Caspase-9 Mediates Photoreceptor Death After Blunt Ocular Trauma

Ahmed, Zubair; Thompson, Adam; Akpan, Nsikan; Snead, David; Berry, Martin; Troy, Carol M.; Scott, Robert A H; Logan, Ann

doi:10.1167/iovs.13-13708

Cited by 12 publications

(27 citation statements)

References 22 publications

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“…It is known that disks die from apoptosis, for which a causative explanation is still lacking (Fain et al ., ). One pathway triggering caspase‐mediated apoptosis is the formation of apoptosomes, involving caspase 9 activation by Cyt c and their binding to cytosolic Apaf‐1 (Blanch et al ., ). Our previous proteomic analysis showed that Cyt c was expressed in the disks and that ATP synthase in the disk was outward facing (Panfoli et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Effect of polyphenolic phytochemicals on ectopic oxidative phosphorylation in rod outer segments of bovine retina

Calzia

Oneto

Caicci

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEThe rod outer segments (OS) of the retina are specialized organelles where phototransduction takes place. The mitochondrial electron transport complexes I-IV, cytochrome c and FoF1-ATP synthase are functionally expressed in the OS disks. Here, we have studied the effect of some polyphenolic compounds acting as inhibitors of mitochondrial ATPase/synthase activity on the OS ectopic FoF1-ATP synthase. The mechanism of apoptosis in the OS was also investigated studying the expression of cytochrome c, caspase 9 and 3 and Apaf-1. EXPERIMENTAL APPROACHWe prepared OS from fresh bovine retinae. Semi-quantitative Western blotting, confocal and electron microscopy, and cytofluorimetry were used along with biochemical analyses such as oximetry, ATP synthesis and hydrolysis. KEY RESULTSResveratrol and curcumin plus piperine inhibited ATP synthesis and oxygen consumption in the OS. Epigallocatechin gallate and quercetin inhibited ATP hydrolysis and oxygen consumption in the OS. Malondialdehyde and hydrogen peroxide were produced in respiring OS in the presence of substrates. Cytochrome c was located inside the disk membranes. Procaspase 9 and 3, as well as Apaf-1 were expressed in the OS. CONCLUSIONS AND IMPLICATIONSThese polyphenolic phytochemicals modulated the FoF1-ATP synthase activity of the the OS reducing production of reactive oxygen intermediates by the OS ectopic electron transport chain. Polyphenols decrease membrane peroxidation and cytochrome c release from disks, preventing the induction of caspase-dependent apoptosis in the OS Such effects are relevant in the design of protection against functional impairment of the OS following oxidative stress from exposure to intense illumination.

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Section: Introductionmentioning

confidence: 97%

Effect of polyphenolic phytochemicals on ectopic oxidative phosphorylation in rod outer segments of bovine retina

Calzia

Oneto

Caicci

et al. 2015

British J Pharmacology

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“…9 Additionally, photoreceptor damage and degeneration after direct blunt ocular trauma has been well documented in human 34,35 and animal models. [36][37][38] Our method of whole globe histological analysis revealed an acute anterior uveitis, a finding not previously reported in studies utilizing the FPI model where instead delayed axonal swelling and damage to the optic nerve has been documented, as well as disruption of the bloodbrain barrier (BBB). 26 We did see BBB damage 24 h post LFPI, demonstrated by the immunohistochemical staining of mouse IgG at the injury site; additionally, a loss of BBB integrity using the bTBI model occurring within the 24 h post injury has been previously well established.…”

Section: Discussionmentioning

confidence: 76%

“…While we did not assess visual acuity in the bTBI mice, the loss of the photoreceptor layer observed would ultimately impair vision and this photoreceptor degeneration could mirror one of the mechanisms leading to vision loss seen in some human blast injuries 9. Additionally, photoreceptor damage and degeneration after direct blunt ocular trauma has been well documented in human34, 35 and animal models 36, 37, 38…”

Section: Discussionmentioning

confidence: 99%

Acute vitreoretinal trauma and inflammation after traumatic brain injury in mice

Evans

Newell

Mahajan

et al. 2018

Ann Clin Transl Neurol

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ObjectiveLimited attention has been given to ocular injuries associated with traumatic brain injury (TBI). The retina is an extension of the central nervous system and evaluation of ocular damage may offer a less‐invasive approach to gauge TBI severity and response to treatment. We aim to characterize acute changes in the mouse eye after exposure to two different models of TBI to assess the utility of eye damage as a surrogate to brain injury.MethodsA model of blast TBI (bTBI) using a shock tube was compared to a lateral fluid percussion injury model (LFPI) using fluid pressure applied directly to the brain. Whole eyes were collected from mice 3 days post LFPI and 24 days post bTBI and were evaluated histologically using a hematoxylin and eosin stain.Results bTBI mice showed evidence of vitreous detachment in the posterior chamber in addition to vitreous hemorrhage with inflammatory cells. Subretinal hemorrhage, photoreceptor degeneration, and decreased cellularity in the retinal ganglion cell layer was also seen in bTBI mice. In contrast, eyes of LFPI mice showed evidence of anterior uveitis and subcapsular cataracts.InterpretationWe demonstrated that variations in the type of TBI can result in drastically different phenotypic changes within the eye. As such, molecular and phenotypic changes in the eye following TBI may provide valuable information regarding the mechanism, severity, and ongoing pathophysiology of brain injury. Because vitreous samples are easily obtained, molecular changes within the eye could be utilized as biomarkers of TBI in human patients.

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Section: Discussionmentioning

confidence: 99%

“…Improvement of our blast model in the future may also include looking at the visual system injury effects over a wide range of reasonable pressures (e.g., 10 -30 psi), repetitive blasts or combined primary and secondary insults (e.g., blast followed by weight drop induced skull-concussion). Others have shown that repetitive low level blasts, head concussions, or blunt force trauma to the eyes alone can lead to severe retinal degeneration in mice and rats (Blanch, 2012(Blanch, , 2014Tzekov, 2014;Choi, 2015).Also, while behavioral impairments in visual acuity tracking reflex (i.e., optokinetics) have been looked at (Hines-Beard, 2012;Bricker-Anthony, 2014b), no one has attempted to translate the retinal injuries into actual loss of performance on vision dependent psychomotor tasks. Indeed, for blasted rats, we saw a 30% decrease in retinal signaling with a 2 and 3-fold more neuronal cell damage in their retinas and brain optic tracts, respectively; however, most rats still performed quite well on the visual discrimination task.…”

mentioning

confidence: 99%

Evaluation of Novel Polyunsaturated Fatty Acid Derived Lipid Mediators of Inflammation to Ameliorate the Deleterious Effects of Blast Over Pressure on Eye and Brain Visual Processing Centers in Rats

DeMar¹

2015

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching e» sting data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information , 1215 Jefferson Davis HighWay, Suite 1204, Adington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. Blast inj ury has emerged as arguably the greatest threat to warfighters in current theaters of operation, and is a leading cause of vision loss in military personnel due to non-penetrating traumatic inj uries to the eyes and brain visual centers, likely caused by blast shock waves. In light of the difficult lifelong disability that permanent loss of vision represents, we propose there is an urgent need for new drug therapies that can arrest progression of neuronal cell death in the eye (retina) and brain, as result of exposure to blast w aves. Our hypothesis is that novel omega-6 and omega-3 polyunsaturated fatty acid derived lipid mediators of inflammation, i.e. , lipoxins, neuroprotectins, and resolvins, will aid as drugs in healing of neurons critical to visual function after blast wave induced eye and brain inj uries. Using an adult rat model of blast w ave exposure, during the first phase of the study, we rigorously characterized the cellular and functional damage to the eyes (retinas) and brain visual centers, by electroretinography (ERG), visual discrimination behavioral testing, and histopathology. Blast w ave inj ury was carried out by placing the rats in a compressed air driven shock tube and exposing them, in a right side on orientation, once to a 20 psi (260Hz) blast over pressure wave. Rats were assessed at baseline and then 1, 7, and 14 days post-exposure. By 7 to 14 days out, blasted rats versus shams showed significantly decreased ERG waveform amplitudes of retinal response to a light flash stimulus for the right side eyes (-30% less; n = 15 vs.14), a trend for impaired ability to visually discern a cue light to earn food rewards (-30% less; n = 10 vs. 11 ), and significant neuronal cell degeneration within the right side retinas and both brain optic tracts (2 and 3-fold more, respectively ; n = 15 vs. 14 ). ERG and histopathology results significantly correlated with each other (r = -0.7). There also was a strong relationship between the retina and brain optic tract cell damage (r = 0.8). Overall, our findings demonstrate that blast w ave exposure leads to loss of vision in rats, likely through retinal cell death follow ed by anter...

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Caspase-9 Mediates Photoreceptor Death After Blunt Ocular Trauma

Cited by 12 publications

References 22 publications

Effect of polyphenolic phytochemicals on ectopic oxidative phosphorylation in rod outer segments of bovine retina

Effect of polyphenolic phytochemicals on ectopic oxidative phosphorylation in rod outer segments of bovine retina

Acute vitreoretinal trauma and inflammation after traumatic brain injury in mice

Evaluation of Novel Polyunsaturated Fatty Acid Derived Lipid Mediators of Inflammation to Ameliorate the Deleterious Effects of Blast Over Pressure on Eye and Brain Visual Processing Centers in Rats

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