Neuroprotective Effect of Ketone Bodies and Ketogenic Diet in Nmda-Induced Rgc Damage in Rat. Possible Involvement of Kynurenic Acid?

Abstract

Purpose: : To investigate neuroprotective properties of ketogenic diet and the ketone bodies acetoacetate (ACA) and β-hydroxybutyrate (BHB) in a rat model of NMDA-induced damage of rat retinal ganglion cells (RGCs). Additionally the influence of ACA and BHB on retinal kynurenic acid (KYNA) production after NMDA was assessed in vitro in calf retinal slices.

Methods: : ACA in a dose of 250 mg/kg body weight, BHB in a dose of 291.2 mg/kg or PBS as control was administered intraperitoneally once a day for 21 days. Brown Norway rats 3 weeks of age and adult rats were fed with ketogenic diet or standard diet as control for 2 weeks prior to experiments. On day 14 animals received intravitreal NMDA (2µl, 10mM). RGC numbers were assessed 7 days thereafter using a retrolabelling method.For HPLC measurements of KYNA production, calf retinal slices were incubated with NMDA and different concentrations of ACA or BHB.

Results: : Numbers of RGC in retinas from animals treated with ACA, BHB or fed with ketogenic diet (only young animals) were significantly higher (48%, 41% and 25% increases respectively, P<0.05, U Mann-Whitney) than in those treated with PBS or fed with standard diet. However in adult rats ketogenic diet turned out to be ineffective. De novo KYNA production in calf retinal slices was reduced by NMDA. ACA or BHB attenuated this effect significantly (82.8% and 94.0% higher, P<0.001).

Conclusions: : The ketone bodies ACA and BHB act neuroprotectively in a rat model of NMDA-induced RGC damage. Ketogenic diet shows similar properties, but its effect is age-related. Attenuation of NMDA induced reduction of KYNA production may be essential for ketone bodies to exert their neuroprotective effects.

Keywords: neuroprotection