Valproic Acid Regulates Antioxidant Enzymes and Prevents Ischemia/Reperfusion Injury in the Rat Retina

Abstract

Purposes: To investigate whether valproic acid (VPA) has a neuroprotective effect against ischemia/reperfusion (I/R) injury in the rat retina, and to elucidate the potential antioxidant mechanisms involved.

Methods: Adult male Wistar rats were randomly divided into four groups: sham (group A), sham plus VPA (group B), I/R plus vehicle (group C), and I/R plus VPA (group D). Retinal I/R injury was produced by inducing an exceedingly high intraocular pressure (IOP). Prior to insult, VPA was administered subcutaneously (300 mg/kg twice daily) for 7 days, after which the animal was sacrificed. Levels of retinal malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) were determined. Protein expressions of retinal poly(ADP-ribose) (PAR) and nitrotyrosine (NT) were analyzed by Western blotting 24 h after injury. Apoptosis of retinal cells was evaluated 24 h after I/R injury by immunofluorescence of activated caspase-3 in histological sections of retina. Seven days after reperfusion, electroretinography (ERG) was performed, and retinal histological changes were examined by light microscopy.

Results: Following ischemia, the thickness of the entire retina, including the inner nuclear layer (INL) and inner plexiform layer (IPL), as well as the number of cells in the ganglion cell layer (GCL) were significantly greater in group D than in group C (p < 0.05). VPA suppressed I/R-induced reductions in ERG a- and b-wave amplitudes (p < 0.05). VPA attenuated I/R-induced activation of caspase-3 in ganglion cells and INL cells (p < 0.001). VPA significantly decreased MDA levels and increased activities of SOD, GSH-Px, and CAT in group D (p < 0.05). VPA attenuated activation of PAR and accumulation of NT in the retina after I/R (p < 0.01).

Conclusions: VPA protects the retina from I/R injury by enhancing anti-oxidative effects and inhibiting apoptosis of retinal cells.

KEYWORDS::

• Retina
• Valproic acid
• Ischemia/Reperfusion injury
• Oxidative stress
• Apoptosis

ACKNOWLEDGEMENTS

This study was supported by the Key Program of National Administration of Traditional Chinese Medicine, Shanghai, China (Grant No. 20062001) and the Opening Project of Shanghai Key Laboratory of Fundus Diseases, Shanghai, China (Grant No. 07Z22911).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. The paper has not been submitted simultaneously for publication elsewhere.