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Microsphere antioxidant and sustained erythropoietin-R76E release functions cooperate to reduce traumatic optic neuropathy.

ABSTRACT: Wild-type erythropoietin (EPO) is promising for neuroprotection, but its therapeutic use is limited because it causes a systemic rise in hematocrit. We have developed an EPO-R76E derivative that maintains neuroprotective function without effects on hematocrit, but this protein has a short half-life in vivo. Here, we compare the efficacy and carrier-induced inflammatory response of two polymeric microparticle (MP) EPO-R76E sustained release formulations based on conventional hydrolytically degradable poly(lactic-co-glycolic acid) (PLGA) and reactive oxygen species (ROS)-degradable poly(propylene sulfide) (PPS). Both MP types effectively loaded EPO-R76E and achieved sustained release, providing detectable levels of EPO-R76E at the injection site in the eye in vivo for at least 28 days. Testing in an in vitro oxidative stress assay and a mouse model of blast-induced indirect traumatic optic neuropathy (bITON) showed that PPS and PLGA MP-mediated delivery of EPO-R76E provided therapeutic protection. While unloaded PLGA MPs inherently increase levels of pro-inflammatory cytokines in the bITON model, drug-free PPS MPs have innate antioxidant properties that provide therapeutic benefit both in vitro and in vivo. Both PLGA and PPS MPs enabled sustained release of EPO-R76E, providing therapeutic benefits including reduction in inflammation and axon degeneration, and preservation of visual function as measured by electroretinogram. The PPS-based MP platform is especially promising for further development, as the delivery system provides inherent antioxidant benefits that can be harnessed to work in complement with EPO-R76E or other drugs for neuroprotection in the setting of traumatic eye injury.

SUBMITTER: DeJulius CR

PROVIDER: S-EPMC8162757 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTraumatic optic neuropathy (TON) is an important cause of severe visual loss following blunt or penetrating head trauma. Following the initial injury, optic nerve swelling within the optic nerve canal can result in secondary retinal ganglion cell loss. Optic nerve decompression with steroids or surgical interventions or both has therefore been advocated as a means of improving visual prognosis in TON.ObjectivesThe aim of this review was to examine the effectiveness and safety of using steroids in TON.Search methodsWe searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 4), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to May 2013), EMBASE (January 1980 to May 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to May 2013), Web of Science Conference Proceedings Citation Index- Science (CPCI-S) (January 1990 to May 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (http://clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 21 May 2013. We also searched the reference lists of included studies, other reviews and book chapters on TON to find references to additional trials. The Science Citation Index was used to look for papers that cited the studies included in this review. We did not manually search any journals or conference proceedings. We contacted trial investigators and experts in the field to identify additional published and unpublished studies.Selection criteriaWe planned to include only randomised controlled trials (RCTs) of TON in which any steroid regime, either on its own or in combination with surgical optic nerve decompression, was compared to surgery alone or no treatment.Data collection and analysisTwo review authors independently assessed the titles and abstracts identified from the electronic searches.Main resultsWe included one study that met our selection criteria; a double-masked, placebo-controlled, randomised trial of high dose intravenous steroids in patients with indirect TON diagnosed within seven days of the initial injury. A total of 31 eligible participants were randomised to receive either high dose intravenous steroids (n = 16) or placebo (n = 15), and they were all followed-up for three months. Mean final best corrected visual acuity (BCVA) was 1.78±1.23 Logarithm of the Minimum Angle of Resolution (LogMAR) in the placebo group, and 1.11±1.14 LogMAR in the steroid group. The mean difference in BCVA between the placebo and steroid groups was 0.67 LogMAR (95% confidence interval -1.54 to 0.20), and this difference was not statistically significant (P = 0.13). At three months follow-up, an improvement in BCVA of 0.40 LogMAR occurred in eight eyes (8/15, 53.3%) in the placebo group, and in 11 eyes (11/16, 68.8%) in the treatment group. This difference was not statistically significant (P = 0.38).Authors' conclusionsThere is a relatively high rate of spontaneous visual recovery in TON and there is no convincing data that steroids provide any additional visual benefit over observation alone. Recent evidence also suggests a possible detrimental effect of steroids in TON and further studies are urgently needed to clarify this important issue. Each case therefore needs to be assessed on an individual basis and proper informed consent is paramount.

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Microsphere antioxidant and sustained erythropoietin-R76E release functions cooperate to reduce traumatic optic neuropathy.

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