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Epilepsy Curr. 2006 May; 6(3): 91–92.
PMCID: PMC1464156

Ketones Keep Neurons Alive

Ketogenic Diet Reduces Hypoglycemia-Induced Neuronal Death in Young Rats

Yamada KA, Rensing N, Thio LL

Neurosci Lett 2005;385(3):210–214 [PubMed]

Hypoglycemia is an important complication of insulin treatment in diabetic children and may contribute to lasting cognitive impairment. Previous studies demonstrated that 21-day-old rats (P21) subjected to brief, repetitive episodes of hypoglycemia sustain cortical neuronal death. The developing brain is capable of utilizing alternative energy substrates acetoacetate and β-hydroxybutyrate. In these studies, we tested the hypothesis that the developing brain adapted to ketone utilization and provided with ketones during hypoglycemia by eating a ketogenic diet would sustain less brain injury compared to littermates fed a standard diet. Supporting this hypothesis, P21 rats weaned to a ketogenic diet and subjected to insulin-induced hypoglycemia at P25 had significantly less neuronal death than rats on a standard diet. This animal model may provide insight into the determinants influencing the brain's susceptibility to hypoglycemic injury.

COMMENTARY

Regulation of glucose levels is critical for numerous metabolic processes as well as for optimal neuronal function. The realization that glucose modifies neuronal excitability has important implications for seizure susceptibility and control (1). Abnormal glucose levels, whether too high or too low, can cause seizures. In young children with diabetes, hypoglycemia, particularly when induced by insulin treatment, can cause seizures and long-term cognitive impairment—both events occur as a result of neuronal injury (2). In this context, the experimental results of Yamada and colleagues are relevant clinically. These workers previously showed repetitive, brief episodes of hypoglycemia in rat pups resulted in cortical (but not hippocampal, thalamic, or striatal) neuronal death and alteration of synaptic function (3). Here, they hypothesize that a ketogenic diet may be neuroprotective against hypoglycemia-related brain injury, because ketone bodies provide an alternative energy substrate during the period when glucose availability is limited.

In this study, day 21 postnatal (P21) rat pups were weaned onto standard rat chow or an experimental ketogenic diet. Five days later, all rats were made hypoglycemic (defined as a blood glucose level less than 20 μg/mL) by an injection of insulin. Blood glucose measurements were made 1 and 2.5 hours later, and the hypoglycemic episode was terminated by oral refeeding at the latter time point. Rats were sacrificed on P28, and brains were examined for cell death, using FluorojadeB.

The researchers found that the single hypoglycemic episode resulted in neocortical neuronal death in both controls and ketogenic-fed rat pups, but the rats fed the ketogenic diet had significantly less brain injury. Furthermore, rat pups on the ketogenic diet exhibited fewer symptoms (e.g., loss of balance and protective reflexes) during hypoglycemia. A subset of controls was treated with minocycline, which protects against hypoxia-ischemia–induced neuronal injury in newborn rats by reducing caspase-3 activation. Minocycline afforded no protection against neuronal death, suggesting that the neuroprotection seen in their study was not mediated by this apoptosis pathway.

The findings were attributed to chronic adaptation to ketosis in the ketogenic-fed animals. Whether this short (5 day) period of ketosis is sufficient to enable neuroprotection, or whether another mechanism prevented hypoglycemia-induced cell death is unclear. For example, some mechanisms through which the ketogenic diet might work include prevention of reactive oxygen species (4), calorie restriction (5), or effects of lipids or ketones on neuronal excitability (6). None of these actions is ruled out by the present experiments, which do not address mechanism. From a clinical standpoint, whether ketosis can protect against hypoglycemia-induced neuronal injury is uncertain, since children at risk are not likely to be placed on a ketogenic diet prophylactically (i.e., before the hypoglycemic episode). These practical considerations do not, however, diminish the importance of the present results, which take significant steps toward a better understanding of both the ketogenic diet and the role of glucose levels in neuronal excitability and survival. It would be interesting to know if treatment with the ketogenic diet after the hypoglycemic episode could ameliorate neuronal death in this model. Similarly, the protective effect needs to be examined over a wider range of ages; the ketogenic diet works across the age spectrum but has been thought to be maximally effective in young children. Finally, potential neuroprotective effects of less restrictive diets warrant investigation (7, 8).

References

1. Schwechter EM, Veliskova J, Velisek L. Correlation between extracellular glucose and seizure susceptibility in adult rats. Ann Neurol. 2003;53:91–101. [PubMed]
2. Yager JY. Hypoglycemic injury to the immature brain. Clin Perinatol. 2002;29:651–674. [PubMed]
3. Yamada KA, Rensing N, Izumi Y, De Erausquin GA, Gazit V, Dorsey DA, Herrera DG. Repetitive hypoglycemia in young rats impairs hippocampal long-term potentiation. Pediatr Res. 2004;55:372–379. [PubMed]
4. Sullivan PG, Rippy NA, Dorenbos K, Concepcion RC, Agarwal AK, Rho JM. The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann Neurol. 2004;55:576–580. [PubMed]
5. Mantis JG, Centeno NA, Todorova MT, McGowan R, Seyfried TN. Management of multifactorial idiopathic epilepsy in EL mice with caloric restriction and the ketogenic diet: role of glucose and ketone bodies. Nutr Metab. 2004;1:11. [PMC free article] [PubMed]
6. Cunnane SC, Musa K, Ryan MA, Whiting S, Fraser DD. Potential role of polyunsaturates in seizure protection achieved with the ketogenic diet. Prostagl Leukotr Essen Fatty Acids. 2002;67:131–135. [PubMed]
7. Kossoff EH, Krauss GL, McGrogan JR, Freeman JM. Efficacy of the Atkins diet as a therapy for intractable epilepsy. Neurology. 2003;61:1789–1791. [PubMed]
8. Pfeifer HH, Thiele EA. Low-glycemic index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy. Neurology. 2005;65:1810–1812. [PubMed]

Articles from Epilepsy Currents are provided here courtesy of American Epilepsy Society