of the mitochondrial electron transport chain (ETC) in the regulation of HIF-1alpha. We assessed cellular hypoxia by pimonidazole staining and blotting of the O2-labile HIF-1 alpha-subunit in human osteosarcoma cell cultures (U2OS and 143B). In conventional, gas-impermeable cell culture dishes, ETC inhibitors had no effect on pimonidazole staining or HIF-1alpha abundance in a 20% O2 atmosphere; both parameters were undetectable. Pimonidazole staining and HIF activity were substantial in 0.1% O2 irrespective of ETC inhibition. At an intermediate oxygen concentration (3% O2) pimonidazole staining and HIF-alpha expression were detectable but strongly reduced after ETC inhibition in conventional cell cultures. All effects of ETC inhibition on HIF-1alpha regulation were eliminated in gas-permeable dishes. As shown in a 143B subclone deficient in mitochondrial DNA (206rho0), genetic inactivation of the ETC led to similar responses with respect to HIF-1alpha regulation as ETC inhibitors. Our data demonstrate that reduction of oxygen consumption reduces the O2 gradient in conventional cell cultures, causing elevation of the cellular O2 concentration, which leads to degradation of HIF-alpha.
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http://dx.doi.org/10.1182/blood-2005-03-1138DOI Listing
October 2005
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