energy metabolism and seizures · energy metabolism and seizures carl e. stafstrom, md, phd...
TRANSCRIPT
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ENERGY METABOLISM AND SEIZURES
Carl E. Stafstrom, MD, PhD Professor of Neurology & Pediatrics Lederer Chair in Pediatric Epilepsy
Director, Pediatric Neurology Johns Hopkins University
Baltimore, MD
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Faculty Disclosure
• None.
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Educational Need/Practice Gap
Gap = Difference between current practice and optimal practice relevant to the educational need. At least 1/3 of patients have seizures that do not respond to conventional medications, devices, or surgery. Need = The issue/problem that underlies the practice gap Currently, epilepsy is treated mainly with therapies that target ion channels or synaptic transmission.
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Objectives
Upon completion of this educational activity, you will be able to: - Explain how seizures are regulated by
metabolism - Name several metabolic treatments for
epilepsy - Describe how glycolytic inhibition affects
neuronal excitability
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Expected Outcome
• What is the desired change/result in practice resulting from this educational intervention?
Consider metabolic approaches as alternative therapeutic strategies for drug-resistant epilepsy.
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OUTLINE • I. Excitation/inhibition imbalance in epilepsy:
paradigm shift • II. Overview of metabolism and neuronal excitability
• III. Inhibition of glycolysis as potential mechanism for
seizure suppression: 2-Deoxyglucose (2DG)
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Seizures and Epilepsy
▲
IMBALANCE OF EXCITATION vs INHIBITION
SEIZURE
E I
and/or
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Standard paradigm: ion channels and synapses
▲
E I
and/or
• ↑ Na channel activity • ↑ Excitatory synapse function - ↑ glutamate - ↑ network connectivity
• ↓K channel activity • ↓ Inhibitory synapse function - ↓ GABA
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Restoring the E/I balance
▲
E I Retigabine Benzodiazepines Phenobarbital Vigabatrin
Carbamazepine Phenytoin Topiramate Perampanel Felbamate
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Excitation/inhibition balance
• Emerging roles of metabolism and its regulation in excitability, seizure generation, and epileptogenesis
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Metabolic control of excitability and epilepsy
• Brain has an extremely high metabolic rate
• Energy needed for resting potential maintenance, action potential generation, synaptic potentials, pumps (Na-K ATPase)
• Derives majority of energy/ATP from aerobic oxidation of glucose
• Seizures very energy-consuming; energy failure promotes epileptogenesis
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Dependence of neural activity on energy from glucose
• Under normal conditions: Brain uses glucose as obligate energy source
• Under conditions of low glucose availability: Brain can use ketones from fat breakdown as its energy source
ATP
ATP
acetoacetate Β-hydroxybutyrate acetone
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The Ketogenic Diet
• High fat, low carbohydrate, adequate protein
• Causes metabolic shift/adaptation from carbs to fat as primary energy source
KD: 4:1 ratio of fat to carb + protein by weight 90% calories from fat
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The Ketogenic Diet
• Effective in wide variety of intractable epilepsy • Numerous uncontrolled studies, case series:
– ~ half patients get >50% seizure reduction
• Double blind, controlled study:
Lancet Neurol 7:500, 2008
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The Ketogenic Diet
Search for mechanism: - Role of ketones - Role of carbohydrate restriction
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The Ketogenic Diet
Bough & Rho, Epilepsia 48: 43, 2007
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The Ketogenic Diet
• Search for mechanism: – Animal models
• KD effective in several models: kindling, PTZ, KA • Ketosis necessary but not sufficient • Direct ketone application: no effect on membrane ionic currents or E/I synaptic currents
Thio et al., Neurology 54:325, 2000
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Observation: Ingestion of small amounts of carbohydrate reverses seizure control in patients on the
ketogenic diet
Huttenlocher, Ped Res 10:536, 1976
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Observation: Ingestion of small amounts of carbohydrate reverses seizure control in patients on the
ketogenic diet
Hypothesis: Carbohydrate restriction by inhibition of glycolysis might protect against seizures
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Metabolic Pathways and Sites of Potential Seizure Suppression
Anapleurosis
LGIT LGIT
Stafstrom et al., Epilepsia 49 S8:97-100, 2008
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Glycolytic inhibition as potential mechanism for seizure suppression
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Bypassing glycolysis has acute anticonvulsant effect (CA3; 7.5 mM K+)
Stafstrom et al., Ann Neurol 65:435, 2009
5 sec
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Metabolic Pathways and Sites of Potential Seizure Suppression
Anapleurosis
LGIT LGIT
Stafstrom et al., Epilepsia 49 S8:97-100, 2008
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2-DEOXY-D-GLUCOSE (2DG)
• Glucose analog • Crosses blood-brain barrier
• Decades of use as a PET tracer 18F-2DG
• Approved for Phase 2 clinical trials as adjuvant
chemotherapy for cancer
• Inhibits glycolysis by blocking phosphoglucose isomerase (PGI)
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Metabolism of 2DG and effect on glycolysis:
glycolysis inhibitor
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Acute anticonvulsant effects in vitro
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baseline
10 mM 2DG
washout
2DG reduces interictal and ictal bursts in CA3 in 7.5 mM [K+]o
Stafstrom et al., Ann Neurol 65:435, 2009
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Current (pA)100 200 300 400
Num
ber o
f AP
s
0
10
20
30
40
Ctrl, 1 minCtrl, 10 min2-DG, 1 min2-DG, 10 min
1 min 10 min
2-DG does not alter intrinsic membrane excitability in CA1 pyramidal cells
100 ms
25 mV
A
B
-60 mV
-60 mV
*
Ctrl 2-DGInpu
t Res
ista
nce
(m
)
0
40
80
120
1601 min10 min
Ctrl 2-DG
AP
Thr
esho
ld (m
V)
-60
-40
-20
0
1 min10 min
2-DG
CA1
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2-DG blocks neuronal firing in CA3 and CA1 pyramidal cells
A
B
10 mM 2-DG
2 min
20 mV -66 mV
CA3
0.5 s 20 mV
CA1
2 min
20 mV
10 mM 2-DG
7.5 mM [K+]o
-66 mV
5 s 20 mV
aCSF
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CA1
CA3
5 min
1 mV
A
B
1 2 3
1 2 3
2-DG abolishes network bursting in both CA1 and CA3
Time (min)0 15 30 45
Freq
uenc
y (H
z)
0.0
0.5
1.0
1.5
Time (min)0 15 30 45
Am
plitu
de (m
V)
0.0
0.5
1.0
1.5 10 mM 2-DG 10 mM 2-DG
10 mM 2-DG
2 s
0 Mg2+ + 50 μM 4-AP
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Acute anticonvulsant effects in vivo
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2DG has ACUTE in vivo anticonvulsant action
kainic acid status epilepticus audiogenic seizures 6 hz seizures
NIH ASP NIH ASP
Stafstrom et al., Ann Neurol 65:435, 2009 Gasior et al., Epilepsia 51:1385, 2010
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Kindling • Electrical stimulation of neural pathway leads to
permanent epileptic state (epileptogenesis) • Stimuli are initially subconvulsive • Increase current until an afterdischarge occurs • Subsequent daily stimuli result in increasingly longer
ADs, culminating in clinical seizures (focal dyscognitive with secondary generalization) Measure: ** AD threshold ** # ADs to seizure classes
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2DG Anticonvulsant effect in vivo: increases kindling afterdischarge (AD) threshold
Garriga-Canut et al., Nat Neurosci 9:1382, 2006
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Antiepileptic action in vivo:
reduces rate of kindling progression by ~ 2-fold
implications for intractability, memory dysfunction, cognitive deficits
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Model for prevention of kindling progression by 2DG
2DG Inhibits glycolysis
Repression of BDNF/trkB gene expression via CtBP/REST
↑ seizure threshold
(Huang & McNamara 2006)
Garriga-Canut et al., Nat Neurosci. 2006;9:1382-7
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NRSF required for 2DG effect but not for ketogenic diet effect
Hu et al., Epilepsia 52:1609, 2011
NRSF knock out
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“Disease-modifying” actions of 2DG when administered AFTER seizures
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“Disease-modifying” actions of 2DG when administered AFTER seizures
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2DG safety profile
• General health of animals – good, including weight gain
• Cardiotoxicity reported • Behavioral/cognitive testing
– Exploratory activity (open field) – Fear conditioning – Spatial learning & memory (water maze)
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2DG does not alter water maze learning
Ockuly et al., Epilepsy Res 101:246, 2012
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SUMMARY 1 2DG has acute anticonvulsant effects in vitro by several methods of seizure induction:
- high K+ - bicuculline - DHPG - 4-AP/zero Mg 2DG has acute anticonvulsant effects in vivo against: - kindling - 6 Hz - audiogenic/Fring’s - KA seizure latency
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SUMMARY 2 • 2DG has chronic antiepileptic effects in vivo against progression of kindled seizures and adverse cognitive
consequences often associated with seizures • 2DG has a favorable preliminary toxicity profile
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SUMMARY 2 • 2DG has chronic antiepileptic effects in vivo against progression of kindled seizures and adverse cognitive
consequences often associated with seizures • 2DG has a favorable preliminary toxicity profile
Inhibition of glycolysis (e.g., 2DG) is a novel therapeutic approach to epilepsy
Rethinking of E/I paradigm
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↑Excitability, seizures
Synapse formation
Neurotransmitters/receptors
Metabolic factors
Ion channels
Networks/circuits
Molecular signaling
Glia homeostasis
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• Metabolic approaches hold much promise for: • control of neuronal excitability • suppression of seizure generation • modification of epileptogenesis
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Unresolved questions
• Mechanisms of acute and chronic effects • Age-dependence • Clinical trials
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Collaborators
University of Wisconsin-Madison Tom Sutula Avtar Roopra Paul Rutecki Jeff Ockuly Yuzhen Pan NIH Jim Stables Johns Hopkins University Li Rong Shao