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Published in final edited form as: J Neurochem. 2012 Nov;123(0 2):52–57. doi: 10.1111/j.1471-4159.2012.07943.x

Stroke outcome in the ketogenic state - a systematic review of the animal data

Claire L Gibson *, Anne N Murphy **, Sean P Murphy *
PMCID: PMC3970216  NIHMSID: NIHMS403422  PMID: 23050642

Abstract

As a predictor of potential clinical outcome, we performed a systematic review of controlled studies that assessed experimental stroke outcome in rodents maintained on special diets (calorie restriction, ketogenic diet) or following the direct administration of ketone bodies. Pre-clinical studies were identified by searching web databases and the reference lists of relevant original articles and reviews. Sixteen published studies (a total of 733 experimental animals) met specific criteria and were analyzed using Cochrane Review Manager software. This resulted in objective evidence to suggest beneficial effects of the ketogenic pathway on pathologic and functional outcomes following experimental stroke.

Keywords: meta-analysis, systematic review, caloric restriction, ketogenic diet, stroke

For decades we have known that caloric restriction and intermittent fasting extend the lifespan of rodent species (and probably primates) by reducing free radical production, inflammation, and/or increasing resistance to stress. Such strategies would, therefore, be predicted to benefit both cardio- and cerebro-vasculature (Mattson and Wan, 2005; Yamada, 2008). Other dietary regimens can also be beneficial to neurologic function. For instance, the ketogenic diet, in which fat replaces carbohydrate, is clinically useful in the treatment of epilepsy and there is growing interest in extending use of this diet to other neurological disorders (http://www.clinicaltrials.gov/ct2/results?term=ketogenic+diet&pg=1), including acute injury such as stroke and trauma (Gasior et al., 2006). To provide a prediction of potential clinical outcome we performed a systematic review and meta-analysis of controlled rodent studies that assessed stroke outcome where the use of ketone bodies as an energy source had been promoted. These include ketogenic diets, as well as calorie restriction, which promote the use of triacylglycerols and fatty acids. In addition, ketone bodies can be directly administered. All three dietary interventions are evaluated here.

Methods

Study Identification

Experimental animal studies assessing the effect of dietary interventions related to ketone body utilization on outcomes following experimental stroke were identified from Embase, PubMed, Web of Science and Google Scholar by searching for all published articles up to the end of April 2012. The earliest study for analysis was that of Go et al. (1988). Search keywords included combinations of caloric restriction, cerebral ischemia, ketogenic diet, rodent. Additional publications were identified from reference lists of all identified articles and narrative reviews. Pre-specified exclusion criteria were used to aid selection and prevent bias, and studies were only included if (i) experimental ischemia was induced, (ii) animals were exposed to a ketogenic state, (iii) there was a control group, and, (iv) an appropriate outcome was measured following stroke.

Data extraction

The term ‘intervention’ refers to any intervention that induces a ketogenic state in animals such that the brain is deprived of its usual energy source, i.e. glucose, and instead uses ketones as an alternative. A ketogenic state, experimentally, can be induced by; (i) restriction of caloric intake, (ii) ketogenic diet or (iii) exogenous administration of ketones. From the relevant studies data were extracted on animal species, number, type of brain injury, type of intervention, timing of intervention relative to onset of experimental injury, and outcome post-stroke. Outcomes included lesion volume, brain water content, neuron counts, survival rate and functional measures. Data for functional outcomes included: (i) open field activity (distance travelled), (ii) 8-arm radial maze (working memory errors) and, (iii) novel object recognition task (discrimination index = time spent exploring novel object/total exploration time).

A comparison (C) was defined as the assessment of outcome in intervention and control groups, whereby intervention constituted either a dietary intervention (caloric restriction, ketogenic diet) or administration of a ketone body at a stated time point relative to the induction of ischemia. For each comparison, data were extracted for mean outcome, standard deviation and the number of animals per group. Data were not extracted if mean values were not reported, i.e. if only median and confidence intervals were given. If published studies (S) used multiple groups, for example to assess dose-response relationships, then data were individually extracted. If numerical data were not reported in the text, they were extracted from enlarged versions of the graphs. The methodological quality of each study was determined by minor modification to the ten-point scale of O'Collins et al. (2012).

Data analysis

The data were analysed using Cochrane Review Manager (version 5), as in a previous animal meta-analysis (White & Murphy, 2011). The effect of ketogenic state, as compared with control, on post-stroke outcomes was assessed using the standardized mean difference, whereby the difference in effect between intervention and control treatment is divided by the total standard deviation. A standardised mean difference of zero represents a lack of intervention effect, whereas a positive value indicates a beneficial effect and a negative value demonstrates a detrimental effect of the intervention. This allows comparisons to be made even though different methods of measurement and/or different animal models are used. Statistical heterogeneity was accounted for through the use of the DerSimonian and Laird (1986) pooling model of random effects. The data were grouped and stratified meta-analyses based on: (i) type of intervention used to induce ketogenic state, (ii) quality score, (iii) type of outcome assessed following ischemia, (iv) quality score, and (iv) duration (chronic or acute) of intervention. For those tests in which an increase in nominal value represented an improvement in outcome (e.g. neuron counts following FluoroJade labelling) the inverse of the extracted data was used for data comparisons. Studies were weighted by sample size and the results are expressed as standardised mean difference with 95% confidence intervals. The significance was set at α = 0.05 and P values of <0.05 from meta-analyses were considered to be significant.

Results

Design of studies

Based on the stated search criteria, we identified 19 studies that investigated the effect of a ketogenic state on outcome following cerebral ischemia. However, three of these (Chiba et al., 2010, Combs et al., 1987; Marie et al., 1990) were excluded, as mean values and the distribution of data (standard error or standard deviation) were not reported. The main characteristics of the 16 included studies are reported in Table 1. All of these reported the effect of inducing a ketogenic state, versus control, on one or more outcomes following cerebral ischemia. The 16 included studies represent published data from 12 research groups; four research groups published two studies each with the remaining 8 studies coming from separate research groups. Data from a total of 733 experimental subjects were included for analysis.

Table 1.

Characteristics of the studies included in the review

Study Parameters assessed Intervention First dose timing* Species Model of ischemia
Arumugam et al., 2010 lesion volume, neurological score calorie restriction −3m C57 mouse MCAO
Bobyn et al., 2005 open field, neuronal viability calorie restriction −28d gerbil 2VO
Go et al., 1988 survival, edema calorie restriction −4d rat global
Gueldry et al., 1990 edema ketone administration −0.5h SD rat microspheres
Massieu et al., 2003 lesion volume ketone administration −14d, −7d, 0h Wistar rat iodoacetate
McEwen and Paterson, 2010 open field, neuronal count calorie restriction +1h Gerbil 2VO
Puchowicz et al., 2008 lesion volume, edema ketogenic diet −21d Wistar rat MCAO
Roberge et al., 2008a radial maze, neuronal count calorie restriction −3m Wistar rat 4VO
Roberge et al., 2008b elevated maze, open field, neuronal count calorie restriction −3m Wistar rat 4VO
Robertson et al., 1992 lesion volume calorie restriction, ketone administration −12h LE rat 2VO
Suzuki et al., 2001 survival, edema ketone administration −0.5h ddY mouse global
Suzuki et al., 2002 lesion volume, edema ketone administration +0.5h Wistar rat MCAO
Tai et al., 2008 neuronal count ketogenic diet −25d SD rat 4VO
Xu et al., 2010 NOR ketogenic diet −21d F344 rat hypoxia
Yoon et al., 2011 lesion volume calorie restriction −3m C57 mouse MCAO
Yu and Mattson, 1999 lesion volume, neurological score calorie restriction −3m SD rat MCAO
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*

First dose timing in relation to onset of experimental stroke.

MCAO = middle cerebral artery occlusion; m = months; d = days; h = hours; VO = vessel occlusion; SD = Sprague-Dawley rat; LE = Long Evans rat; NOR = novel object recognition.

In terms of the type of intervention used to induce a ketogenic state, three studies utilised a ketogenic diet (Puchowicz et al., 2008; Tai et al., 2008; Xu et al., 2010), five studies exogenously administered ketone bodies (Gueldry et al., 1990; Massieu et al., 2003; Robertson et al., 1992; Suzuki et al., 2001, 2002), and the remaining 8 studies along with the study by Robertson et al., 1992 used calorie restriction. Of the five studies that exogenously administered ketone bodies, two administered β-hydroxybutyrate (Suzuki et al., 2001, 2002), two administered 1,3 butanediol (Gueldry et al., 1990; Robertson et al., 1992), one administered acetoacetate (Massieu et al., 2003), and the study by Robertson et al. (1992) also administered triacetin. When applying an intervention to induce a ketogenic state, the majority of studies did so prior to the onset of cerebral ischemia. Ten of the included studies introduced the intervention at least 7 days prior to the onset of cerebral ischemia whereas 4 studies (Gueldry et al., 1990; Go et al., 1988; Robertson et al., 1992; Suzuki et al., 2001) introduced the intervention less than 7 days prior to the onset of cerebral ischemia. The remaining two studies (McEwen & Paterson 2010; Suzuki et al., 2002), along with the study by Massieu et al. (2003), examined the effects of inducing a ketogenic state following the induction of ischemia.

In order to assess the effects of a ketogenic state on outcome following cerebral ischemia, the majority of studies utilised various models to induce cerebral ischemia; thirteen used vessel occlusion (filament occlusion of the middle cerebral artery, or clip occlusion of a number of vessels including the middle cerebral artery), one study used microspheres (Gueldry et al., 1990), one study used a model of glutamate excitotoxicity via application of iodoacetate (Massieu et al., 2003), and one study used a hypoxic chamber (Xu et al., 2010). Male rat models (F344, Long Evans, Sprague-Dawley, Wistar) were used in 12 of the 16 studies; the remaining 4 used either a mouse strain (Arumugam et al., 2010; Suzuki et al., 2001; Yoon et al., 2011) or gerbils (McEwen & Paterson, 2010).

In terms of assessing outcome following cerebral ischemia, the majority of studies used lesion volume (see Table 1), five used % water content (Go et al.,1998; Gueldry et al., 1990; Puchowicz et al., 2008;Suzuki et al., 2001, 2002), three used neuron count (McEwen & Paterson 2010; Roberge et al., 2008a, 2008b), two studies used survival rate (Go et al., 1988; Suzuki et al., 2001), and one study used neurological score (Arumugam et al., 2010). A number of studies also used measures of functional outcome, including the elevated maze (Roberge et al., 2008b), open field activity (Bobyn et al., 2005; McEwen & Paterson 2010), radial maze (Roberge et al., 2008a), and novel object recognition (Xu et al., 2010).

Overall efficacy of inducing a ketogenic state

We determined initially that there was an overall significant protective effect of a ketogenic state on outcome following cerebral ischemia (1.24, 1.55 - 0.93, P < 0.001), regardless of individual study characteristics. Our literature search indicated that studies tended to induce a ketogenic state either by intervention (calorie restriction or a ketogenic diet) or through the exogenous administration of ketones. Thus, we also determined if a beneficial effect was seen following either intervention (1.12, 1.55 – 0.69, P < 0.001) or exogenous ketone administration (1.42, 1.84 – 1.0, P < 0.001; Fig. 1).

Fig. 1.

Fig. 1

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Standardised mean difference and 95% CI of all outcome measures by type of intervention i.e. all, dietary restriction only, exogenous administration of ketones. A beneficial effect following any type of intervention was observed. N, number of animals; C, number of comparisons; S, number of studies.

Type of parameter used to assess outcome

The effect of intervention on cerebral ischemia outcome was analysed according to type (Fig 2). First, data were grouped according to intervention, i.e. all, intervention, or exogenous administration, and then analysed to determine if they had a significant beneficial effect on either pathology or function (Fig. 2A). Pathological outcomes included lesion volume, brain water content and neuronal counts, whereas functional outcomes included all measures of behaviour. Regardless of whether a dietary intervention or administration had been used to induce a ketogenic state, a significant beneficial effect was seen on both outcomes (P < 0.01). However, a variety of outcomes were used in the included studies and we went on to analyse each separately (Fig. 2B). Induction of a ketogenic state was found to have a beneficial effect on functional tests (1.46, 2.19 – 0.73 P < 0.001), lesion volume (1.29, 1.7 – 0.88, P <0.001) and brain water content (1.04, 1.65 – 0.43 P < 0.001). However, a ketogenic state did not have a beneficial effect on neuron count, as assessed by FluoroJade labelling (−0.03, 0.39 - −0.44, P = 0.9), which included data from 3 studies, 4 comparisons and 91 experimental subjects.

Fig. 2.

Fig. 2

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Standardised mean difference and 95% CI of all outcome measures by type of outcome following cerebral ischemia. A beneficial effect of any type of intervention was observed when assessing pathologic or functional outcomes (A). When data were analysed according to the different types of outcome, i.e. function, edema, lesion volume, and cell viability, a beneficial effect of a ketogenic state was observed for all outcomes, apart from the last. N, number of animals; C, number of comparisons; S, number of studies.

Reported study quality

The quality scores of the included studies ranged from 1 (low) to 5 with a median score of 3. In order to determine whether the quality score of an individual study had any impact on whether or not the intervention had a beneficial effect following cerebral ischemia, included studies were analysed according to quality score (Fig.3). Only those with a score of 2, 3 or 5 demonstrated a significant (P < 0.01) beneficial effect of the intervention. Studies that had the lowest quality score had no significant beneficial effect (P = 0.07). In addition, three studies received a quality score of 4 and these showed no beneficial effect (P = 0.08).

Fig. 3.

Fig. 3

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Standardised mean difference and 95% CI for all outcome measures when data are grouped according to study quality. A beneficial effect was only observed in those studies that received a quality score of 2, 3 or 5. N, number of animals; C, number of comparisons; S, number of studies.

Duration of intervention

When comparing data across all studies it was determined that there was a beneficial effect of intervention to induce a ketogenic state, regardless of whether this occurred pre- or post-experimental ischemia (Fig. 4). A beneficial effect was observed when the intervention began more than 7 days prior to the onset of experimental ischemia (1.44, 1.88 – 1.0 P < 0.001) or less than 7 days prior to the onset of experimental ischemia (1.42, 1.95 – 0.89 P < 0.001). In addition, a significant beneficial effect was observed if the intervention began following the onset of experimental ischemia (0.82, 1.38 – 0.26 P = 0.004).

Fig. 4.

Fig. 4

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Standardised mean difference and 95% CI for all outcome measures when data are grouped according to onset of intervention. A beneficial effect was observed regardless of whether the ketogenic state was induced more than 7 days prior to onset, less than 7 days prior to onset, or at a time point following onset of experimental ischemia. N, number of animals; C, number of comparisons; S, number of studies.

Discussion

To restate the major findings from our analyses, we found beneficial effects on pathologic and functional outcomes of dietary intervention, or exogenous ketone administration, either prior to or following experimental stroke.

Neuropathologies, such as a stroke, cause a mismatch between energy demand and supply: blood flow goes awry, oxygen levels fall, and mitochondria malfunction. A period of fasting results in a short-term ketosis, and increased reliance on ketone bodies appears to be a form of cerebral metabolic adaptation (Manzanero et al., 2011). Ketone metabolism is enzymatically simpler and more efficient than glucose or pyruvate metabolism (Veech, 2004), and is reported to increase global cerebral blood flow (Gasior et al., 2006; Prins, 2008). Indeed, ketone bodies are the only circulating substrates in addition to glucose known to contribute significantly to cerebral metabolism. The precise mechanisms whereby caloric restriction, the ketogenic diet, and ketone bodies provide protection in ischemic stroke are not clear but there is notable improvement in mitochondrial function, a decrease in inflammation, and an increase in expression of neurotrophins such as BDNF and bFGF (Maalouf et al., 2009; Manzanero et al., 2011). Whether this relates to the higher level of potential energy available in the C-H bonds of beta hydroxybutyrate compared to pyruvate is unclear but potentially important to recovering ATP levels during reperfusion (Veech, 2004). More recently, the sirtuins have also been implicated. These histone deacetylases localize to different subcellular compartments and have a variety of substrates. Activity depends on nicotinamide adenine dinucleotide (NAD+), which links this family of enzymes to cellular energy levels. Indeed, some sirtuins (SIRT3) are located within mitochondria. Caloric restriction could activate and/or increase expression of sirtuins, which then modulate proteins involved in cell survival and apoptotic cell death (Maalouf et al., 2009; Morris et al., 2011).

Caloric restriction and the ketogenic diet appear to represent cost-effective and efficient strategies through which stroke incidence and/or subsequent pathology could be reduced.

Acknowledgements

Support for this study is provided by American Diabetes Association and NIH-NIDDK (A.N.M.), American Heart Association and NIH-NINDS (S.P.M.).

Footnotes

The authors declare that they have no conflicts of interest.

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