SIRT1 promotes RGC survival and delays loss of function following optic nerve crush

Activation of SIRT1 deacetylase prevents retinal ganglion cell (RGC) loss in experimental optic neuritis, an inflammatory optic neuropathy. While mechanisms of this effect are not known, evidence suggests it involves reduction of oxidative stress. We hypothesized that SIRT1 reduces RGC loss due to oxidative stress in noninflammatory optic neuropathies, and examined effects following traumatic injury. Optic nerve crush injury was induced in wild-type C57BL/6 mice, mice overexpressing SIRT1, and mice with conditional deletion of SIRT1 in neurons. Wild-type mice were treated daily with vehicle or 250 mg/kg resveratrol, a naturally occurring polyphenol that activates SIRT1. RGC function was assessed by pupillometry and optokinetic responses (OKR), and RGC survival was measured. Superoxide levels were measured to assess oxidative stress. Significant decreases in pupillary light responses, OKR and RGC survival occurred 1 week after optic nerve crush, with progressive worsening at 2 to 4 weeks. Resveratrol treatment and SIRT1 overexpression delayed RGC loss and loss of pupillary light responses following optic nerve crush, although no change in RGC loss occurred in neuronal SIRT1-deficient mice. A significant accumulation of superoxide was detected in wild-type optic nerves following crush, and was reduced in mice overexpressing SIRT1 or treated with resveratrol. SIRT1 delays RGC loss following traumatic injury. Effects are associated with reduced oxidative stress. Results suggest SIRT1-activating drugs may have a specific role in preventing traumatic optic nerve damage, and suggest a broader role for this strategy in treating a variety of optic neuropathies that may include a component of oxidative stress.