Simvastatin Improves Retinal Ganglion Cell Survival and Spatial Vision after Acute Retinal Ischemia/Reperfusion in Mice

Krempler, Katja; Schmeer, Christian; Isenmann, Stefan; Witte, Otto W.; Löwel, Siegrid

doi:10.1167/iovs.10-6005

Cited by 24 publications

(18 citation statements)

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“…Sun et al also demonstrated that Cobalt protophorphyrin-induced Heme Oxygenase-1 attenuated I/R induced injury in retina [49]. The hypolopodemic drug Simvastatin also improved retinal ganglion cell survival in mouse model of retinal I/R injury [50]. More recently, Fujita et al showed that pharmacological blocking of Angiotensin II type 1 receptor signaling produced neuroprotection via suppression of ROS production [51].…”

Section: Discussionmentioning

confidence: 99%

Progressive morphological changes and impaired retinal function associated with temporal regulation of gene expression after retinal ischemia/reperfusion injury in mice

Kim

Braun

Wordinger

et al. 2013

Mol Neurodegeneration

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Retinal ischemia/reperfusion (I/R) injury is an important cause of visual impairment. However, questions remain on the overall I/R mechanisms responsible for progressive damage to the retina. In this study, we used a mouse model of I/R and characterized the pathogenesis by analyzing temporal changes of retinal morphology and function associated with changes in retinal gene expression. Transient ischemia was induced in one eye of C57BL/6 mice by raising intraocular pressure to 120 mmHg for 60 min followed by retinal reperfusion by restoring normal pressure. At various time points post I/R, retinal changes were monitored by histological assessment with H&E staining and by SD-OCT scanning. Retinal function was also measured by scotopic ERG. Temporal changes in retinal gene expression were analyzed using cDNA microarrays and real-time RT-PCR. In addition, retinal ganglion cells and gliosis were observed by immunohistochemistry. H&E staining and SD-OCT scanning showed an initial increase followed by a significant reduction of retinal thickness in I/R eyes accompanied with cell loss compared to contralateral control eyes. The greatest reduction in thickness was in the inner plexiform layer (IPL) and inner nuclear layer (INL). Retinal detachment was observed at days 3 and 7 post- I/R injury. Scotopic ERG a- and b-wave amplitudes and implicit times were significantly impaired in I/R eyes compared to contralateral control eyes. Microarray data showed temporal changes in gene expression involving various gene clusters such as molecular chaperones and inflammation. Furthermore, immunohistochemical staining confirmed Müller cell gliosis in the damaged retinas. The time-dependent changes in retinal morphology were significantly associated with functional impairment and altered retinal gene expression. We demonstrated that I/R-mediated morphological changes the retina closely associated with functional impairment as well as temporal changes in retinal gene expression. Our findings will provide further understanding of molecular pathogenesis associated with ischemic injury to the retina.

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Section: Discussionmentioning

confidence: 99%

Progressive morphological changes and impaired retinal function associated with temporal regulation of gene expression after retinal ischemia/reperfusion injury in mice

Kim

Braun

Wordinger

et al. 2013

Mol Neurodegeneration

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“…19,20 Briefly, mice were anesthetized with an intraperitoneal injection of 5% chloral hydrate in phosphate-buffered saline (PBS; 500 mg/kg body weight; Fluka, Seelze, Germany). After application of topical anesthesia (oxybuprocaine-hydrochloride 4 mg/mL; Bausch & Lomb GmbH, Feldkirchen, Germany), the anterior chamber of the right eye was cannulated with a 30-gauge needle connected to an elevated normal saline reservoir.…”

Section: Transient Retinal Ischemiamentioning

confidence: 99%

“…Our results are in agreement with previous studies. 19,20 Immunostaining and Evaluation of RGC Numbers…”

Section: Transient Retinal Ischemiamentioning

confidence: 99%

Increased Frataxin Levels Protect Retinal Ganglion Cells After Acute Ischemia/Reperfusion in the Mouse Retina In Vivo

Schultz

Witte

Schmeer

2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Schultz R, Witte OW, Schmeer C. Increased frataxin levels protect retinal ganglion cells after acute ischemia/reperfusion in the mouse retina in vivo. Invest Ophthalmol Vis Sci. 2016;57:4115-4124. DOI:10.1167/iovs.16-19260 PURPOSE. The mitochondrial protein frataxin (FXN) is highly expressed in metabolically active tissues and has been shown to improve cell survival in response to oxidative stress after ischemia. Retinal ischemia/hypoxia is a complication of ocular diseases such as diabetic retinopathy and glaucoma. There are no effective therapeutic approaches currently available. This study was performed to evaluate the neuroprotective effects of FXN after acute retinal ischemia/reperfusion in vivo. METHODS.Retinal ischemia/reperfusion was induced in adult wild-type and FXN-overexpressing mice by transient elevation of intraocular pressure (IOP) for 45 minutes. Expression of FXN was evaluated by quantitative (q)RT-PCR and Western blot analysis between 6 and 48 hours after ischemia. Retinal ganglion cell (RGC) survival was determined with immunofluorescent staining and fluorescence microscopy 14 days after lesion. Expression of hypoxiainducible factors Hif-1a and Hif-2a and of oxidative stress markers heme oxygenase-1 (Hmox1), glutathione peroxidase 1 (Gpx1), superoxidase dismutase 1 and 2 (Sod1, Sod2), and catalase was evaluated by qRT-PCR.RESULTS. Endogenous FXN levels were upregulated for up to 24 hours after retinal ischemia in vivo. Retinal ganglion cell survival was significantly improved in FXN-overexpressing mice 14 days after ischemia. Expression of antioxidative enzymes Gpx1, Sod2, and catalase was significantly increased in FXN-overexpressing mice after lesion. CONCLUSIONS.Retinal FXN levels are increased in response to ischemia. Furthermore, elevated FXN levels had a clear neuroprotective effect as shown by increased ganglion cell survival after acute retinal ischemia/reperfusion. Frataxin's neuroprotective effect was associated with an upregulation of antioxidative enzymes. The data suggest that FXN induces neuroprotection by decreasing oxidative stress.Keywords: frataxin, retinal ischemia, retinal ganglion cell, antioxidants F rataxin (FXN) is a nuclear-encoded mitochondrial protein highly conserved among eukaryotes. The mouse gene (Frda) encodes a 207-amino acid protein showing 73% amino acid identity to its human counterpart.1 It is abundantly expressed in metabolically active tissues such as liver, skeletal and cardiac muscle, and brain.1 In the retina of normal mice, immunoreactivity to FXN is found in the external and internal plexiform layers, the ganglion cell layer, and the inner nuclear layer.2 Frataxin deficiency is closely related to Friedreich ataxia (FRDA), a neurodegenerative disease associated with abnormal influx of iron into the mitochondria, which increases the susceptibility of the nervous system to oxidative stress. [3][4][5][6][7][8] Furthermore, complete absence of FXN leads to early embryonic lethality in transgenic mice. Conditional FXN knockout strains for st...

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“…Therefore, using the aforementioned behavioral techniques in rodent models that display disease etiology that is similar to humans, such as the DBA/2 mouse, allows us to conduct studies that obtain valuable information on disease mechanisms and therapeutic strategies at considerably lower cost with more data points. We can use these techniques in mice to evaluate therapeutic intervention in rodent models of disease (Adamus et al, 2012; Cahill et al, 2011; Krempler et al, 2011; Savigni et al, 2013), and RGC axon regeneration (de Lima et al, 2012), test variables such as age and gender (van Alphen et al, 2009), neuronal and RGC disease mechanisms in glaucomatous mice (Burroughs et al, 2011; Feng et al, 2013; Kaja et al, 2011), similar to the assessment of visual deficits in other animal models of disease (Pinto et al, 2007; Pinto et al, 2005; Puk et al, 2009; Richards et al, 2008; Roeser and Baier, 2003; Schmucker and Schaeffel, 2006; Umino and Solessio, 2013). Such data contribute to the pre-clinical development of promising therapeutic interventions prior to human clinical trials and benefit from their non-invasive and comprehensive nature resembling many of the aspects of human clinical trials.…”

Section: Clinical Relevance Of Data Derived From Behavioral Assaysmentioning

confidence: 99%

Psychophysical testing in rodent models of glaucomatous optic neuropathy

Grillo

Koulen

2015

Experimental Eye Research

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Processing of visual information begins in the retina, with photoreceptors converting light stimuli into neural signals. Ultimately, signals are transmitted to the brain through signaling networks formed by interneurons, namely bipolar, horizontal and amacrine cells providing input to retinal ganglion cells (RGCs), which form the optic nerve with their axons. As part of the chronic nature of glaucomatous optic neuropathy, the increasing and irreversible damage and ultimately loss of neurons, RGCs in particular, occurs following progressive damage to the optic nerve head (ONH), eventually resulting in visual impairment and visual field loss. There are two behavioral assays that are typically used to assess visual deficits in glaucoma rodent models, the visual water task and the optokinetic drum. The visual water task can assess an animal’s ability to distinguish grating patterns that are associated with an escape from water. The optokinetic drum relies on the optomotor response, a reflex turning of the head and neck in the direction of the visual stimuli, which usually consists of rotating black and white gratings. This reflex is a physiological response critical for keeping the image stable on the retina. Driven initially by the neuronal input from direction-selective RGCs, this reflex is comprised of a number of critical sensory and motor elements. In the presence of repeatable and defined stimuli, this reflex is extremely well suited to analyze subtle changes in the circuitry and performance of retinal neurons. Increasing the cycles of these alternating gratings per degree, or gradually reducing the contrast of the visual stimuli, threshold levels can be determined at which the animal is no longer tracking the stimuli, and thereby visual function of the animal can be determined non-invasively. Integrating these assays into an array of outcome measures that determine multiple aspects of visual function is a central goal in vision research and can be realized, for example, by the combination of measuring optomotor reflex function with electroretinograms (ERGs) and optical coherence tomography (OCT) of the retina. These structure-function correlations in vivo are urgently needed to identify disease mechanisms as potential new targets for drug development. Such a combination of the experimental assessment of the optokinetic reflex (OKN) or optomotor reflex (OMR) with other measures of retinal structure and function is especially valuable for research on GON. The chronic progression of the disease is characterized by a gradual decrease in function accompanied by a concomitant increase in structural damage to the retina, therefore the assessment of subtle changes is key to determining the success of novel intervention strategies.

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Simvastatin Improves Retinal Ganglion Cell Survival and Spatial Vision after Acute Retinal Ischemia/Reperfusion in Mice

Cited by 24 publications

References 50 publications

Progressive morphological changes and impaired retinal function associated with temporal regulation of gene expression after retinal ischemia/reperfusion injury in mice

Progressive morphological changes and impaired retinal function associated with temporal regulation of gene expression after retinal ischemia/reperfusion injury in mice

Increased Frataxin Levels Protect Retinal Ganglion Cells After Acute Ischemia/Reperfusion in the Mouse Retina In Vivo

Psychophysical testing in rodent models of glaucomatous optic neuropathy

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