Publications by authors named "Andrea Issberner"

7 Publications

  • Page 1 of 1

Neuroprotective Properties of Dimethyl Fumarate Measured by Optical Coherence Tomography in Non-inflammatory Animal Models.

Front Neurol 2020 13;11:601628. Epub 2021 Jan 13.

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

While great advances have been made in the immunomodulatory treatment of multiple sclerosis (MS), there is still an unmet need for drugs with neuroprotective potential. Dimethyl fumarate (DMF) has been suggested to exert both immunomodulatory and neuroprotective effects in MS. To investigate if DMF has neuroprotective effects independent of immunomodulation we evaluated its effects in the non-inflammatory animal models of light-induced photoreceptor loss and optic nerve crush. This might also reveal applications for DMF besides MS, such as age related macular degeneration. Retinal neurodegeneration was longitudinally assessed by retinal imaging using optical coherence tomography (OCT), and glutathione (GSH) measurements as well as histological investigations were performed to clarify the mode of action. For light-induced photoreceptor loss, one eye of C57BL/6J mice was irradiated with a LED cold light lamp while for optic nerve crush the optic nerve was clamped behind the eye bulb. The other eye served as control. GSH was measured in the optic nerve, choroid and retina and immunohistological staining of retinal microglia (Iba1) was performed. Mice were treated with 15 or 30 mg DMF/kg bodyweight or vehicle. While no protective effects were observed in optic nerve crush, in the light-induced retinal degeneration model DMF treatment significantly reduced retinal degeneration. In these mice, GSH levels in the retina and surrounding choroid were increased and histological investigations revealed less microglial activation in the outer retinal layers, suggesting both antioxidant and anti-inflammatory effects.
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http://dx.doi.org/10.3389/fneur.2020.601628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838501PMC
January 2021

Comparison of different optomotor response readouts for visual testing in experimental autoimmune encephalomyelitis-optic neuritis.

J Neuroinflammation 2020 Jul 18;17(1):216. Epub 2020 Jul 18.

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.

Optomotor response is increasingly used in preclinical research for evaluating the visual function in rodents. However, the most suitable measuring protocol for specific scientific questions is not always established. We aimed to determine the optimal parameters for visual function analysis in experimental autoimmune encephalomyelitis optic neuritis (EAEON), an animal model for multiple sclerosis. Contrast sensitivity as well as spatial frequency both had a low variance and a good test-retest reliability. Also, both parameters were able to differentiate between the EAEON and the control group. Correlations with the retinal degeneration, assessed by optical coherence tomography, the infiltration of immune cells, and the clinical disability score revealed that spatial frequency was superior to contrast sensitivity analysis. We therefore conclude that spatial frequency testing is better suited as visual acuity assessment in C57Bl/6 J EAEON mice. Furthermore, contrast sensitivity measurements are more time consuming, possibly leading to more stress for the animals.
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http://dx.doi.org/10.1186/s12974-020-01889-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368714PMC
July 2020

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Brain 2020 04;143(4):1127-1142

NeuroCure Clinical Research Center and Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.
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http://dx.doi.org/10.1093/brain/awaa062DOI Listing
April 2020

Monitoring retinal changes with optical coherence tomography predicts neuronal loss in experimental autoimmune encephalomyelitis.

J Neuroinflammation 2019 Nov 4;16(1):203. Epub 2019 Nov 4.

Division of Neuroimmunology and Glial Biology, Department of Neurology, University of California, San Francisco, San Francisco, USA.

Background: Retinal optical coherence tomography (OCT) is a clinical and research tool in multiple sclerosis, where it has shown significant retinal nerve fiber (RNFL) and ganglion cell (RGC) layer thinning, while postmortem studies have reported RGC loss. Although retinal pathology in experimental autoimmune encephalomyelitis (EAE) has been described, comparative OCT studies among EAE models are scarce. Furthermore, the best practices for the implementation of OCT in the EAE lab, especially with afoveate animals like rodents, remain undefined. We aimed to describe the dynamics of retinal injury in different mouse EAE models and outline the optimal experimental conditions, scan protocols, and analysis methods, comparing these to histology to confirm the pathological underpinnings.

Methods: Using spectral-domain OCT, we analyzed the test-retest and the inter-rater reliability of volume, peripapillary, and combined horizontal and vertical line scans. We then monitored the thickness of the retinal layers in different EAE models: in wild-type (WT) C57Bl/6J mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG) or with bovine myelin basic protein (MBP), in TCR mice immunized with MOG, and in SJL/J mice immunized with myelin proteolipid lipoprotein (PLP). Strain-matched control mice were sham-immunized. RGC density was counted on retinal flatmounts at the end of each experiment.

Results: Volume scans centered on the optic disc showed the best reliability. Retinal changes during EAE were localized in the inner retinal layers (IRLs, the combination of the RNFL and the ganglion cell plus the inner plexiform layers). In WT, MOG EAE, progressive thinning of IRL started rapidly after EAE onset, with 1/3 of total loss occurring during the initial 2 months. IRL thinning was associated with the degree of RGC loss and the severity of EAE. Sham-immunized SJL/J mice showed progressive IRL atrophy, which was accentuated in PLP-immunized mice. MOG-immunized TCR mice showed severe EAE and retinal thinning. MBP immunization led to very mild disease without significant retinopathy.

Conclusions: Retinal neuroaxonal damage develops quickly during EAE. Changes in retinal thickness mirror neuronal loss and clinical severity. Monitoring of the IRL thickness after immunization against MOG in C57Bl/6J mice seems the most convenient model to study retinal neurodegeneration in EAE.
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http://dx.doi.org/10.1186/s12974-019-1583-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827223PMC
November 2019

Early alpha-lipoic acid therapy protects from degeneration of the inner retinal layers and vision loss in an experimental autoimmune encephalomyelitis-optic neuritis model.

J Neuroinflammation 2018 Mar 7;15(1):71. Epub 2018 Mar 7.

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.

Background: In multiple sclerosis (MS), neurodegeneration is the main reason for chronic disability. Alpha-lipoic acid (LA) is a naturally occurring antioxidant which has recently been demonstrated to reduce the rate of brain atrophy in progressive MS. However, it remains uncertain if it is also beneficial in the early, more inflammatory-driven phases. As clinical studies are costly and time consuming, optic neuritis (ON) is often used for investigating neuroprotective or regenerative therapeutics. We aimed to investigate the prospect for success of a clinical ON trial using an experimental autoimmune encephalomyelitis-optic neuritis (EAE-ON) model with visual system readouts adaptable to a clinical ON trial.

Methods: Using an in vitro cell culture model for endogenous oxidative stress, we compared the neuroprotective capacity of racemic LA with the R/S-enantiomers and its reduced form. In vivo, we analyzed retinal neurodegeneration using optical coherence tomography (OCT) and the visual function by optokinetic response (OKR) in MOG-induced EAE-ON in C57BL/6J mice. Ganglion cell counts, inflammation, and demyelination were assessed by immunohistological staining of retinae and optic nerves.

Results: All forms of LA provided equal neuroprotective capacities in vitro. In EAE-ON, prophylactic LA therapy attenuated the clinical EAE score and prevented the thinning of the inner retinal layer while therapeutic treatment was not protective on visual outcomes.

Conclusions: A prophylactic LA treatment is necessary to protect from visual loss and retinal thinning in EAE-ON, suggesting that a clinical ON trial starting therapy after the onset of symptoms may not be successful.
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http://dx.doi.org/10.1186/s12974-018-1111-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840773PMC
March 2018

Extracellular cyclic GMP and its derivatives GMP and guanosine protect from oxidative glutamate toxicity.

Neurochem Int 2013 Apr 26;62(5):610-9. Epub 2013 Jan 26.

Department of Neurology, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany.

Cell death in response to oxidative stress plays a role in a variety of neurodegenerative diseases and can be studied in detail in the neuronal cell line HT22, where extracellular glutamate causes glutathione depletion by inhibition of the glutamate/cystine antiporter system xc(-), elevation of reactive oxygen species and eventually programmed cell death caused by cytotoxic calcium influx. Using this paradigm, we screened 54 putative extracellular peptide or small molecule ligands for effects on cell death and identified extracellular cyclic guanosine monophosphate (cGMP) as a protective substance. Extracellular cGMP was protective, whereas the cell-permeable cGMP analog 8-pCPT-cGMP or the inhibition of cGMP degradation by phosphodiesterases was toxic. Interestingly, metabolites GMP and guanosine were even more protective than cGMP and the inhibition of the conversion of GMP to guanosine attenuated its effect, suggesting that GMP offers protection through its conversion to guanosine. Guanosine increased system xc(-) activity and cellular glutathione levels in the presence of glutamate, which can be explained by transcriptional upregulation of xCT, the functional subunit of system xc(-). However, guanosine also provided protection when added late in the cell death cascade and significantly reduced the number of calcium peaking cells, which was most likely not mediated by transcriptional mechanisms. We observed no changes in the classical protective pathways such as phosphorylation of Akt, ERK1/2 or induction of Nrf2 or ATF4. We conclude that extracellular guanosine protects against endogenous oxidative stress by two probably independent mechanisms involving system xc(-) induction and inhibition of cytotoxic calcium influx.
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http://dx.doi.org/10.1016/j.neuint.2013.01.019DOI Listing
April 2013

Effects of dimethyl fumarate on neuroprotection and immunomodulation.

J Neuroinflammation 2012 Jul 7;9:163. Epub 2012 Jul 7.

Department of Neurology, Heinrich-Heine-University Düsseldorf, Medical Faculty, Düsseldorf 40225, Germany.

Background: Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms. We aimed to clarify whether neuroprotective concentrations of dimethyl fumarate have immunomodulatory effects.

Findings: We determined time- and concentration-dependent effects of dimethyl fumarate and its metabolite monomethyl fumarate on viability in a model of endogenous neuronal oxidative stress and clarified the mechanism of action by quantitating cellular glutathione content and recycling, nuclear translocation of transcription factors, and the expression of antioxidant genes. We compared this with changes in the cytokine profiles released by stimulated splenocytes measured by ELISPOT technology and analyzed the interactions between neuronal and immune cells and neuronal function and viability in cell death assays and multi-electrode arrays. Our observations show that dimethyl fumarate causes short-lived oxidative stress, which leads to increased levels and nuclear localization of the transcription factor nuclear factor erythroid 2-related factor 2 and a subsequent increase in glutathione synthesis and recycling in neuronal cells. Concentrations that were cytoprotective in neuronal cells had no negative effects on viability of splenocytes but suppressed the production of proinflammatory cytokines in cultures from C57BL/6 and SJL mice and had no effects on neuronal activity in multi-electrode arrays.

Conclusions: These results suggest that immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity.
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http://dx.doi.org/10.1186/1742-2094-9-163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419128PMC
July 2012