Neuroprotection by acetoacetate and β-hydroxybutyrate against NMDA-induced RGC damage in rat--possible involvement of kynurenic acid

TY - JOUR

T1 - Neuroprotection by acetoacetate and β-hydroxybutyrate against NMDA-induced RGC damage in rat--possible involvement of kynurenic acid

AU - Thaler, Sebastian

AU - Choragiewicz, Tomasz J

AU - Rejdak, Robert

AU - Fiedorowicz, Michal

AU - Turski, Waldemar A

AU - Tulidowicz-Bielak, Maria

AU - Zrenner, Eberhart

AU - Schuettauf, Frank

AU - Zarnowski, Tomasz

PY - 2010/12

Y1 - 2010/12

N2 - PURPOSE: This study investigated the effects of systemically administered lithium acetoacetate (ACA) and sodium β-hydroxybutyrate (BHB) in a rat model of N-methyl-D-aspartate (NMDA)-induced damage of retinal ganglion cells (RGC). Additionally, the influence of ACA and BHB on kynurenic acid (KYNA) production was assessed in vitro in bovine retinal slices.METHODS: Female adult Brown-Norway rats in groups of 5-8 animals were used. ACA and BHB were administered intraperitoneally once a day for 21 consecutive days, and phosphate buffered saline (PBS) was administered to control animals. After 2 weeks, the animals received intraocular NMDA (2 μl of a 10 mM solution in PBS) or intraocular PBS as a control. On day 19, retinal ganglion cells were labeled retrogradely with hydroxystilbamidine. Two days later, RGC density (cells per mm(2)) was assessed on retinal flatmounts. Additionaly, bovine retinal slices were incubated with NMDA and ACA or BHB at concentrations of 1.0 mM and 3.0 mM, and de novo KYNA production was measured using HPLC.RESULTS: Intraperitoneal ACA (250 mg/kg) or BHB (291.2 mg/kg) significantly protected RGC against NMDA-induced neurodegeneration. De novo KYNA production in bovine retinal slices was lowered by NMDA. Both ACA and BHB at a concentration of 3.0 mM significantly reduced the effects of NMDA.CONCLUSIONS: ACA and BHB had a significant dose-dependent neuroprotective effect on RGC in a rat model of NMDA-induced RGC damage. Both ketone bodies also significantly attenuated NMDA-induced reduction of retinal KYNA production in vitro, suggesting that this mechanism may be essential for the neuroprotective effects of ACA and BHB in vivo. Our results imply that ketone bodies may represent an additional treatment option in chronic neurodegenerative disorders of the eye.

AB - PURPOSE: This study investigated the effects of systemically administered lithium acetoacetate (ACA) and sodium β-hydroxybutyrate (BHB) in a rat model of N-methyl-D-aspartate (NMDA)-induced damage of retinal ganglion cells (RGC). Additionally, the influence of ACA and BHB on kynurenic acid (KYNA) production was assessed in vitro in bovine retinal slices.METHODS: Female adult Brown-Norway rats in groups of 5-8 animals were used. ACA and BHB were administered intraperitoneally once a day for 21 consecutive days, and phosphate buffered saline (PBS) was administered to control animals. After 2 weeks, the animals received intraocular NMDA (2 μl of a 10 mM solution in PBS) or intraocular PBS as a control. On day 19, retinal ganglion cells were labeled retrogradely with hydroxystilbamidine. Two days later, RGC density (cells per mm(2)) was assessed on retinal flatmounts. Additionaly, bovine retinal slices were incubated with NMDA and ACA or BHB at concentrations of 1.0 mM and 3.0 mM, and de novo KYNA production was measured using HPLC.RESULTS: Intraperitoneal ACA (250 mg/kg) or BHB (291.2 mg/kg) significantly protected RGC against NMDA-induced neurodegeneration. De novo KYNA production in bovine retinal slices was lowered by NMDA. Both ACA and BHB at a concentration of 3.0 mM significantly reduced the effects of NMDA.CONCLUSIONS: ACA and BHB had a significant dose-dependent neuroprotective effect on RGC in a rat model of NMDA-induced RGC damage. Both ketone bodies also significantly attenuated NMDA-induced reduction of retinal KYNA production in vitro, suggesting that this mechanism may be essential for the neuroprotective effects of ACA and BHB in vivo. Our results imply that ketone bodies may represent an additional treatment option in chronic neurodegenerative disorders of the eye.

KW - 3-Hydroxybutyric Acid/administration & dosage

KW - Acetoacetates/administration & dosage

KW - Animals

KW - Cell Count

KW - Chromatography, High Pressure Liquid

KW - Dose-Response Relationship, Drug

KW - Female

KW - Injections, Intraperitoneal

KW - Kynurenic Acid/metabolism

KW - N-Methylaspartate/toxicity

KW - Neuroprotective Agents/administration & dosage

KW - Rats

KW - Rats, Inbred BN

KW - Retinal Ganglion Cells/cytology

U2 - 10.1007/s00417-010-1425-7

DO - 10.1007/s00417-010-1425-7

M3 - SCORING: Journal article

C2 - 20532550

VL - 248

SP - 1729

EP - 1735

JO - GRAEF ARCH CLIN EXP

JF - GRAEF ARCH CLIN EXP

SN - 0721-832X

IS - 12

ER -