692 MCT 0.6:1 30% MCT 40% LCT 10%~15% 1~ 2:1 10~30 g d g d g d kg 175 cm kcal d -1 KD ( 1) kcal 3 ( 2) (GI) 50 KD RE RE

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1 691 ( ) (KD) (RE) KD RE 41% Research Progress of the Ketogenic Diet in the Treatment of Adults with Refractory Epilepsy SHANG Li 1, WANG Man 2, WANG Kai-yan 1 1 Department of Neurology, Huashan Hospital, Fudan University, Shanghai Department of Epilepsy Center, Deji Hospital, Shanghai , China KEY WORDS ketogenic diet; refractory epilpsy; ketone body; glycolysis inhibitor; mammalian target of rapamycin ABSTRACT The ketogenic diet(kd) has been used to treat children with refractory epilepsy(re) for about one hundred years. The mechanisms of KD are different from antiepileptic drugs. Recently, the modified KD was used to treat adults with RE. Its efficiency was nearly 41%, which was independent of ketone body levels. Its side effects appeared similar to those encountered in children with RE. (ketogenic diet KD) KD RE KD RE ( ) KD RE 50%~60% KD (90%) 10% KD 4:1 ( KD (refractory epilepsy RE) 1 g 4 g ) (antiepileptic 3:1 [1] drugs AEDs) KD (long-chain triglyceride LCT) RE KD MCT (60%) MCT RE RE (2013) R742.1 A, ( 1982-),,,, @163.com

2 692 MCT 0.6:1 30% MCT 40% LCT 10%~15% 1~ 2:1 10~30 g d g d g d kg 175 cm kcal d -1 KD ( 1) kcal 3 ( 2) (GI) 50 KD RE RE 70 kg 175 cm KD 4: kcal( 2000 ) [3] 4:1 1 4 g 1 g 1 g 9 kcal (9 4 36) 1 g 4 kcal (4 1=4) 1 4:1 36 4=40 kcal RE 4:1 40 kcal kcal =60 RE 4: KD 240 g d -1 60

3 693 [3] 1=60 g VGLUTs 70% 80% g 60 52=8 g 3 ( 2) KD AEDs [4] KD (K ATP ) ATP β- ATP 1930 K ATP [5] Dravet ATP KD β- [6] [9] KD 6:1 4:1 Bcl-2 1. BAD [10] S155 BAD [7] β- K ATP [8] S155 BAD (vesicular glutamate transporters γ- A 2. ATP ATP K ATP BAD(BCL-2-associated agonist of cell death) 155(S155) BAD VGLUTs) K ATP ( 1) [11] β- Gim nez-cassina [12] B C L - 2 B A D ( S ) K A T P, K A T P Notes BCL-2-associated agonist of cell death (BAD) can be viewed as a relay: Its dephosphorylation on S155 regulates mitochondria increasing the utilization of ketones instead of glucose. Cell membrane K ATP channels are closed in neurons with glycolytic mitochondria which will increase seizure, as opposed to the ones where ketone bodies used by mitochondria and K ATP channels are opened, which will reduce seizures

4 694 BAD BAD S155 ( BAD( ) ( ) ) A ATP KD K ATP KD MCT 1 h BAD [17] K ATP K ATP MAD LGIT KD KD [13~15] Coppola [13] 15 11~22 RE LGIT D (2-Deoxy-D-glucose 2DG) [19] 6 75%~90% 2 50% LGIT γ- A 2DG Kossoff [16] MAD 1 (NADH) 5 (CtBP) (NRSF) (BDNF) KD B(TrkB) KD 1. KD ( 2) [20] ( ) KD [18] 2DG NADH KD (A) NADH CtBP NRSF NRSF BDNF TrkB (B)2DG NADH CtBP NRSF NRSF BDNF T r k B Notes (A) In normal circumstances, NADH generated by glycolysis destabilize the interaction of CtBP and NRSF, which allow NRSF target genes, such as BDNF and TrkB, to transcribe and maintain normal neuronal excitability. (B)2DG inhibits glycolysis and reduces NADH concentrations. The co-repressor CtBP combines with the NRSF and reduces NRSF target genes transcription. Lower expression of BDNF and TrkB leads to reduced neuronal excitability and increase seizure threshold

5 695 Zeng [26] 2.KD (mammalian target of rapamycin mtor) mtor / KDm TOR McDaniel [27] KD mtor [21] mtor 2 PI3K /Akt/mTORC1 γ- NMDA hamartin/tuberin (mtor ) mtor mtor LKB1/AMPK/ mtorc1 [22, 23] mtor P I 3 K/ A k t / [24] mtor Canpolat [25] 7 mtorc1 mtor RE mtor 6 ( 3) [28] d mtor KD 3. KD A 1 KD PI3K/Akt mtor mtorc1 m T O R Notes The ketogenic diet decreases insulin levels, and would be expected to inhibit mtor activity indirectly by decreasing PI3K/Akt signaling. Rapamycin directly inhibit mtorc1, thereby prevent the downstream effects implicated in epileptogenesis caused by mtor dysregulation of any etiology [29] A 1 A 2A A 2B A 3 4 A 1 (adenosine

6 696 kinase, ADK) AMP ( >2 mmol L -1 ) KD 3 MAD ADK A 1 1/3 4 2/3 5 [30] A 1 7 KD RE MAD 1 15 g d -1 KD 20~30 g d -1 [31] RE KD 1 3~6 RE MAD MAD MAD ( ) RE KD RE ( ) RE KD 2 MAD( 3) KD 12:00 RE >6 ( > ( KD 12~48 h 50%) 41% RE ) 21:00 6 h KD >0.5 mmol L -1 2 >(+++) KD

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