Neuroprotection by acetoacetate and β-hydroxybutyrate against NMDA-induced RGC damage in rat--possible involvement of kynurenic acid.
OBJECTIVE
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.
Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
Sebastian
S
Thaler
Tomasz J
TJ
Choragiewicz
Robert
R
Rejdak
Michal
M
Fiedorowicz
Waldemar A
WA
Turski
Maria
M
Tulidowicz-Bielak
Eberhart
E
Zrenner
Frank
F
Schuettauf
Tomasz
T
Zarnowski
D020155:3-Hydroxybutyric Acid / Q000008:administration & dosage*; D000090:Acetoacetates / Q000008:administration & dosage*; D000818:Animals; D002452:Cell Count; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D007274:Injections, Intraperitoneal; D007736:Kynurenic Acid / Q000378:metabolism*; D016202:N-Methylaspartate / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051381:Rats; D011914:Rats, Inbred BN; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D000090:Acetoacetates; D018696:Neuroprotective Agents; C016635:acetoacetic acid; D016202:N-Methylaspartate; D007736:Kynurenic Acid; D020155:3-Hydroxybutyric Acid