Stroke in the eye of the beholder

Ishikawa, Hiroto; Caputo, Matthew; Franzese, Nicholas; Weinbren, Nathan L.; Slakter, Adam; Patel, Milan; Stahl, Christine E.; Jacotte, Maria Alejandra; Acosta, Sandra; Franyuti, Giorgio; Shinozuka, Kazutaka; Tajiri, Naoki; Loveren, Harry van; Kaneko, Yuji; Borlongan, Cesar V.

doi:10.1016/j.mehy.2012.12.030

Cited by 6 publications

(4 citation statements)

References 25 publications

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“…However, there is still a question of whether the smaller peptide sequence in ProTα has neuroprotective activity. Since the retina is more accessible than other areas of the central nervous system, and retinal ischemia mimics the physiological response of ischemic stroke (Minhas et al, 2012;D'Onofrio and Koeberle, 2013;Ishikawa et al, 2013), the aim of present study was to investigate the protective activity of ProTα-derived 6-amino acid peptides using retinal ischemia model.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective impact of prothymosin alpha-derived hexapeptide against retinal ischemia–reperfusion

et al. 2016

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Prothymosin alpha (ProTα) has robustness roles against brain and retinal ischemia or serum-starvation stress. In the ProTα sequence, the active core 30-amino acid peptide/P30 (a.a.49-78) is necessary for the original neuroprotective actions against ischemia. Moreover, the 9-amino acid peptide sequence/P9 (a.a.52-60) in P30 still shows neuroprotective activity against brain and retinal ischemia, though P9 is less potent than P30. As the previous structure-activity relationship study for ProTα may not be enough, the possibility still exists that any sequence smaller than P9 retains potent neuroprotective activity. When different P9- and P30-related peptides were intravitreally injected 24h after retinal ischemia in mice, the 6-amino acid peptide/P6 (NEVDEE, a.a.51-56) showed potent protective effects against ischemia-induced retinal functional deficits, which are equipotent to the level of P30 peptide in electroretinography (ERG) and histological damage in Hematoxylin and Eosin (HE) staining. Further studies using ERG and HE staining suggested that intravitreal or intravenous (i.v.) injection with modified P6 peptide/P6Q (NEVDQE) potently inhibited retinal ischemia-induced functional and histological damage. In an immunohistochemical analysis, the ischemia-induced loss of retinal ganglion, bipolar, amacrine and photoreceptor cells were inhibited by a systemic administration with P6Q peptide 24h after the ischemic stress. In addition, systemic post-treatment with P6Q peptide significantly inhibited retinal ischemia-induced microglia and astrocyte activation in terms of increased ionized calcium-binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) intensity, respectively, as well as their morphological changes, increased number and migration. Thus, this study demonstrates the therapeutic significance of modified P6 peptide P6Q (NEVDQE) derived from 6-amino acid peptide (P6) in ProTα against ischemic damage.

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Section: Introductionmentioning

confidence: 99%

Neuroprotective impact of prothymosin alpha-derived hexapeptide against retinal ischemia–reperfusion

et al. 2016

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“…Hence, we suggest that stroke patients should also be screened for retinal damage as part of the disease differential diagnosis and its treatment regimen to improve the overall clinical outcome. Clinical outcomes from transplantation of stem cells in stroke, although mostly focused on repairing the brain [32][33][34][35][36][37][38][39][40] , may benefit from exploring the grafted cells deposition and function in the eye 41,42 .…”

Section: Discussionmentioning

confidence: 99%

Eyeballing stroke: Blood flow alterations in the eye and visual impairments following transient middle cerebral artery occlusion in adult rats

et al. 2020

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Middle cerebral artery occlusion in rodents remains a widely used model of ischemic stroke. Recently, we reported the occurrence of retinal ischemia in animals subjected to middle cerebral artery occlusion, owing in part to the circulatory juxtaposition of the ophthalmic artery to the middle cerebral artery. In this study, we examined the eye hemodynamics and visual deficits in middle cerebral artery occlusion-induced stroke rats. The brain and eye were evaluated by laser Doppler at baseline (prior to middle cerebral artery occlusion), during and after middle cerebral artery occlusion. Retinal function-relevant behavioral and histological outcomes were performed at 3 and 14 days post-middle cerebral artery occlusion. Laser Doppler revealed a typical reduction of at least 80% in the ipsilateral frontoparietal cortical area of the brain during middle cerebral artery occlusion compared to baseline, which returned to near-baseline levels during reperfusion. Retinal perfusion defects closely paralleled the timing of cerebral blood flow alterations in the acute stages of middle cerebral artery occlusion in adult rats, characterized by a significant blood flow defect in the ipsilateral eye with at least 90% reduction during middle cerebral artery occlusion compared to baseline, which was restored to near-baseline levels during reperfusion. Moreover, retinal ganglion cell density and optic nerve depth were significantly decreased in the ipsilateral eye. In addition, the stroke rats displayed eye closure. Behavioral performance in a light stimulus-mediated avoidance test was significantly impaired in middle cerebral artery occlusion rats compared to control animals. In view of visual deficits in stroke patients, closely monitoring of brain and retinal perfusion via laser Doppler measurements and examination of visual impairments may facilitate the diagnosis and the treatment of stroke, including retinal ischemia.

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“…In addition, neuronal function and survival are very sensitive to mitochondrial dysfunction. Recently researches have shown that mitochondrial dysfunction is closely associated with retinal neuronal damage, which can be remedied by stem cell-mediated mitochondrial repair49,50 Thus, we suppose that neurotrophic treatment, visual stimulation, and mitochondrial transplantation should be incorporated in integrated therapeutic strategy for promoting retinal neuronal repair. Technical concerns also need to be taken into consideration; further studies involving a longer follow-up period and more comprehensive evaluation of visual function are warranted.We report the upregulation of SP1 and LINGO-1 expression in RGCs in the ONC-injured retina.…”

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confidence: 99%

SP1‐mediated upregulation of LINGO‐1 promotes degeneration of retinal ganglion cells in optic nerve injury

Zhan

Quan

et al. 2020

CNS Neurosci Ther

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Backgrounds Insults to the axons in the optic nerve head are the primary cause of loss of retinal ganglion cells (RGCs) in traumatic, ischemic nerve injury or degenerative ocular diseases. The central nervous system–specific leucine‐rich repeat protein, LINGO‐1, negatively regulates axon regeneration and neuronal survival after injury. However, the upstream molecular mechanisms that regulate LINGO‐1 signaling and contribute to LINGO‐1–mediated death of RGCs are unclear. Methods The expression of SP1 was profiled in optic nerve crush (ONC)–injured RGCs. LINGO‐1 level was examined after SP1 overexpression by qRT‐PCR. Luciferase assay was used to examine the binding of SP1 to the promoter regions of LINGO‐1. Primary RGCs from rat retina were isolated by immunopanning and RGCs apoptosis were determined by Tunnel. SP1 and LINGO‐1 expression was investigated using immunohistochemistry and Western bolting. Neuroprotection was assessed by RGC counts, RNFL thickness, and VEP tests after inhibition of SP1 shRNA. Results We demonstrate that SP1 was upregulated in ONC‐injured RGCs. SP1 was bound to the LINGO‐1 promoter, which led to increased expression of LINGO‐1. Treatment with recombinant Nogo‐66 or LINGO‐1 promoted apoptosis of RGCs cultured under serum‐deprivation conditions, while silencing of SP1 promoted the survival of RGCs. SP1 and LINGO‐1 colocalized and were upregulated in ONC‐injured retinas. Silencing of SP1 in vivo reduced LINGO‐1 expression and protected the structure of RGCs from ONC‐induced injury, but there was no sign of recovery in VEP. Conclusions Our findings imply that SP1 regulates LINGO‐1 expression in RGCs in the injured retina and provide insight into mechanisms underlying LINGO‐1–mediated RGC death in optic nerve injury.

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Stroke in the eye of the beholder

Cited by 6 publications

References 25 publications

Neuroprotective impact of prothymosin alpha-derived hexapeptide against retinal ischemia–reperfusion

Neuroprotective impact of prothymosin alpha-derived hexapeptide against retinal ischemia–reperfusion

Eyeballing stroke: Blood flow alterations in the eye and visual impairments following transient middle cerebral artery occlusion in adult rats

SP1‐mediated upregulation of LINGO‐1 promotes degeneration of retinal ganglion cells in optic nerve injury

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