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Li-Rong Shao
Division of Pediatric Neurology, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland

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Journal article
Published: 01 January 2021 in Journal of Neurophysiology
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Despite the extensive literature showing the importance of the Na+-K+ pump in various neuronal functions, its roles in the developing brain are not well understood. This study reveals that the Na+-K+ pump differentially regulates the excitability of CA3 and CA1 neurons in the developing hippocampus, and the pump activity is crucial for maintaining network activity. Compromised Na+-K+ pump activity desynchronizes neuronal firing and transmitter release, leading to cessation of ongoing epileptiform network bursting.

ACS Style

Li-Rong Shao; Remi Janicot; Carl E. Stafstrom. Na+-K+-ATPase functions in the developing hippocampus: regional differences in CA1 and CA3 neuronal excitability and role in epileptiform network bursting. Journal of Neurophysiology 2021, 125, 1 -11.

AMA Style

Li-Rong Shao, Remi Janicot, Carl E. Stafstrom. Na+-K+-ATPase functions in the developing hippocampus: regional differences in CA1 and CA3 neuronal excitability and role in epileptiform network bursting. Journal of Neurophysiology. 2021; 125 (1):1-11.

Chicago/Turabian Style

Li-Rong Shao; Remi Janicot; Carl E. Stafstrom. 2021. "Na+-K+-ATPase functions in the developing hippocampus: regional differences in CA1 and CA3 neuronal excitability and role in epileptiform network bursting." Journal of Neurophysiology 125, no. 1: 1-11.

Short communication
Published: 03 November 2020 in Epilepsy Research
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Treatment of pediatric status epilepticus (SE) remains challenging as up to 50 % of patients are refractory to conventional anti-seizure medications. The glycolytic intermediate, fructose-1,6-bisphosphate (FBP), has been reported to exert significant anticonvulsant effects in both adult animals and in in vitro models of seizures. This study aims to examine FBP efficacy in controlling seizures in a rat model of juvenile SE. Sprague Dawley rats (P11-P17) were injected with pilocarpine (300 mg/kg, i.p.) to induce SE, which was monitored by video-electroencephalography (v-EEG). Thirty minutes into SE, FBP was administrated (500 or 1000 mg/kg, i.p.). v-EEG recording was continued for ∼60 additional minutes to assess the anticonvulsant effect of FBP, compared with vehicle (saline) treatment. SE consistently occurred in rat pups 10−15 min after pilocarpine injection and persisted over the 90-min recording period. Neither saline nor a lower dose of FBP (500 mg/kg) treatment stopped behavioral and electrographic seizures. At higher doses (1000 mg/kg), FBP terminated SE in ∼15 min in 60 % (6 of 10) of the rat pups. The endogenous glycolytic metabolite, FBP, promptly suppresses ongoing seizure activity and represents a potential alternative metabolic therapy to improve the treatment of SE in the juvenile age range.

ACS Style

Remi Janicot; Carl E. Stafstrom; Li-Rong Shao. The efficacy of fructose-1,6-bisphosphate in suppressing status epilepticus in developing rats. Epilepsy Research 2020, 168, 106500 .

AMA Style

Remi Janicot, Carl E. Stafstrom, Li-Rong Shao. The efficacy of fructose-1,6-bisphosphate in suppressing status epilepticus in developing rats. Epilepsy Research. 2020; 168 ():106500.

Chicago/Turabian Style

Remi Janicot; Carl E. Stafstrom; Li-Rong Shao. 2020. "The efficacy of fructose-1,6-bisphosphate in suppressing status epilepticus in developing rats." Epilepsy Research 168, no. : 106500.

Journal article
Published: 19 June 2020 in Epilepsia
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Objective Neonatal status epilepticus (SE) is a life‐threatening medical emergency. Unfortunately, up to 50% of neonates with SE are resistant to current antiseizure drugs, highlighting the need for better treatments. This study aims to explore a novel metabolic approach as a potential alternative treatment to control neonatal SE, using the glycolytic inhibitor 2‐deoxyglucose (2‐DG). Methods SE was induced by pilocarpine (300 mg/kg, intraperitoneally [ip]) in neonatal Sprague Dawley rats (postnatal day 10 [P10]‐P17) and was monitored by video‐electroencephalography (V‐EEG). After 30 minutes of SE, 2‐DG or one of two conventional antiseizure drugs with different mechanisms of action, phenobarbital or levetiracetam, was administrated ip, and V‐EEG recording was continued for ~60 additional minutes. The time to seizure cessation after drug injection, EEG scores, and power spectra before and after drug or saline treatment were used to assess drug effects. Results Once SE became sustained, administration of 2‐DG (50, 100, or 500 mg/kg, ip) consistently stopped behavioral and electrographic seizures within 10‐15 minutes; lower doses took longer (25‐30 minutes) to stop SE, demonstrating a dose‐dependent effect. Administration of phenobarbital (30 mg/kg, ip) or levetiracetam (100 mg/kg, ip) also stopped SE within 10‐15 minutes in neonatal rats. Significance Our results suggest that the glycolysis inhibitor 2‐DG acts quickly to reduce neuronal hyperexcitability and effectively suppress ongoing seizure activity, which may provide translational value in the treatment of neonatal SE.

ACS Style

Remi Janicot; Carl E. Stafstrom; Li‐Rong Shao. 2‐Deoxyglucose terminates pilocarpine‐induced status epilepticus in neonatal rats. Epilepsia 2020, 61, 1 .

AMA Style

Remi Janicot, Carl E. Stafstrom, Li‐Rong Shao. 2‐Deoxyglucose terminates pilocarpine‐induced status epilepticus in neonatal rats. Epilepsia. 2020; 61 (7):1.

Chicago/Turabian Style

Remi Janicot; Carl E. Stafstrom; Li‐Rong Shao. 2020. "2‐Deoxyglucose terminates pilocarpine‐induced status epilepticus in neonatal rats." Epilepsia 61, no. 7: 1.

Review
Published: 06 January 2020 in Children
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Infantile spasms (IS) is an epileptic encephalopathy with unique clinical and electrographic features, which affects children in the middle of the first year of life. The pathophysiology of IS remains incompletely understood, despite the heterogeneity of IS etiologies, more than 200 of which are known. In particular, the neurobiological basis of why multiple etiologies converge to a relatively similar clinical presentation has defied explanation. Treatment options for this form of epilepsy, which has been described as “catastrophic” because of the poor cognitive, developmental, and epileptic prognosis, are limited and not fully effective. Until the pathophysiology of IS is better clarified, novel treatments will not be forthcoming, and preclinical (animal) models are essential for advancing this knowledge. Here, we review preclinical IS models, update information regarding already existing models, describe some novel models, and discuss exciting new data that promises to advance understanding of the cellular mechanisms underlying the specific EEG changes seen in IS—interictal hypsarrhythmia and ictal electrodecrement.

ACS Style

Remi Janicot; Li-Rong Shao; Carl Stafstrom. Infantile Spasms: An Update on Pre-Clinical Models and EEG Mechanisms. Children 2020, 7, 5 .

AMA Style

Remi Janicot, Li-Rong Shao, Carl Stafstrom. Infantile Spasms: An Update on Pre-Clinical Models and EEG Mechanisms. Children. 2020; 7 (1):5.

Chicago/Turabian Style

Remi Janicot; Li-Rong Shao; Carl Stafstrom. 2020. "Infantile Spasms: An Update on Pre-Clinical Models and EEG Mechanisms." Children 7, no. 1: 5.

Review
Published: 05 February 2019 in Children
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Mechanisms underlying seizures and epilepsy have traditionally been considered to involve abnormalities of ion channels or synaptic function. Those considerations gave rise to the excitation/inhibition (E/I) imbalance theory, whereby increased excitation, decreased inhibition, or both favor a hyperexcitable state and an increased propensity for seizure generation and epileptogenesis. Several recent findings warrant reconsideration and expansion of the E/I hypothesis: novel genetic mutations have been identified that do not overtly affect E/I balance; neurotransmitters may exert paradoxical effects, especially during development; anti-seizure medications do not necessarily work by decreasing excitation or increasing inhibition; and metabolic factors participate in the regulation of neuronal and network excitability. These novel conceptual and experimental advances mandate expansion of the E/I paradigm, with the expectation that new and exciting therapies will emerge from this broadened understanding of how seizures and epilepsy arise and progress.

ACS Style

Li-Rong Shao; Christa W. Habela; Carl E. Stafstrom. Pediatric Epilepsy Mechanisms: Expanding the Paradigm of Excitation/Inhibition Imbalance. Children 2019, 6, 23 .

AMA Style

Li-Rong Shao, Christa W. Habela, Carl E. Stafstrom. Pediatric Epilepsy Mechanisms: Expanding the Paradigm of Excitation/Inhibition Imbalance. Children. 2019; 6 (2):23.

Chicago/Turabian Style

Li-Rong Shao; Christa W. Habela; Carl E. Stafstrom. 2019. "Pediatric Epilepsy Mechanisms: Expanding the Paradigm of Excitation/Inhibition Imbalance." Children 6, no. 2: 23.

Original research article
Published: 15 June 2018 in Frontiers in Cellular Neuroscience
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Manipulation of metabolic pathways (e.g., ketogenic diet (KD), glycolytic inhibition) alters neural excitability and represents a novel strategy for treatment of drug-refractory seizures. We have previously shown that inhibition of glycolysis suppresses epileptiform activity in hippocampal slices. In the present study, we aimed to examine the role of a “branching” metabolic pathway stemming off glycolysis (i.e., the pentose-phosphate pathway, PPP) in regulating seizure activity, by using a potent PPP stimulator and glycolytic intermediate, fructose-1,6-bisphosphate (F1,6BP). Employing electrophysiological approaches, we investigated the action of F1,6BP on epileptiform population bursts, intrinsic neuronal firing, glutamatergic and GABAergic synaptic transmission and voltage-activated calcium currents (ICa) in the CA3 area of hippocampal slices. Bath application of F1,6BP (2.5–5 mM) blocked epileptiform population bursts induced in Mg2+-free medium containing 4-aminopyridine, in ~2/3 of the slices. The blockade occurred relatively rapidly (~4 min), suggesting an extracellular mechanism. However, F1,6BP did not block spontaneous intrinsic firing of the CA3 neurons (when synaptic transmission was eliminated with DNQX, AP-5 and SR95531), nor did it significantly reduce AMPA or NMDA receptor-mediated excitatory postsynaptic currents (EPSCAMPA and EPSCNMDA). In contrast, F1,6BP caused moderate reduction (~50%) in GABAA receptor-mediated current, suggesting it affects excitatory and inhibitory synapses differently. Finally and unexpectedly, F1,6BP consistently attenuated ICa by ~40% without altering channel activation or inactivation kinetics, which may explain its anticonvulsant action, at least in this in vitro seizure model. Consistent with these results, epileptiform population bursts in CA3 were readily blocked by the nonspecific Ca2+ channel blocker, CdCl2 (20 μM), suggesting that these bursts are calcium dependent. Altogether, these data demonstrate that the glycolytic metabolite, F1,6BP, blocks epileptiform activity via a previously unrecognized extracellular effect on ICa, which provides new insight into the metabolic control of neural excitability.

ACS Style

Li-Rong Shao; Guangxin Wang; Carl E. Stafstrom. The Glycolytic Metabolite, Fructose-1,6-bisphosphate, Blocks Epileptiform Bursts by Attenuating Voltage-Activated Calcium Currents in Hippocampal Slices. Frontiers in Cellular Neuroscience 2018, 12, 1 .

AMA Style

Li-Rong Shao, Guangxin Wang, Carl E. Stafstrom. The Glycolytic Metabolite, Fructose-1,6-bisphosphate, Blocks Epileptiform Bursts by Attenuating Voltage-Activated Calcium Currents in Hippocampal Slices. Frontiers in Cellular Neuroscience. 2018; 12 ():1.

Chicago/Turabian Style

Li-Rong Shao; Guangxin Wang; Carl E. Stafstrom. 2018. "The Glycolytic Metabolite, Fructose-1,6-bisphosphate, Blocks Epileptiform Bursts by Attenuating Voltage-Activated Calcium Currents in Hippocampal Slices." Frontiers in Cellular Neuroscience 12, no. : 1.

Journal article
Published: 01 July 2017 in Journal of Neurophysiology
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Neuronal activity is energy demanding and coupled to cellular metabolism. In this study, we investigated the effects of glycolytic inhibition with 2-deoxy-d-glucose (2-DG) on basal membrane properties, spontaneous neuronal firing, and epileptiform network bursts in hippocampal slices. The effect of glycolytic inhibition on basal membrane properties was examined in hippocampal CA1 neurons, which are not ordinarily active spontaneously. Intracellular application of 2-DG did not significantly alter the membrane input resistance, action-potential threshold, firing pattern, or input-output relationship of these neurons compared with simultaneously recorded neighboring neurons without intracellular 2-DG. The effect of glycolytic inhibition on neuronal firing was tested in spontaneously active hippocampal neurons (CA3) when synaptic transmission was left intact or blocked with AMPA, NMDA, and GABAA receptor antagonists (DNQX, APV, and bicuculline, respectively). Under both conditions (synaptic activity intact or blocked), bath application of 2-DG (2 mM) blocked spontaneous firing in ~2/3 (67 and 71%, respectively) of CA3 pyramidal neurons. In contrast, neuronal firing of CA3 neurons persisted when 2-DG was applied intracellularly, suggesting that glycolytic inhibition of individual neurons is not sufficient to stop neuronal firing. The effects of 2-DG on epileptiform network bursts in area CA3 were tested in Mg2+-free medium containing 50 µM 4-aminopyridine. Bath application of 2-DG abolished these epileptiform bursts in a dose-dependent and all-or-none manner. Taken together, these data suggest that altered glucose metabolism profoundly affects cellular and network hyperexcitability and that glycolytic inhibition by 2-DG can effectively abrogate epileptiform activity. NEW & NOTEWORTHY Neuronal activity is highly energy demanding and coupled to cellular metabolism. In this study, we demonstrate that glycolytic inhibition with 2-deoxy-d-glucose (2-DG) effectively suppresses spontaneous neuronal firing and epileptiform bursts in hippocampal slices. These data suggest that an altered metabolic state can profoundly affect cellular and network excitability, and that the glycolytic inhibitor 2-DG may hold promise as a novel treatment of drug-resistant epilepsy.

ACS Style

Li-Rong Shao; Carl E. Stafstrom. Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model. Journal of Neurophysiology 2017, 118, 103 -113.

AMA Style

Li-Rong Shao, Carl E. Stafstrom. Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model. Journal of Neurophysiology. 2017; 118 (1):103-113.

Chicago/Turabian Style

Li-Rong Shao; Carl E. Stafstrom. 2017. "Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model." Journal of Neurophysiology 118, no. 1: 103-113.

Review
Published: 24 May 2016 in Seminars in Pediatric Neurology
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Epileptic encephalopathies are syndromes in which seizures or interictal epileptiform activity contribute to or exacerbate brain function, beyond that caused by the underlying pathology. These severe epilepsies begin early in life, are associated with poor lifelong outcome, and are resistant to most treatments. Therefore, they represent an immense challenge for families and the medical care system. Furthermore, the pathogenic mechanisms underlying the epileptic encephalopathies are poorly understood, hampering attempts to devise novel treatments. This article reviews animal models of the three classic epileptic encephalopathies-West syndrome (infantile spasms), Lennox-Gastaut syndrome, and continuous spike waves during sleep or Landau-Kleffner syndrome-with discussion of how animal models are revealing underlying pathophysiological mechanisms that might be amenable to targeted therapy.

ACS Style

Li-Rong Shao; Carl E. Stafstrom. Pediatric Epileptic Encephalopathies: Pathophysiology and Animal Models. Seminars in Pediatric Neurology 2016, 23, 98 -107.

AMA Style

Li-Rong Shao, Carl E. Stafstrom. Pediatric Epileptic Encephalopathies: Pathophysiology and Animal Models. Seminars in Pediatric Neurology. 2016; 23 (2):98-107.

Chicago/Turabian Style

Li-Rong Shao; Carl E. Stafstrom. 2016. "Pediatric Epileptic Encephalopathies: Pathophysiology and Animal Models." Seminars in Pediatric Neurology 23, no. 2: 98-107.