生酮饮食治疗癫痫作用机制研究进展_Journal of Epilepsy

Authors：

 徐秦岚 ¹ , 朱飞 ¹ , 郭安臣 ² ,  王群 ¹

1. ;
2. ;

Corresponding author：

王群, Email: wangq@ccmu.edu.cn

Keywords：

生酮饮食; 抗癫痫; 神经保护; 机制

DOI：

10.7507/2096-0247.20160060

Video：

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生酮饮食（Ketogenic diet，KD）是一种高脂肪、低碳水化合物，适量蛋白质、维生素和矿物质的饮食。KD用于治疗癫痫已有很长的历史，其疗效明确但作用机制尚不清楚。基于临床观察和研究，最初人们认为KD的作用机制与脱水、酸中毒相关。近几年，基于越来越多的动物实验和临床研究，人们逐渐提出了更多假说。KD减少了葡萄糖的摄入，机体利用葡萄糖受限，而酮体、脂肪酸升高，这可能与其产生抗癫痫作用相关。此外研究发现，KD的抗癫痫机制可能与神经递质、神经元兴奋性及突触传递有关。KD还有神经保护功能，如抗炎、氧化应激等，这与其抗癫痫作用也有关联。但是上述机制并不明确，目前关于KD的抗癫痫机制仍在探索之中。

Citation： 徐秦岚, 朱飞, 郭安臣, 王群. 生酮饮食治疗癫痫作用机制研究进展. Journal of Epilepsy, 2016, 2(4): 338-343. doi: 10.7507/2096-0247.20160060 Copy

1.	Lima PA, Sampaio LP, Damasceno NR. Neurobiochemical mechanisms of a ketogenic diet in refractory epilepsy. Clinics, 2014, 69(11):699-705.
2.	Kawamura MJr, Ruskin DN, Masino SA. Metabolic autocrine regulation of neurons involves cooperation among pannexin hemichannels, adenosine receptors, and K_ATP channels. J Neurosci, 2010, 30(8):3886-3895.
3.	Tanner GR, Lutas A, Martinez-Francois JR, et al. Single K ATP channel opening in response to action potential firing in mouse dentate granule neurons. J Neurosci, 2011, 31(2):8689-8696.
4.	Koranda JL, Ruskin DN, Masino SA, et al. A ketogenic diet reduces long-term potentiation in the dentate gyrus of freely behaving rats. J Neurophysiol, 2011, 106(5):662-666.
5.	Vamecq J, Vallee L, Lesage F, et al. Antiepileptic popular ketogenic diet:emerging twists in an ancient story. Prog Neurobiol, 2005, 75(8):1-28.
6.	Lesage F. Pharmacology of neuronal background potassium channels. Neuropharmacology, 2003, 44(9):1-7.
7.	Franks NP, Honore E. The TREK K_2P channels and their role in general anaesthesia and neuroprotection. Trends Pharmacol Sci, 2004, 25(4):601-608.
8.	Thio LL, Wong M, Yamada KA. Ketone bodies do not directly alter excitatory or inhibitory hippocampal synaptic transmission. Neurology, 2000, 54(11):325-331.
9.	Bough KJ, Paquet M, Pare JF, et al. Evidence against enhanced glutamate transport in the anticonvulsant mechanism of the ketogenic diet. Epilepsy Res, 2007, 74(10):232-236.
10.	McNally MA, Hartman AL. Ketone bodies in epilepsy. J Neurochem, 2012, 121(2):28-35.
11.	Feunekes GI, Van Staveren WA, De Vries JH, et al. Relative and biomarker-based validity of a food-frequency questionnaire estimating intake of fats and cholesterol. Am J Clin Nutr, 1993, 58(10):489-496.
12.	Haag M. Essential fatty acids and the brain. Can J Psychiatry, 2003, 48(9):195-203.
13.	Taha AY, Alizadeh S, Zeng QH, et al. Assessing the metabolic and toxic effects of anticonvulsant doses of polyunsaturated fatty acids on the liver in rats. J Toxicol Environ Health A, 2009, 72(8):1191-1200.
14.	Sampath H, Ntambi JM. Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu Rev Nutr, 2005, 25(7):317-340.
15.	Kersten S, Mandard S, Escher P, et al. The peroxisome proliferator-activated receptor alpha regulates amino acid metabolism. Faseb J, 2001, 15(3):1971-1978.
16.	Smith SA. Peroxisome proliferator-activated receptors and the regulation of mammalian lipid metabolism. Biochem Soc Trans, 2002, 30(6):1086-1090.
17.	Lin Q, Ruuska SE, Shaw NS, et al. Ligand selectivity of the peroxisome proliferator-activated receptor alpha. Biochemistry, 1999, 38(11):185-190.
18.	Porta N, Vallee L, Lecointe C, et al. Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, exerts anticonvulsive properties. Epilepsia, 2009, 50(12):943-948.
19.	Vezzani A, Granata T. Brain inflammation in epilepsy:experimental and clinical evidence. Epilepsia, 2005, 46(9):1724-1743.
20.	Dhir A, Naidu PS, Kulkarni SK. Effect of cyclooxygenase inhibitors on pentylenetetrazol (PTZ)-induced convulsions:Possible mechanism of action. Prog Neuropsychopharmacol Biol Psychiatry, 2006, 30(7):1478-1485.
21.	Dupuis N, Auvin S. Inflammation and epilepsy in the developing brain:clinical and experimental evidence. CNS Neurosci Ther, 2015, 21(3):141-151.
22.	Auvin S. Fatty acid oxidation and epilepsy. Epilepsy Res, 2012, 100(5):224-228.
23.	Butovich IA, Lukyanova SM, Bachmann C. Dihydroxydocosah-exaenoicacids of the neuroprotectin D family:synthesis, structure, and inhibition of human 5-lipoxygenase. J Lipid Res, 2006, 47(12):2462-2474.
24.	Dahlin M, Elfving A, Ungerstedt U, et al. The ketogenic diet influences the levels of excitatory and inhibitory amino acids in the CSF in children with refractory epilepsy. Epilepsy Res, 2005, 64(6):115-125.
25.	Lund TM, Risa O, Sonnewald U, et al. Availability of neurotransmitter glutamate is diminished when beta-hydroxybutyrate replaces glucose in cultured neurons. J Neurochem, 2009, 110(10):80-91.
26.	Peng L, Gu L, Zhang H, et al. Glutamine as an energy substrate in cultured neurons during glucose deprivation. J Neurosci Res, 2007, 85(3):3480-3486.
27.	Juge N, Gray JA, Omote H, et al. Metabolic control of vesicular glutamate transport and release. Neuron, 2010, 68(7):99-112.
28.	Yudkoff M, Daikhin Y, Nissim I, et al. Brain amino acid metabolism and ketosis. J Neurosci Res, 2001, 66(5):272-281.
29.	Wang ZJ, Bergqvist C, Hunter JV, et al. In vivo measurement of brain metabolites using two-dimensional double-quantum MR spectroscopy——exploration of GABA levels in a ketogenic diet. Magn Reson Med, 2003, 49(3):615-619.
30.	Suzuki Y, Takahashi H, Fukuda M, et al. Beta-hydroxybutyrate alters GABA-transaminase activity in cultured astrocytes. Brain Res, 2009, 1268(120):17-23.
31.	Weinshenker D. The contribution of norepinephrine and orexigenic neuropeptides to the anticonvulsant effect of the ketogenic diet. Epilepsia, 2008, 49(Suppl 8):104-107.
32.	Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci, 2009, 122(6):3589-3594.
33.	Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med, 2010, 363(15):1801-1811.
34.	Raab-Graham KF, Haddick PC, Jan YN, et al. Activity-and mTOR-dependent suppression of Kv 1.1 channel mRNA translation in dendrites. Science, 2006, 314(15):144-148.
35.	Jaworski J, Spangler S, Seeburg DP, et al. Control of dendritic arborization by the phosphoinositide-3'-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci, 2005, 25(11):11300-11312.
36.	Weston MC, Chen H, Swann JW. Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission. J Neurosci, 2012, 32(10):11441-11452.
37.	McDaniel SS, Rensing NR, Thio LL, et al. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia, 2011, 52(4):e7-11.
38.	Hartman AL, Santos P, Dolce A, et al. The mTOR inhibitor rapamycin has limited acute anticonvulsant effects in mice. PLoS One, 2012, 7(2):e45156.
39.	Hartman AL, Lyle M, Rogawski MA, et al. Efficacy of the ketogenic diet in the 6-Hz seizure test. Epilepsia, 2008, 49(3):334-339.
40.	Liang LP, Ho YS, Patel M. Mitochondrial superoxide production in kainate-induced hippocampal damage. Neuroscience, 2000, 101(7):563-570.
41.	Liang LP, Patel M. Seizure-induced changes in mitochondrial redox status. Free Radic Biol Med, 2006, 40(18):316-322.
42.	Haces ML, Hernandez-Fonseca K, Medina-Campos ON, et al. Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions. Exp Neurol, 2008, 211(8):85-96.
43.	Kim do Y, Davis LM, Sullivan PG, et al. Ketone bodies are protective against oxidative stress in neocortical neurons. J Neurochem, 2007, 101(10):1316-1326.
44.	Greco T, Glenn TC, Hovda DA, et al. Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity. J Cereb Blood Flow Metab, 2015, 10(13):0271678X15610584.
45.	Milder JB, Liang LP, Patel M. Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet. Neurobiol Dis, 2010, 40(6):238-244.
46.	Bough KJ, Wetherington J, Hassel B, et al. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol, 2006, 60(11):223-235.
47.	Sullivan PG, Rippy NA, Dorenbos K, et al. The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann Neurol, 2004, 55(6):576-580.
48.	Azzu V, Brand MD. The on-off switches of the mitochondrial uncoupling proteins. Trends Biochem Sci, 2010, 35(7):298-307.
49.	Kovac S, Domijan AM, Walker MC, et al. Prolonged seizure activity impairs mitochondrial bioenergetics and induces cell death. J Cell Sci, 2012, 125(21):1796-1806.
50.	Kim do Y, Simeone KA, Simeone TA, et al. Ketone bodies mediate antiseizure effects through mitochondrial permeability transition. Ann Neurol, 2015, 78(9):77-87.

1. Lima PA, Sampaio LP, Damasceno NR. Neurobiochemical mechanisms of a ketogenic diet in refractory epilepsy. Clinics, 2014, 69(11):699-705.
2. Kawamura MJr, Ruskin DN, Masino SA. Metabolic autocrine regulation of neurons involves cooperation among pannexin hemichannels, adenosine receptors, and K_ATP channels. J Neurosci, 2010, 30(8):3886-3895.
3. Tanner GR, Lutas A, Martinez-Francois JR, et al. Single K ATP channel opening in response to action potential firing in mouse dentate granule neurons. J Neurosci, 2011, 31(2):8689-8696.
4. Koranda JL, Ruskin DN, Masino SA, et al. A ketogenic diet reduces long-term potentiation in the dentate gyrus of freely behaving rats. J Neurophysiol, 2011, 106(5):662-666.
5. Vamecq J, Vallee L, Lesage F, et al. Antiepileptic popular ketogenic diet:emerging twists in an ancient story. Prog Neurobiol, 2005, 75(8):1-28.
6. Lesage F. Pharmacology of neuronal background potassium channels. Neuropharmacology, 2003, 44(9):1-7.
7. Franks NP, Honore E. The TREK K_2P channels and their role in general anaesthesia and neuroprotection. Trends Pharmacol Sci, 2004, 25(4):601-608.
8. Thio LL, Wong M, Yamada KA. Ketone bodies do not directly alter excitatory or inhibitory hippocampal synaptic transmission. Neurology, 2000, 54(11):325-331.
9. Bough KJ, Paquet M, Pare JF, et al. Evidence against enhanced glutamate transport in the anticonvulsant mechanism of the ketogenic diet. Epilepsy Res, 2007, 74(10):232-236.
10. McNally MA, Hartman AL. Ketone bodies in epilepsy. J Neurochem, 2012, 121(2):28-35.
11. Feunekes GI, Van Staveren WA, De Vries JH, et al. Relative and biomarker-based validity of a food-frequency questionnaire estimating intake of fats and cholesterol. Am J Clin Nutr, 1993, 58(10):489-496.
12. Haag M. Essential fatty acids and the brain. Can J Psychiatry, 2003, 48(9):195-203.
13. Taha AY, Alizadeh S, Zeng QH, et al. Assessing the metabolic and toxic effects of anticonvulsant doses of polyunsaturated fatty acids on the liver in rats. J Toxicol Environ Health A, 2009, 72(8):1191-1200.
14. Sampath H, Ntambi JM. Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu Rev Nutr, 2005, 25(7):317-340.
15. Kersten S, Mandard S, Escher P, et al. The peroxisome proliferator-activated receptor alpha regulates amino acid metabolism. Faseb J, 2001, 15(3):1971-1978.
16. Smith SA. Peroxisome proliferator-activated receptors and the regulation of mammalian lipid metabolism. Biochem Soc Trans, 2002, 30(6):1086-1090.
17. Lin Q, Ruuska SE, Shaw NS, et al. Ligand selectivity of the peroxisome proliferator-activated receptor alpha. Biochemistry, 1999, 38(11):185-190.
18. Porta N, Vallee L, Lecointe C, et al. Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, exerts anticonvulsive properties. Epilepsia, 2009, 50(12):943-948.
19. Vezzani A, Granata T. Brain inflammation in epilepsy:experimental and clinical evidence. Epilepsia, 2005, 46(9):1724-1743.
20. Dhir A, Naidu PS, Kulkarni SK. Effect of cyclooxygenase inhibitors on pentylenetetrazol (PTZ)-induced convulsions:Possible mechanism of action. Prog Neuropsychopharmacol Biol Psychiatry, 2006, 30(7):1478-1485.
21. Dupuis N, Auvin S. Inflammation and epilepsy in the developing brain:clinical and experimental evidence. CNS Neurosci Ther, 2015, 21(3):141-151.
22. Auvin S. Fatty acid oxidation and epilepsy. Epilepsy Res, 2012, 100(5):224-228.
23. Butovich IA, Lukyanova SM, Bachmann C. Dihydroxydocosah-exaenoicacids of the neuroprotectin D family:synthesis, structure, and inhibition of human 5-lipoxygenase. J Lipid Res, 2006, 47(12):2462-2474.
24. Dahlin M, Elfving A, Ungerstedt U, et al. The ketogenic diet influences the levels of excitatory and inhibitory amino acids in the CSF in children with refractory epilepsy. Epilepsy Res, 2005, 64(6):115-125.
25. Lund TM, Risa O, Sonnewald U, et al. Availability of neurotransmitter glutamate is diminished when beta-hydroxybutyrate replaces glucose in cultured neurons. J Neurochem, 2009, 110(10):80-91.
26. Peng L, Gu L, Zhang H, et al. Glutamine as an energy substrate in cultured neurons during glucose deprivation. J Neurosci Res, 2007, 85(3):3480-3486.
27. Juge N, Gray JA, Omote H, et al. Metabolic control of vesicular glutamate transport and release. Neuron, 2010, 68(7):99-112.
28. Yudkoff M, Daikhin Y, Nissim I, et al. Brain amino acid metabolism and ketosis. J Neurosci Res, 2001, 66(5):272-281.
29. Wang ZJ, Bergqvist C, Hunter JV, et al. In vivo measurement of brain metabolites using two-dimensional double-quantum MR spectroscopy——exploration of GABA levels in a ketogenic diet. Magn Reson Med, 2003, 49(3):615-619.
30. Suzuki Y, Takahashi H, Fukuda M, et al. Beta-hydroxybutyrate alters GABA-transaminase activity in cultured astrocytes. Brain Res, 2009, 1268(120):17-23.
31. Weinshenker D. The contribution of norepinephrine and orexigenic neuropeptides to the anticonvulsant effect of the ketogenic diet. Epilepsia, 2008, 49(Suppl 8):104-107.
32. Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci, 2009, 122(6):3589-3594.
33. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med, 2010, 363(15):1801-1811.
34. Raab-Graham KF, Haddick PC, Jan YN, et al. Activity-and mTOR-dependent suppression of Kv 1.1 channel mRNA translation in dendrites. Science, 2006, 314(15):144-148.
35. Jaworski J, Spangler S, Seeburg DP, et al. Control of dendritic arborization by the phosphoinositide-3'-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci, 2005, 25(11):11300-11312.
36. Weston MC, Chen H, Swann JW. Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission. J Neurosci, 2012, 32(10):11441-11452.
37. McDaniel SS, Rensing NR, Thio LL, et al. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia, 2011, 52(4):e7-11.
38. Hartman AL, Santos P, Dolce A, et al. The mTOR inhibitor rapamycin has limited acute anticonvulsant effects in mice. PLoS One, 2012, 7(2):e45156.
39. Hartman AL, Lyle M, Rogawski MA, et al. Efficacy of the ketogenic diet in the 6-Hz seizure test. Epilepsia, 2008, 49(3):334-339.
40. Liang LP, Ho YS, Patel M. Mitochondrial superoxide production in kainate-induced hippocampal damage. Neuroscience, 2000, 101(7):563-570.
41. Liang LP, Patel M. Seizure-induced changes in mitochondrial redox status. Free Radic Biol Med, 2006, 40(18):316-322.
42. Haces ML, Hernandez-Fonseca K, Medina-Campos ON, et al. Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions. Exp Neurol, 2008, 211(8):85-96.
43. Kim do Y, Davis LM, Sullivan PG, et al. Ketone bodies are protective against oxidative stress in neocortical neurons. J Neurochem, 2007, 101(10):1316-1326.
44. Greco T, Glenn TC, Hovda DA, et al. Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity. J Cereb Blood Flow Metab, 2015, 10(13):0271678X15610584.
45. Milder JB, Liang LP, Patel M. Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet. Neurobiol Dis, 2010, 40(6):238-244.
46. Bough KJ, Wetherington J, Hassel B, et al. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol, 2006, 60(11):223-235.
47. Sullivan PG, Rippy NA, Dorenbos K, et al. The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann Neurol, 2004, 55(6):576-580.
48. Azzu V, Brand MD. The on-off switches of the mitochondrial uncoupling proteins. Trends Biochem Sci, 2010, 35(7):298-307.
49. Kovac S, Domijan AM, Walker MC, et al. Prolonged seizure activity impairs mitochondrial bioenergetics and induces cell death. J Cell Sci, 2012, 125(21):1796-1806.
50. Kim do Y, Simeone KA, Simeone TA, et al. Ketone bodies mediate antiseizure effects through mitochondrial permeability transition. Ann Neurol, 2015, 78(9):77-87.

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