Abstract
Purpose:
SIRT1 activation prevents loss of retinal ganglion cells (RGCs) in experimental optic neuritis. While the mechanism of this effect is unknown, a role in reduction of oxidative stress has been suggested. Because oxidative stress is a common mechanism of neuronal damage, we hypothesized that SIRT1 may reduce RGC loss due to oxidative stress following traumatic injury.
Methods:
Optic nerve crush injury was induced in wild-type C57/Bl6 mice as well as mice overexpressing SIRT1, and mice with a conditional knockdown of SIRT1 in neurons. Wild-type control and optic nerve crush mice were treated daily with vehicle or 250 mg/kg resveratrol, a naturally-occurring polyphenol that can activate SIRT1. Visual function was assessed by pupillometry and optokinetic responses (OKR), and RGC survival was measured by counting fluorogold labeled cells. Accumulation of the reactive oxygen species superoxide was measured by MitoSOX Red staining to assess oxidative stress.
Results:
Optic nerve crush induced significant decreases in pupillary light responses, OKR and RGC survival one week after optic nerve crush, with progressive worsening at 2-4 weeks. Overexpression of SIRT1 and treatment with resveratrol delayed loss of vision and RGCs following optic nerve crush, although no change in RGC loss occurred in neuronal SIRT1-deficient mice. MitoSOX Red staining showed accumulation of superoxide in wild type optic nerves following crush, and was reduced in mice overexpressing SIRT1 or treated with resveratrol.
Conclusions:
SIRT1 delays RGC loss following traumatic injury, similar to its ability to prevent RGC loss during optic neuritis. Effects are likely due to 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 wide variety of optic neuropathies that may include a component of oxidative stress.
Keywords: 613 neuro-ophthalmology: optic nerve •
615 neuroprotection •
531 ganglion cells