Acidic Fibroblast Growth Factor (FGF) Potentiates Glial-mediated Neurotoxicity by Activating FGFR2 IIIb Protein

Lee, Moon-Hee; Kang, Yunhee; Suk, Kyoungho; Schwab, Claudia; Yu, Songyan; McGeer, Patrick L.

doi:10.1074/jbc.m111.270470

Cited by 34 publications

(25 citation statements)

References 22 publications

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“…FGF, in spite of being an angiogenesis promoter,26 is involved also in inflammation27–30 and seems to play key roles in neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases as well as in AMD, through activation of microglial cells 19. The aim of the present interventional case was to find out whether intravitreal dobesilate, a FGF inhibitor,5 could constitute a therapeutic option in the treatment of dry AMD.…”

Section: Discussionmentioning

confidence: 96%

“…Microglial cells are the resident macrophages of the central nervous system that synthesise fibroblast growth factor (FGF) when they become activated. Since they also express FGF receptors, these growth factors should autocrinely contribute to sustain a chronic inflammation 17–19. In healthy retina, microglial cells are located in inactivated conditions mainly in the inner retina.…”

Section: Discussionmentioning

confidence: 99%

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Treatment of dry age-related macular degeneration with dobesilate

Cuevas

Outeiriño²,

Angulo³

et al. 2012

Case Reports

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BACKGROUNDThis is a very safe and promising effi cient treatment for dry age-related macular degeneration (AMD). CASE PRESENTATIONThis is a representative case from an institutional trial using dobesilate therapy in early dry AMD. This early stage of AMD may not be evident by ophthalmoscopic examination but can be inferred by reduced retinal function. 1 Optical coherence tomography (OCT) is unequivocally the method for accurate early morphological detection, in vivo, of outer retinal layer changes in dry AMD. 2 3 This study was performed with patient's consent after the Ethical Committee approval of our Institution. A 54-year-old man presented with methamorphia in his right eye. A comprehensive ocular examination including Shellen visual acuity measurements and OCT was performed at baseline and 7 and 14 days after dobesilate injection. Fundus-monitored microperimetry was performed at baseline and after 14 days of treatment. The patient received an intravitreal solution of dobesilate (150 μl) under sterile conditions, following the International Guidelines for intravitreal injections 4 in his right eye. Dobesilate was administered as a 12.5% solution of diethylammonium 2,5-dihydroxybenzenesulfonate (etamsylate; Dicynone Sanofi -Aventis). The pH of the solution was 3.2 at the opening of the phial and 5.2 after a 1:20 dilution in Milli-Q water, respectively. Mitogenesis experiments carried out as described by Fernández et al 5 show that etamsylate inhibits FGF-driven mitogenesis with the same effi ciency than the potassium dobesilate salt employed in those studies which fi rst demonstrated this inhibitory activity (not shown).As depicted in the OCT image before treatment ( fi gure 1A ), the patient had both foveal and temporal extrafoveal photoreceptor disruption. At baseline, inner retinal layers were normal, whereas the outer retinal layers showed structural alterations: 1) the integrity of photoreceptor inner segment and outer segment was not preserved (layers corresponding to those labelled 1 and 2 at the inset); 2) retinal pigment epithelium (RPE) showed rarefactions and thinning (layer labelled 3 at the red framed inset). In contrast, as fi gure 1B,C show, normalisation of outer retinal layers was achieved after dobesilate treatment. In addition, central foveal thickness increased after dobesilate treatment (138 μm at baseline vs 200 μm after 7 days of treatment ). Retinal sensitivity map assessed by fundus-monitored microperimetry normalised after 14 days of treatment ( fi gure 2A,B ). The normalisation of retinal structure was associated with a gain of visual acuity: 0.4 at baseline versus 0.8 and 0.9 after 7 and 14 days of treatment, respectively. As an additional functional assessment, a full fi eld electroretinogram (ERG) of the treated right eye of the patient was performed after 1 month of treatment, according to standard protocols recommended by the International Society for Clinical Electrophysiology of Vision, and compared with the record of the normal untreated left eye. As fi gure 3 shows, ERG p...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Treatment of dry age-related macular degeneration with dobesilate

Cuevas

Outeiriño²,

Angulo³

et al. 2012

Case Reports

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“…The expression of these two isoforms for FGFR1-3 affects their signaling, ligand selectivity, binding to other partnering proteins and cell-type specificity [41]. The IIIb isoform is more common in early brain development, and there is some indication that activation of the IIIb isoform later in life could have deleterious consequences [42]. …”

Section: The Fgf Systemmentioning

confidence: 99%

Dysregulated fibroblast growth factor (FGF) signaling in neurological and psychiatric disorders

Turner

Eren-Koçak

Inui³

et al. 2016

Seminars in Cell & Developmental Biology

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The role of the fibroblast growth factor (FGF) system in brain-related disorders has received considerable attention in recent years. To understand the role of this system in neurological and psychiatric disorders, it is important to identify the specific members of the FGF family that are implicated, their location and the various mechanisms they can be modulated. Each disorder appears to impact specific molecular players in unique anatomical locations, and all of these could conceivably become targets for treatment. In the last several years, the issue of how to target this system directly has become an area of increasing interest. To date, the most promising therapeutics are small molecule inhibitors and antibodies that modulate FGF receptor (FGFR) function. Beyond attempting to modify the primary players affected by a given brain disorder, it may prove useful to target molecules, such as membrane-bound or extracellular proteins that interact with FGF ligands or FGFRs to modulate signaling.

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“…We found that IL-6, the principal inflammatory cytokine produced by astrocytes (Lee et al, 2011b;Qin and Benveniste, 2012) contributed 22% to the overall toxicity of the CM. In microglia, IL-6 in combination with TNFa and IL-1b, contributed 37-38% of overall toxicity (Lee et al, 2011a).…”

Section: Discussionmentioning

confidence: 98%