Role of glial cell damage in onset and progression of neuronal degeneration after retinal ischemia and putative strategies for neuroprotection
Final Report Abstract
The present study aimed to examine: i) to what extent glial cells modulate onset and progression of neuronal damage in the retina of rodents both in vivo and in vitro, and ii) the putative glio- and neuroprotective effects of erythropoietin and erythropoietin analogues, as well as the possible involvement of frataxin in vitro. In order to validate our lesion paradigm, we first evaluated the effect of different durations of ischemia in the mouse eye in vivo. In addition, we determined the effect of statin delivery on functional outcome after lesion. Results show a mild effect after 30 min of ischemia. After 60 min of ischemia mice were completely blind. These results indicate that in our lesion model in the mouse severity of the lesion is dependent on the duration of ischemia, as described for the rat. Our study shows that statins are partially neuroprotective at the functional levels after ischemia. To elucidate the role of retinal glia in the onset and progression of neuronal damage after ischemia, we impaired Müller glia metabolism in the ischemic retina and evaluated the retinal ganglion cell response to the lesion. Results show that during the acute phase of injury Müller glia function supports neuronal integrity. However, during reperfusion, Müller glia activity turns detrimental for neuronal survival. These findings indicate a dual role of Müller glia after an ischemic lesion in the retina. To examine putative glio- and neuroprotective effects of erythropoietin and the erythropoietin analogues, as well as the possible involvement of frataxin, we chose an in vivo approach after attemps to establish a neuron-glia co-culture failed due to an inadequate neuronal cell line. We show for the first time that frataxin and endogenous erythropoietin are upregulated after ischemia, indicating their involvement in the intrinsic cellular response to lesion. In addition, we found that both erythropoietin and its non-hematopoietic derivative carbamyerythropoietin are neuroprotective after ischemia and further increase frataxin expression after lesion. Erythropoietin-mediated increase in frataxin expression was also shown in unlesioned retinas. In order to determine whether enhancement of glial cell resistance to stress by overexpression of frataxin would improve neuronal outcome after ischemia, we developed a transgenic mouse strain selectively overexpressing this enzyme in Müller glia. Results show that increased frataxin expression improves neuronal survival after ischemia. Unexpectedly, in contrast to the effects observed after erythropoietin- and carbamylerythropoietin delivery, we found that constitutive overexpressed frataxin impairs Müller glia activity after lesion, suggesting that protective frataxin effects are dependent on appropriate protein levels. Our study represents a great worth for future development of more efficient clinical and therapeutic approaches since it highlights the role of glia, the most abundant cell type in the central nervous system, in onset and progression of neuronal degeneration. Furthermore, we show for the first time that the mitochondrial enzyme frataxin is part of the intrinsic response to ischemia in the retina and its expression can be modulated after lesion. This study further undelines the importance of frataxin as a therapeutic target to improve neuronal survival after injury.
Publications
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(2010) -Simvastatin improves visual acuity in mice following acute retinal ischemia. FENS Abstr., vol.5, 081.17
Krempler K, Schmeer C, Isenmann S, Witte OW, Löwel S
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(2011) Simvastatin improves retinal ganglion cell survival and spatial vision after acute retinal ischemia/reperfusion in mice. Invest Ophthalmol Vis Sci 52, 2606-2618
Krempler K, Schmeer C, Isenmann S, Witte OW, Löwel S
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(2012) Frataxin overexpression in retinal Müller cells increases neuronal survival after acute retinal ischemia/reperfusion in the mouse in vivo. XX Biennial Meeting of the International Society for Eye Research, Berlin. O335
Schultz R, Menning J, Ristow M, Y.-Z. Le, Witte OW, Schmeer C
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(2012) Role of frataxin in erythropoietin- and carbamoylated erythropoietin-mediated neuroprotective effects in the mouse retina after acute retinal ischemia/reperfusion in vivo. 7th International Symposium on Neuroprotection and Neurorepair, Berlin. PIII -40
Schultz R, Witte OW, Schmeer C
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(2013) Metabolic impairment of Müller glia differentially affects retinal ganglion cell survival after acute ischemia/reperfusion in the mouse eye in vivo. GLIA 61, T07-07B, S129- S130
Vohra T, Schultz R, Witte OW, Schmeer C
