Abstract
Purpose: :
To investigate how OPA1 expression and distribution is altered by increased nitric oxide (NO), and whether aminoguanidine, a relative selective NO synthase-2 (NOS-2) inhibitor, can restore OPA1 expression and subsequently increase retinal ganglion cell (RGC) survival in ocular hypertensive rats.
Methods: :
Elevated intraocular pressure was induced unilaterally by translimbal laser photocoagulation of the trabecular meshwork in Sprague-Dawley rats. Aminoguanidine (100mg/kg) was administered by intraperitoneal injection for 3 consecutive days in rats following laser treatment. Preservation of FluoroGold-labeled RGCs was assessed 2 weeks later. GFAP, NOS-2 or OPA1 protein expression and distribution were assessed by Western blot and immunohistochemistry. OPA1 mRNA was measured by qPCR.
Results: :
OPA1 mRNA and protein expression were significantly increased in vehicle-treated hypertensive rat retina. Aminoguanidine treatment significantly reduced the expression of the 90- and 65-kDa OPA1 isoforms, but did not significantly change the 80-kDa OPA1 isoform in hypertensive retina. Also, the increase of NOS-2 and GFAP protein expression were blocked by aminoguanidine treatment in hypertensive retina. NOS-2 immunoreactivity was induced in cells of the ganglion cell layer in vehicle-treated hypertensive retina. Aminoguanidine treatment significantly increased RGC survival at 2 weeks following IOP elevation.
Conclusions: :
While NOS-2/NO induction may contribute to hypertensive retinal cell death, mitochondrial OPA1 increase may provide an important cellular defense mechanism against pressure-mediated retinal damage. These findings suggest that mitochondrial preservation following inhibition of NOS-2 may be useful for protecting RGCs against glaucomatous damage.
Keywords: mitochondria • nitric oxide • neuroprotection