Remote Ischemic Post-Conditioning Therapy is Protective in Mouse Model of Traumatic Optic Neuropathy
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ORIGINAL PAPER
Remote Ischemic Post‑Conditioning Therapy is Protective in Mouse Model of Traumatic Optic Neuropathy Muhammad Nadeem1 · Adam Kindelin2 · Laura Mahady1 · Kanchan Bhatia2,3 · Md Nasrul Hoda1 · Andrew F. Ducruet2 · Saif Ahmad1,2 Received: 26 September 2020 / Accepted: 30 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Traumatic optic neuropathy (TON) is characterized by visual dysfunction after indirect or direct injury to the optic nerve following blunt head trauma. TON is associated with increased oxidative stress and inflammation resulting in retinal ganglion cell (RGC) death. Remote ischemic post-conditioning (RIC) has been shown to enhance endogenous protective mechanisms in diverse disease models including stroke, vascular cognitive impairment (VCI), retinal injury and optic nerve injury. However, the protective mechanisms underlying the improvement of retinal function and RGC survival after RIC treatment remain unclear. Here, we hypothesized that RIC therapy may be protective following TON by preventing RGC death, oxidative insult and inflammation in the mouse retina. To carry out the study, mice were divided in three different groups (Control, TON and TON + RIC). We harvested retinal tissue 5 days after TON induction for western blotting and histochemical analysis. We observed increased TON-induced retinal cell death compared with controls by cleaved caspase-3 immunohistochemistry. Furthermore, the TON cohort demonstrated increased TUNEL positive cells which were significantly attenuated by RIC. Immunofluorescence data showed that oxidative stress markers dihydroethidium (DHE), NOX-2 and nitrotyrosine expression were elevated in the TON group relative to controls and RIC therapy significantly reduced the expression level of these markers. Next, we found that the proinflammatory cytokine TNF-α was increased and anti-inflammatory IL-10 was decreased in plasma of TON animals, and RIC therapy reversed this expression level. Interestingly, western blotting of retinal tissue showed that RGC marker Brn3a and tight junction proteins (ZO-1 and Occludin), and AMPKα1 expression were downregulated in the TON group compared to controls. However, RIC significantly increased the expression levels of these proteins. Together these data suggest that RIC therapy activates endogenous protective mechanisms which may attenuate TON-induced oxidative stress and inflammation, and improves BRB integrity. Keywords Remote-limb ischemic conditioning (RIC) · Optic nerve injury · Oxidative stress · Inflammation · Tight junction
Introduction Traumatic optic neuropathy (TON) has been recognized as common visual impairment in head or ocular trauma suffered during a motor vehicle accident, natural disaster and in war. TON patients exhibit visual deficits varying from * Saif Ahmad [email protected] 1
Department of Neurobiology, Barrow Neurological Institute, SJHMC, Dignity Health, Phoenix, AZ 85013, USA
2
Department of Neurosurgery, Barrow Neurological Institute, S
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