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Graefe's Archive for Clinical and Experimental Ophthalmology
 
Graefes Arch Clin Exp Ophthalmol. 2010 December; 248(12): 1729–1735.
Published online 2010 June 8. doi:  10.1007/s00417-010-1425-7
PMCID: PMC2974203

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

Abstract

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 mm2) 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.

Keywords: β-hydroxybutyrate, Acetoacetate, Retinal ganglion cells, Kynurenic acid, Neuroprotection

Introduction

The anticonvulsant effects of ketogenic diets have been clinically used for decades in the treatment of epilepsy (see [1] for a review). In recent years, accumulating evidence indicates a neuroprotective action of ketone bodies in various neurodegenerative disorders of the brain.

A ketogenic diet consists of a high fat content (80–90%) with little, but sufficient protein and insufficient carbohydrates for normal metabolism. Under a ketogenic diet, fat is metabolized in the liver into the ketone bodies acetoacetate (ACA), β-hydroxybutyrate (BHB) and acetone, thus providing an alternative energy source for glucose. The production of ketone bodies is especially important in brain metabolism, which under normal circumstances depends mainly on glucose. In contrast to fatty acids, ketone bodies can cross the blood-brain barrier—in the case of BHB and ACA with the help of monocarboxylate transporters [2].

In recent years, several studies have shown neuroprotective properties of the ketone bodies BHB and ACA in experimental models of neurodegenerative diseases of the brain, in particular Parkinson’s disease or Alzheimer’s disease but also in traumatic brain injury or cerebral hypoxia [38].

It is of importance that crucial pathways leading to deceleration of neuronal degeneration in chronic neurodegenerative diseases of other brain regions, i.e., Alzheimer’s or Parkinson’s disease, share similar characteristics with neurodegenerative diseases of the retina, e.g., glaucoma, diabetic retinopathy, ischemia, and secondary degeneration after optic nerve trauma. Glutamate-related excitotoxicity has been implicated as a key contributing factor in different neurodegenerative disorders of the brain (see [9] for a review) including glaucomatous retinal ganglion cell (RGC) loss or in retinal ischemia [10, 11]. Excitotoxic damage is thought to be mediated partly by overstimulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors, leading to intracellular Ca2+ elevation and consecutively to mitochondrial dysfunction and an excess of free radical formation [12]. Increase of oxidative stress and nitric oxide derived (nitrosative) stress has been shown to play an important role in experimental models of glaucoma and other neurodegenerative diseases [1315].

Notably, ketone bodies can exert effective neuroprotection in different models of neuronal excitotoxicity and ischemia [4, 16]. Although the underlying mechanisms are not fully understood, both an elevation of ATP production via Kreb’s cycle, and mitochondrial membrane stabilization, seem to play an important role [17, 18]. Other highly interesting possibilities include enhancement of antioxidative mechanisms and modulation of endogenous neuroprotectants, in particular kynurenic acid (KYNA), an excitatory amino acid antagonist [19].

In the present study, we tested the effects of the systemically applied ketone bodies ACA and BHB on the survival of RGC in a rat model with NMDA-induced excitotoxic RGC damage. We also evaluated the effects of ACA and BHB on de novo production of KYNA in bovine retinas. To our knowledge, this is the first time that effects of ketone bodies in a retinal neurodegeneration model have been systematically studied.

Material and methods

Animals

Adult female Brown–Norway rats (Charles River, Sulzfeld, Germany) with a body weight (BW) of 150–200 g were used. The animals were kept under a 12-hour light–dark cycle with food and water ad libitum. All experiments were performed in compliance with the ARVO (Association for Research in Vision and Ophthalmology) statement for the Use of Animals in Ophthalmic and Vision research.

Ketone bodies—intraperitoneal injections

The ketone bodies lithium acetoacetate (ACA) and sodium β-hydroxybutyrate (BHB) (both Sigma-Aldrich, Munich, Germany) were dissolved in 0.1 M phosphate buffered saline (PBS, pH 7.4) to a concentration of 10% w/v as a stock solution.

Intraperitoneal injections were performed once a day for 21 consecutive days on four treatment groups and one control group (n = 5–8): (1) ACA (62.5 mg/kg BW), (2) ACA (250 mg/kg BW), (3) BHB (72.8 mg/kg BW), (4) BHB (291.2 mg/kg BW), and (5) PBS alone.

NMDA injections

On day 14, animals received intravitreal injections of NMDA versus PBS. Rats were anesthetized with an intraperitoneal injection of chloral hydrate (7%, 6 ml/kg BW). Single injections of 10 mM NMDA (Sigma-Aldrich, Munich, Germany) in 0.1 M PBS (pH 7.4) were administered intravitreally with a heat-pulled glass capillary connected to a microsyringe (Drummond Scientific Co., Broomall, PA, USA) under direct observation through a microscope. The capillary was inserted approximately 1 mm posterior to the corneal limbus at the temporal inferior side (OD: eight o’clock position, OS: four o’clock position). Animals with visible lens damage were excluded from the experiments and not used thereafter. A single injection of 2 μl NMDA was given. In each case, the contralateral eye served as a control eye and was injected with PBS.

Quantification of retinal ganglion cells

On day 19, retrograde labeling of RGC was performed. Animals were anaesthetized with chloral hydrate, and 7 µl of the fluorescent tracer hydroxystilbamidine methanesulfonate (Fluorogold, Molecular Probes, Eugene, OR, USA) was injected stereotaxically into each superior colliculus. Two days later, the number of RGC (cells per mm2) was assessed. The animals were sacrificed with CO2; the eyes were enucleated, and the retinas dissected, flat-mounted on cellulose nitrate filters (pore size 60 m; Sartorius, Long Island, NY) and fixed in 2% paraformaldehyde for 30 min. Labeled cells were defined as surviving. Visualization of RGC was performed on the same day by fluorescence microscopy. Images obtained using a digital imaging system (ImagePro 3.0, Media Cybernetics Inc., Silver Spring, MD, USA) connected to a microscope were coded and analyzed in a masked fashion. Three areas of 0.04 mm2 each per retinal quadrant at three different eccentricities of one-sixth, one-half, and five-sixths of the retinal radius were counted, corresponding to 0.7 mm, 2.0 mm, and 3.3 mm distance from the optic nerve head at the 45°, 135°, 225°, and 315° meridian [20]. Labeled cells were thereby counted in 12 distinct areas of 62,500 µm2 each in each retina. The data are presented as the mean RGC count per mm2 of retina±SEM, unless stated otherwise.

KYNA production—in vitro

Assessment of de novo KYNA production was performed using the method of Turski et al. [21]. Adult bovine eyes were obtained from a local slaughterhouse up to 2 hours post mortem (n = 5–7). Briefly, their retinas were cut in slices with a McIlwain tissue chopper and put on culture wells containing 1 ml oxygenated Krebs-Ringer buffer, pH 7.4. Following 10 min of preincubation at 37°C, the tissues were incubated with 25 μM L-kynurenine, 1–3 mM NMDA (leading to reduction of KYNA production by 40–60%, see also [22]) and 1.0 mM and 3.0 mM ACA or BHB for 2 hours. ACA and BHB were added to the incubation media 15 min before NMDA, and NMDA 15 min before L-kynurenine. Afterwards, the media were separated from the tissue and applied to the cation-exchange columns (Dowex 50+W). KYNA was eluted with 2 ml water, and the eluate was subjected to high-performance liquid chromatography (HPLC). KYNA was detected fluorimetrically according to the method of Shibata [23]. KYNA production was measured in pmol/well.

Statistical analysis

Statistical analysis was performed using GraphPad Prism version 4.01 for Windows (GraphPad Software, San Diego, CA, USA, www.graphpad.com). Analysis of variance (ANOVA) was performed followed by Bonferroni’s multiple comparisonpost-hoc test. Differences were regarded significant when p  < 0.05. Unless stated otherwise, the data are presented as means with respective standard errors.

Results

Effect of NMDA on RGC

When injected intravitreally, NMDA reduced RGC numbers from 2,364 ± 37 cells/mm2 (mean ± SEM; n  = 6; PBS injected controls) to 217 ± 6 cells/mm2 (n  = 6) (Figs. 1 and and22).

Fig. 1
Retinal flatmounts of rat retinas. RGCs were backlabeled with the fluorescent marker hydroxystilbamidine. a Control, no NMDA. b-f Seven days after intraocular injection of NMDA in groups intraperitoneally treated with (b) PBS as control, (c) ACA 62.5 mg/kg, ...
Fig. 2
RGC numbers 7 days after intraocular NMDA injections in systemically ACA- and BHB-treated animals, PBS served as control (n  = 6). ACA was used in the following doses: 250 mg/kg in PBS-treated eyes (n  = 5); ...

Effect of NMDA on RGC in ACA treated animals

RGC density in retinas collected from NMDA-injected eyes after 21 days of treatment intraperitoneally with ACA 62.5 and 250 mg/kg was 190 ± 14 cells/mm2 (n  = 4) and 322 ± 25 cells/mm2 ( = 5) respectively. The mean cell count in rats treated with 250 mg/kg ACA was significantly higher (p  < 0.001) than in the PBS-injected controls (Figs. 1 and and22).

Effect of NMDA on RGC in BHB treated animals

RGC density in retinas collected from NMDA-injected eyes after 21 days of treatment with intraperitoneally injected BHB 72.8 and 291.2 mg/kg was 178 ± 10 cells/mm2 (n  = 5) and 307 ± 17 cells/mm2 (n  = 5) respectively. The mean cell count in eyes treated with BHB in a dose of 291.2 mg/kg was significantly higher ( < 0.01) than in the PBS-injected controls (Figs. 1 and and22).

Effect of ACA and BHB on RGC in control animals

Neither ACA nor BHB treatment affected RGC density in PBS-injected eyes. RGC density in retinas collected from PBS-injected eyes was 2328 ± 60 cells/mm2 (n  = 5) for ACA-treated rats and 2310 ± 51 cells/mm2 ( = 5) for BHB-treated rats.

Effect of ACA on KYNA production in bovine retinal slices

NMDA decreased de novo production of KYNA to 41.2% (p  < 0.001) of that in controls. ACA 3.0 mM significantly countered this: KYNA production after NMDA remained at 75.3% of that in controls (p  < 0.001). However, ACA 1.0 was ineffective in this respect. Incubation of retinal slices with ACA 1.0 or 3.0 mM without NMDA did not change KYNA production (Fig. 3).

Fig. 3
Effect of ACA on de novo KYNA production in bovine retinal slices. Data is given as percentage of control. Control slices (n  = 6) were incubated with 25 µM L-kynurenine alone. NMDA treated slices (n ...

Effect of BHB on KYNA production in bovine retinal slices

NMDA decreased de novo production of KYNA to 60.3% (p  < 0.01) of that in controls, but BHB 3.0 mM provided complete protection against NMDA-induced inhibition of KYNA production ( < 0.001). BHB 1.0 mM was ineffective in this respect. Incubation of retinal slices with BHB 1.0 or 3.0 mM without NMDA did not change KYNA production (Fig. 4).

Fig. 4
Effect of BHB on de novo KYNA production in bovine retinal slices. Data is given as percentage of positive control. Control slices ( = 6) were incubated with 25 µM L-kynurenine alone. NMDA-treated slices ...

Discussion

Ketogenic diets have been used for over 80 years in the treatment of epilepsy. Recently, neuroprotective properties of ketone bodies have been found in diverse models of such neurodegenerative diseases of the brain as Parkinson’s or Alzheimer’s disease, and in models of brain trauma, hypoxia or ischemia [38]. To date, however, similar studies regarding retinal degeneration have not been performed.

Excitotoxicity, which contributes to free radical formation and neuronal cell death, is an important factor in diverse chronic neurodegenerative diseases in the brain and also in the retina [4]. Excitatory neurotoxicity is mediated in part by overactivation of the NMDA-type glutamate receptor [12]. In the present study, an excitotoxic rat model of NMDA-induced RGC damage [24] was used to evaluate the neuroprotective properties of systemic application of the ketone bodies ACA and BHB in the retina.

In rats, a single intravitreal NMDA injection reduced the RGC number to around 10% of that in PBS-injected controls. This RGC loss is comparable to that found in other studies using NMDA-induced retinal degeneration [25, 26].

However, ACA and BHB ameliorated the cell damage induced by NMDA, and resulted in a relative RGC increase of 48.4% and 41.5% respectively when administered intraperitoneally for 21 days.

It is possible that the lithium fraction in the lithium salt of ACA leads to neuroprotective effects, as shown previously in a rat model of partial optic nerve crush. However, the amount of lithium in doses of ACA as high as 250 mg/kg is less than that which showed a significant neuroprotective effect in previous studies of the retina [27]. Furthermore, Massieu et al. demonstrated a protective effect of the lithium salt of ACA (250 mg/kg i.p.) but not of the lithium fraction alone in a model of glutamate-mediated neuronal damage in the hippocampus [4]. Although an additive effect of lithium and ACA cannot be excluded, a substantial modification of ACA’s effects by the lithium fraction seems unlikely. Moreover, the neuroprotective effect of BHB against RGC death was comparable to that of ACA, even though BHB is not a lithium compound.

Two other studies found similar results for ACA but not for BHB in vivo, whereas the effective dose of intraperitoneal ACA after glutamate-mediated neuronal damage in the hippocampus was the same as in our study [4, 28], BHB at 332 mg/kg failed to achieve a neuroprotective effect [28]. In contrast, another study on glutamate-mediated neuronal damage showed reduced levels of lipoperoxidation after a single intraperitoneal injection of 500 mg/kg BHB [29], and Suzuki et al. demonstrated prolonged survival times after intravenous application of 30 mg/kg BHB in a rat model of brain anoxia [6]. In all these studies, however, treatment times were shorter than in our study.

Plasma levels of ACA and BHB in rats have been shown to be increased from 0.06 mM (controls) to 0.6 mM 10 minutes after a single injection of 500 mg/kg ACA or BHB [29]. However, in vitro considerably higher concentrations (5 mM ACA and 4 mM BHB) were the most effective against glutamate toxicity in a mouse hippocampal cell line [16], in good agreement with our in vitro results in bovine retinal tissue.

How ketone bodies confer their neuroprotective effect on neuronal cells remains unclear, and several theories are currently under discussion. An important underlying mechanism may be an increase in neuronal stability due to enhanced ATP production [30, 31]. In accordance with this theory, Bough et al. found an increased number of mitochondrial profiles in rats fed a ketogenic diet, suggesting a stimulation of mitochondrial biogenesis and a higher phosphocreatine/creatine ratio in the hippocampus and higher available energy reserves [32]. Such an increased energy level of the neurons might ensure them a better supply of the Na/K-ATPase, leading to enhanced membrane stability, and thus providing an improved resistance to metabolic stress.

Other studies have found protective effects of ketogenic diet or ketone bodies against excitotoxic neuronal degeneration, and proposed that oxidative stress modulation rather than glutamate receptor modulation may be important for this effect [4, 16, 28, 33]. Direct interaction of ketone bodies with glutamate receptors has been shown only for L-BHB (voltage-dependent blockade of NMDA receptors), whereas ACA or D-BHB were not able to reduce NMDA, AMPA or Kainate receptor-induced currents [34, 35]. Furthermore, even though ACA has been demonstrated to have a protective effect in hippocampal cells, this protective effect was also found in cells which lacked glutamate receptors [16]. Such neuroprotective effects are probably due indirectly to an enhancement of cellular antioxidant capacity. Several studies describe an influence of ketone bodies on different antioxidative mechanisms of neuronal cells. Veech et al. showed that BHB is able to oxidize co-enzyme Q and reduce NADP+, thus reducing free radical formation [36]. In addition, the reduction of mitochondrial free radical formation resulting from an increase the NAD+/NADH ratio, along with the scavenging capacities of ACA and BHB for diverse reactive oxygen species (ROS), may contribute to neuroprotective effects, even when increase in oxidative stress is increased by excitotoxicity [29, 37].

Other factors which possibly play a role here include upregulation of glutathione peroxidase activity, an enzyme that can prevent lipid peroxidation, and upregulation of calbindin [33, 38, 39].

In addition to an indirect influence on glutamate-induced neurotoxicity via the antioxidant effects of ketogenic diet or ketone bodies, indirect glutamate receptor modulation via reversal of the NMDA-inhibiting effect on the production of KYNA, an endogenous NMDA receptor modulator, has been postulated, and may play an additional role in preventing glutamate-induced neurotoxicity [19, 40]. In our study, NMDA-induced reduction of de novo KYNA production in ACA- and BHB-incubated bovine retinas in vitro was significantly attenuated. This effect was much more pronounced than the increase in RGC numbers after treatment with ketone bodies in vivo; therefore, a sole survival effect of KYNA-producing cells in the in vitro setting seems rather unlikely. The in vivo situation, however, is not directly comparable to the in vitro setting; further studies have to show in detail how ketone bodies modify KYNA production in the context of excitotoxicity. Modulation of NMDA receptors via alteration of KYNA-levels is especially of therapeutic interest. Since NMDA receptors are essential for neuronal transmission, a full blockade of NMDA receptors would not be suitable for clinical application; rather, it would be preferable to prevent receptor overstimulation while reducing free radical formation [41, 42]. Ketone bodies therefore seem to offer interesting features for treatment or prevention of cellular damage in different neuronal degenerations.

This study showed for the first time that systemically applied ketone bodies exert a partial neuroprotective action against NMDA-induced RGC damage in rats. Moreover, ACA and BHB were found to attenuate NMDA-induced inhibition of KYNA production in retinas in vitro. We believe that the use of ketone bodies or ketogenic diets should be considered and further evaluated in the quest for effective therapeutic approaches in the treatment of retinal degenerations.

Acknowledgements

Supported by the EU (integrated project EVI-GENORET LSHG-CT-2005-512036).

MF and TC received support from the Kerstan Foundation in the form of a research fellowship. The authors thank Dr T. Kocki (Lublin, Poland) for technical assistance and Dr M. Gasior (USA) for valuable help in designing the experiments.

Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

References

1. Sinha SR, Kossoff EH. The ketogenic diet. Neurologist. 2005;11:161–170. doi: 10.1097/01.nrl.0000160818.58821.d2. [PubMed] [Cross Ref]
2. Pierre K, Pellerin L. Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem. 2005;94:1–14. doi: 10.1111/j.1471-4159.2005.03168.x. [PubMed] [Cross Ref]
3. Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. D-beta-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc Natl Acad Sci USA. 2000;97:5440–5444. doi: 10.1073/pnas.97.10.5440. [PubMed] [Cross Ref]
4. Massieu L, Haces ML, Montiel T, Hernandez-Fonseca K. Acetoacetate protects hippocampal neurons against glutamate-mediated neuronal damage during glycolysis inhibition. Neuroscience. 2003;120:365–378. doi: 10.1016/S0306-4522(03)00266-5. [PubMed] [Cross Ref]
5. Prins ML, Lee SM, Fujima LS, Hovda DA. Increased cerebral uptake and oxidation of exogenous betaHB improves ATP following traumatic brain injury in adult rats. J Neurochem. 2004;90:666–672. doi: 10.1111/j.1471-4159.2004.02542.x. [PubMed] [Cross Ref]
6. Suzuki M, Suzuki M, Sato K, Dohi S, Sato T, Matsuura A, Hiraide A. Effect of beta-hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and rats. Jpn J Pharmacol. 2001;87:143–150. doi: 10.1254/jjp.87.143. [PubMed] [Cross Ref]
7. Masuda R, Monahan JW, Kashiwaya Y. D-beta-hydroxybutyrate is neuroprotective against hypoxia in serum-free hippocampal primary cultures. J Neurosci Res. 2005;80:501–509. doi: 10.1002/jnr.20464. [PubMed] [Cross Ref]
8. Dardzinski BJ, Smith SL, Towfighi J, Williams GD, Vannucci RC, Smith MB. Increased plasma beta-hydroxybutyrate, preserved cerebral energy metabolism, and amelioration of brain damage during neonatal hypoxia ischemia with dexamethasone pretreatment. Pediatr Res. 2000;48:248–255. doi: 10.1203/00006450-200008000-00021. [PubMed] [Cross Ref]
9. Hynd MR, Scott HL, Dodd PR. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochem Int. 2004;45:583–595. doi: 10.1016/j.neuint.2004.03.007. [PubMed] [Cross Ref]
10. Dong CJ, Guo Y, Agey P, Wheeler L, Hare WA. Alpha2 adrenergic modulation of NMDA receptor function as a major mechanism of RGC protection in experimental glaucoma and retinal excitotoxicity. Invest Ophthalmol Vis Sci. 2008;49:4515–4522. doi: 10.1167/iovs.08-2078. [PubMed] [Cross Ref]
11. Casson RJ. Possible role of excitotoxicity in the pathogenesis of glaucoma. Clin Experiment Ophthalmol. 2006;34:54–63. doi: 10.1111/j.1442-9071.2006.01146.x. [PubMed] [Cross Ref]
12. Lipton SA. Pathologically-activated therapeutics for neuroprotection: mechanism of NMDA receptor block by memantine and S-nitrosylation. Curr Drug Targets. 2007;8:621–632. doi: 10.2174/138945007780618472. [PubMed] [Cross Ref]
13. Seki M, Lipton SA. Targeting excitotoxic/free radical signaling pathways for therapeutic intervention in glaucoma. Prog Brain Res. 2008;173:495–510. doi: 10.1016/S0079-6123(08)01134-5. [PubMed] [Cross Ref]
14. Coyle JT, Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science. 1993;262:689–695. doi: 10.1126/science.7901908. [PubMed] [Cross Ref]
15. Morizane C, Adachi K, Furutani I, Fujita Y, Akaike A, Kashii S, Honda Y. N(omega)-nitro-L-arginine methyl ester protects retinal neurons against N-methyl-D-aspartate-induced neurotoxicity in vivo. Eur J Pharmacol. 1997;328:45–49. doi: 10.1016/S0014-2999(97)83026-9. [PubMed] [Cross Ref]
16. Noh HS, Hah YS, Nilufar R, Han J, Bong JH, Kang SS, Cho GJ, Choi WS. Acetoacetate protects neuronal cells from oxidative glutamate toxicity. J Neurosci Res. 2006;83:702–709. doi: 10.1002/jnr.20736. [PubMed] [Cross Ref]
17. Gasior M, Rogawski MA, Hartman AL. Neuroprotective and disease-modifying effects of the ketogenic diet. Behav Pharmacol. 2006;17:431–439. doi: 10.1097/00008877-200609000-00009. [PMC free article] [PubMed] [Cross Ref]
18. Zhao Z, Lange DJ, Voustianiouk A, MacGrogan D, Ho L, Suh J, Humala N, Thiyagarajan M, Wang J, Pasinetti GM. A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neurosci. 2006;7:29. doi: 10.1186/1471-2202-7-29. [PMC free article] [PubMed] [Cross Ref]
19. Hodgkins PS, Schwarcz R. Interference with cellular energy metabolism reduces kynurenic acid formation in rat brain slices: reversal by lactate and pyruvate. Eur J Neurosci. 1998;10:1986–1994. doi: 10.1046/j.1460-9568.1998.00208.x. [PubMed] [Cross Ref]
20. Klöcker N, Cellerino A, Bähr M. Free radical scavenging and inhibition of nitric oxide synthase potentiates the neurotrophic effects of brain-derived neurotrophic factor on axotomized retinal ganglion cells in vivo. J Neuroscience. 1998;18:1038–1046. [PubMed]
21. Turski WA, Nakamura M, Todd WP, Carpenter BK, Whetsell WO, Jr, Schwarcz R. Identification and quantification of kynurenic acid in human brain tissue. Brain Res. 1988;454:164–169. doi: 10.1016/0006-8993(88)90815-3. [PubMed] [Cross Ref]
22. Zarnowski T, Bialek M, Rejdak R, Zrenner E, Junemann A, Zagorski Z, Kocki T, Turski WA. Kynurenic acid synthesis in bovine retinal slices—effect of glutamate agonists. J Neural Transm. 2006;113:1367–1372. doi: 10.1007/s00702-005-0423-0. [PubMed] [Cross Ref]
23. Shibata K. Fluorimetric micro-determination of kynurenic acid, an endogenous blocker of neurotoxicity, by high-performance liquid chromatography. J Chromatogr. 1988;430:376–380. doi: 10.1016/S0378-4347(00)83173-4. [PubMed] [Cross Ref]
24. Siliprandi R, Canella R, Carmignoto G, Schiavo N, Zanellato A, Zanoni R, Vantini G. N-methyl-D-aspartate induced neurotoxicity in the adult rat retina. Vis Neurosci. 1992;8:567–573. doi: 10.1017/S0952523800005666. [PubMed] [Cross Ref]
25. Kido N, Tanihara H, Honjo M, Inatani M, Tatsuno T, Nakayama C, Honda Y. Neuroprotective effects of brain-derived neurotrophic factor in eyes with NMDA-induced neuronal death. Brain Res. 2000;884:59–67. doi: 10.1016/S0006-8993(00)02887-0. [PubMed] [Cross Ref]
26. Schuettauf F, Zurakowski D, Quinto K, Varde MA, Besch D, Laties A, Anderson R, Wen R. Neuroprotective effects of cardiotrophin-like cytokine on retinal ganglion cells. Graefes Arch Clin Exp Ophthalmol. 2005;243:1036–1042. doi: 10.1007/s00417-005-1152-7. [PubMed] [Cross Ref]
27. Schuettauf F, Rejdak R, Thaler S, Bolz S, Lehaci C, Mankowska A, Zarnowski T, Junemann A, Zagorski Z, Zrenner E, Grieb P. Citicoline and lithium rescue retinal ganglion cells following partial optic nerve crush in the rat. Exp Eye Res. 2006;83:1128–1134. doi: 10.1016/j.exer.2006.05.021. [PubMed] [Cross Ref]
28. Massieu L, Del RP, Montiel T. Neurotoxicity of glutamate uptake inhibition in vivo: correlation with succinate dehydrogenase activity and prevention by energy substrates. Neuroscience. 2001;106:669–677. doi: 10.1016/S0306-4522(01)00323-2. [PubMed] [Cross Ref]
29. Haces ML, Hernandez-Fonseca K, Medina-Campos ON, Montiel T, Pedraza-Chaverri J, Massieu L. Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions. Exp Neurol. 2008;211:85–96. doi: 10.1016/j.expneurol.2007.12.029. [PubMed] [Cross Ref]
30. DeVivo DC, Leckie MP, Ferrendelli JS, McDougal DB., Jr Chronic ketosis and cerebral metabolism. Ann Neurol. 1978;3:331–337. doi: 10.1002/ana.410030410. [PubMed] [Cross Ref]
31. Tieu K, Perier C, Caspersen C, Teismann P, Wu DC, Yan SD, Naini A, Vila M, Jackson-Lewis V, Ramasamy R, Przedborski S. D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J Clin Invest. 2003;112:892–901. [PMC free article] [PubMed]
32. Bough KJ, Wetherington J, Hassel B, Pare JF, Gawryluk JW, Greene JG, Shaw R, Smith Y, Geiger JD, Dingledine RJ. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol. 2006;60:223–235. doi: 10.1002/ana.20899. [PubMed] [Cross Ref]
33. Mejia-Toiber J, Montiel T, Massieu L. D-beta-hydroxybutyrate prevents glutamate-mediated lipoperoxidation and neuronal damage elicited during glycolysis inhibition in vivo. Neurochem Res. 2006;31:1399–1408. doi: 10.1007/s11064-006-9189-5. [PubMed] [Cross Ref]
34. Thio LL, Wong M, Yamada KA. Ketone bodies do not directly alter excitatory or inhibitory hippocampal synaptic transmission. Neurology. 2000;54:325–331. [PubMed]
35. Donevan SD, White HS, Anderson GD, Rho JM. Voltage-dependent block of N-methyl-D-aspartate receptors by the novel anticonvulsant dibenzylamine, a bioactive constituent of L-(+)-beta-hydroxybutyrate. Epilepsia. 2003;44:1274–1279. doi: 10.1046/j.1528-1157.2003.07203.x. [PubMed] [Cross Ref]
36. Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF., Jr Ketone bodies, potential therapeutic uses. IUBMB Life. 2001;51:241–247. doi: 10.1080/152165401753311780. [PubMed] [Cross Ref]
37. Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM. Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience. 2007;145:256–264. doi: 10.1016/j.neuroscience.2006.11.065. [PMC free article] [PubMed] [Cross Ref]
38. Ziegler DR, Ribeiro LC, Hagenn M, Siqueira IR, Araujo E, Torres IL, Gottfried C, Netto CA, Goncalves CA. Ketogenic diet increases glutathione peroxidase activity in rat hippocampus. Neurochem Res. 2003;28:1793–1797. doi: 10.1023/A:1026107405399. [PubMed] [Cross Ref]
39. McIntosh TK, Saatman KE, Raghupathi R, Graham DI, Smith DH, Lee VM, Trojanowski JQ. The Dorothy Russell Memorial Lecture. The molecular and cellular sequelae of experimental traumatic brain injury: pathogenetic mechanisms. Neuropathol Appl Neurobiol. 1998;24:251–267. doi: 10.1046/j.1365-2990.1998.00121.x. [PubMed] [Cross Ref]
40. Hodgkins PS, Schwarcz R. Metabolic control of kynurenic acid formation in the rat brain. Dev Neurosci. 1998;20:408–416. doi: 10.1159/000017338. [PubMed] [Cross Ref]
41. Tsukada H, Nishiyama S, Fukumoto D, Sato K, Kakiuchi T, Domino EF. Chronic NMDA antagonism impairs working memory, decreases extracellular dopamine, and increases D1 receptor binding in prefrontal cortex of conscious monkeys. Neuropsychopharmacology. 2005;30:1861–1869. doi: 10.1038/sj.npp.1300732. [PubMed] [Cross Ref]
42. Pernet V, Bourgeois P, Di PA. A role for polyamines in retinal ganglion cell excitotoxic death. J Neurochem. 2007;103:1481–1490. doi: 10.1111/j.1471-4159.2007.04843.x. [PubMed] [Cross Ref]

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