Abstract
Purpose :
Traumatic optic neuropathy (TON) is a condition in which acute injury to the optic nerve, and typically results in permanent vision loss. TON frequently happens in traumatic brain injury (TBI), which can occur during motor vehicle accidents, sports, recreational activities and military combat. At present, there is no proven treatment available for this condition despite numerous prior studies. Therefore, new treatment options for TON are highly needed. Prior studies showed that SIRT1 deacetylase overexpression promotes retinal ganglion cell (RGC) survival and delays loss of visual function in an optic nerve crush model of TON. The ability of SIRT1 overexpression to suppress RGC loss and vision loss in an experimental closed head trauma model of TON was examined.
Methods :
TON was induced in wild-type C57/BL6 mice and mice overexpressing SIRT1 by five consecutive hits in the center of the skull with an interconcussion interval of 48 hours using an Impact one stereotaxic impactor at a strike velocity of 5 m/sec, strike depth of 1 mm and dwell time of 200 millisecond. Visual function was assessed by optokinetic responses (OKR) at baseline, then weekly until sacrifice 6 weeks or 10 weeks post-injury. Retinas were isolated, and RGCs were immunolabeled with Brn3a antibodies and counted to quantify RGC survival.
Results :
Decreases in OKR scores occurred in wild-type TON mice compared to control mice by week 2. SIRT1 knock-in TON mice showed a significant improvement in OKR scores compared with wild-type TON mice (p<0.05). At both 6 weeks and 10 weeks post-injury, TON mice showed significant (p<0.001) loss of RGCs compared to control mice. SIRT1 knock-in TON mice showed a significant preservation of RGCs at 6 weeks post TON, with limited effects in preventing RGC death by 10 weeks post TON.
Conclusions :
Results substantially strengthen evidence that SIRT1 mediated neuroprotection occurs following TON. SIRT1 overexpression delays visual dysfunction and RGC loss following TON. Therefore, SIRT1 activating drugs or gene therapy to overexpress SIRT1 may represent a promising neuroprotective therapy for TON, and suggests a possible broader role for this strategy in the management of a variety of optic neuropathies, which warrants further investigation.
This is a 2020 ARVO Annual Meeting abstract.