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There is growing evidence that ketone bodies (KB)—derived from fatty acid oxidation and produced during fasting or consumption of high-fat diets—can exert broad neuroprotective effects. With respect to epilepsy, KB (such as β-hydroxybutyrate or BHB, acetoacetate and acetone) have been shown to block acutely induced and spontaneous recurrent seizures in various animal models. Although the mechanisms underlying the anti-seizure effects of KB have not been fully elucidated, recent experimental studies have invoked ketone-mediated effects on both inhibitory (e.g., GABAergic, purinergic and ATP-sensitive potassium channels) and excitatory (e.g., vesicular glutamate transporters) neurotransmission, as well as mitochondrial targets (e.g., respiratory chain and mitochondrial permeability transition). Moreover, BHB appears to exert both epigenetic (i.e., inhibition of histone deacetylases or HDACs) and anti-inflammatory (i.e., peripheral modulation of hydroxycarboxylic acid receptor and inhibition of the NOD-like receptor protein 3 or NRLP3 inflammasome) activity. While the latter two effects of BHB have yet to be directly linked to ictogenesis and/or epileptogenesis, parallel lines of evidence indicate that HDAC inhibition and a reduction in neuroinflammation alone or collectively can block seizure activity. Nevertheless, the notion that KB are themselves anti-seizure agents requires clinical validation, as prior studies have not revealed a clear correlation between blood ketone levels and seizure control. Notwithstanding this limitation, there is growing evidence that KB are more than just cellular fuels, and can exert profound biochemical, cellular and epigenetic changes favoring an overall attenuation in brain network excitability.

Epilepsy often occurs with other neurological disorders, such as autism, affective disorders, and cognitive impairment. Research indicates that many neurological disorders share a common pathophysiology of dysfunctional energy metabolism, neuroinflammation, oxidative stress, and gut dysbiosis. The past decade has witnessed a growing interest in the use of metabolic therapies for these disorders with or without the context of epilepsy. Over one hundred years ago, the high-fat, low-carbohydrate ketogenic diet (KD) was formulated as a treatment for epilepsy. For those who cannot tolerate the KD, other diets have been developed to provide similar seizure control, presumably through similar mechanisms. These include, but are not limited to, the medium-chain triglyceride diet, low glycemic index diet, and calorie restriction. In addition, dietary supplementation with ketone bodies, polyunsaturated fatty acids, or triheptanoin may also be beneficial. The proposed mechanisms through which these diets and supplements work to reduce neuronal hyperexcitability involve normalization of aberrant energy metabolism, dampening of inflammation, promotion of endogenous antioxidants, and reduction of gut dysbiosis. This raises the possibility that these dietary and metabolic therapies may not only exert anti-seizure effects, but also reduce comorbid disorders in people with epilepsy. Here, we explore this possibility and review the clinical and preclinical evidence where available.

Background/Objectives: Hyperexcitable neuronal activity associated with seizures may disrupt brain homeostasis resulting in abnormal glucose and nutrient management and metabolism. Specialized ependymal cells known as tanycytes line the third ventricle wall bridging communication between the brain, CSF, and blood. Despite their positional importance, whether tanycytes are impacted by epilepsy is unknown. Here, known protein markers of tanycytes were assessed in the Kcna1-null mouse model of genetic epilepsy with spontaneous recurrent seizures (SRS mice). Further, whether an anti-seizure metabolic ketogenic diet (KD), previously proven effective in SRS mice, restored protein levels was determined. Methods: Known tanycyte proteins, including glucose transporter 1 (GLUT1), glial fibrillary acidic protein (GFAP), and doublecortin (DCX, to determine potential neurogenic differences) were examined throughout the anterior–posterior axis of the third ventricle using immunofluorescent histochemistry. Results: Decreased GLUT1 immunoreactivity and elevated GFAP levels were found in the SRS cohorts. The number of neurogenic DCX-expressing cells did not differ. Two weeks of KD treatment reduced GFAP to WT levels. GLUT1 remained low in KD-treated SRS mice. Conclusions: These data suggest that the expression of proteins important for the structure and function of tanycytes is altered in preclinical epilepsy and is differentially restored with KD treatment. Whether tanycytes actively participate in the pathophysiology of epilepsy or associated comorbidities is an intriguing possibility given their integral role in brain homeostasis.

Ascorbic acid (AA; a.k.a. vitamin C) is well known for its cellular protection in environments of high oxidative stress. Even though physiological concentrations of AA in the brain are significant (0.2–10 mM), surprisingly little is known concerning the role of AA in synaptic neurotransmission under normal, non-disease state conditions. Here, we examined AA effects on neurotransmission, plasticity and spontaneous network activity (i.e., sharp waves and high frequency oscillations; SPW-HFOs), at the synapse between area 3 and 1 of the hippocampal cornu ammonis region (CA3 and CA1) using an extracellular multi-electrode array in in vitro mouse hippocampal slices. We found that AA decreased evoked field potentials (fEPSPs, IC50 = 0.64 mM) without affecting V50s or paired pulse facilitation indicating normal neurotransmitter release mechanisms. AA decreased presynaptic fiber volleys but did not change fiber volley-to-fEPSP coupling, suggesting reduced fEPSPs resulted from decreased fiber volleys. Inhibitory effects were also observed in CA1 stratum pyramidale where greater fEPSPs were required for population spikes in the presence of AA suggesting an impact on the intrinsic excitability of neurons. Other forms of synaptic plasticity and correlates of memory (i.e., short- and long-term potentiation) were also significantly reduced by AA as was the incidence of spontaneous SPW-HFOs. AA decreased SPW amplitude with a similar IC50 as fEPSPs (0.65 mM). Overall, these results indicate that under normal conditions AA significantly regulates neurotransmission, plasticity, and network activity by limiting excitability. Thus, AA may participate in refinement of signal processing and memory formation, as well as protecting against pathologic excitability.

Higher therapeutic concentrations of the antiseizure medication carbamazepine (CBZ) are associated with cognitive side effects. Hippocampal sharp wave-ripple complexes (SPW-Rs) are proposed to participate in memory consolidation during periods of quiet and slow-wave sleep. SPW-Rs are generated in the CA3 region and are regulated by multiple synaptic inputs. Here, we used a multi-electrode array to determine the effects of CBZ on SPW-Rs and synaptic transmission at multiple hippocampal synapses. Our results demonstrate that CBZ reduced SPW-Rs at therapeutically relevant concentrations (IC50 = 37 μM) and altered the core characteristics of ripples, important for information processing and consolidation. Moreover, CBZ inhibited neurotransmission in a synapse-specific manner. CBZ inhibition was most potent at the medial-perforant-path-to-CA3 and mossy-fiber-to-CA3 synapses (IC50s ~ 30 and 60 μM, respectively) and least potent at medial-perforant-path-to-dentate granule cell synapses (IC50 ~ 120 μM). These results suggest that the synapse-specific CBZ inhibition of neurotransmission reduces SPW-Rs and that the CBZ inhibition of SPW-Rs may underlie the cognitive impairments observed with therapeutic doses of CBZ.

Carnitine palmitoyltransferase 2 (CPT2) is an inner mitochondrial membrane protein of the carnitine shuttle and is involved in the beta-oxidation of long chain fatty acids. Beta-oxidation provides an alternative pathway of energy production during early development and starvation. CPT2 deficiency is a genetic disorder that we recently showed can be associated with schizophrenia. We hypothesize that CPT2 deficiency during early brain development causes transcriptional, structural, and functional abnormalities that may contribute to a CNS environment that is susceptible to the emergence of schizophrenia. To investigate the effect of CPT2 deficiency on early vertebrate development and brain function, CPT2 was knocked down in a zebrafish model system. CPT2 knockdown resulted in abnormal lipid utilization and deposition, reduction in body size, and abnormal brain development. Axonal projections, neurotransmitter synthesis, electrical hyperactivity, and swimming behavior were disrupted in CPT2 knockdown zebrafish. RT-qPCR analyses showed significant increases in the expression of schizophrenia-associated genes in CPT2 knockdown compared to control zebrafish. Taken together, these data demonstrate that zebrafish are a useful model for studying the importance of beta-oxidation for early vertebrate development and brain function. This study also presents novel findings linking CPT2 deficiency to the regulation of schizophrenia and neurodegenerative disease-associated genes.

The effect of the antiepileptic drug topiramate on Ca2+ uptake through (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate (AMPA) and kainate (KA) receptors was investigated in different cell culture systems consisting of neurons from the cerebral cortex, hippocampus, and cerebellum. Ca2+ influx was assayed using a fluorescent Ca2+ chelator to monitor changes in the intracellular Ca2+ concentration or cobalt staining to assess the effect of topiramate on Ca2+-permeable AMPA/KA receptors. In all types of neuronal cultures studied, AMPA and KA were found to elicit an influx of Ca2+ in a subset of the neuronal population. Topiramate, at concentrations of 30 and 100 microM, inhibited Ca2+ influx by up to 60%. Modulation of AMPA and KA-evoked Ca2+ influx may contribute to both the antiepileptic and neuroprotective properties of topiramate.

Objective Sudden unexpected death in epilepsy (SUDEP) is a rare but devastating consequence of epilepsy and is the leading cause of death in people with epilepsy. SUDEP is associated with certain characteristics such as the presence of generalized tonic–clonic seizures, duration of epilepsy, and refractoriness to anti‐seizure medications. Despite insights from in vivo models, gaps persist in understanding the biological causes of SUDEP, leading to a lack of preventative tools. Current SUDEP preclinical models and data collection and reporting can vary widely across laboratories, hindering the direct translation of findings to humans. Methods The 2020 SUDEP Coalition Summit brought together a team of experts to chart areas of growth and tactics to address these areas. A critical research priority revealed during the summit was the development of data standardization tools to unify SUDEP research efforts. In response, CURE Epilepsy established a Steering Committee to oversee an effort to develop data standardization tools and worked with community members composed of experts in specific domains of SUDEP research to define these tools. Results Experts developed common data elements (CDEs) and case report forms (CRFs) to systematize preclinical SUDEP research. An accompanying publication describes the priority core and death‐related information CRF, while the current work describes supplemental CRFs that SUDEP researchers can use. Specifically, CDEs related to neurological variables, physiologic measures, therapeutics and pharmacology, neuroimaging, ex vivo electrophysiology, and additional phenotypes related to epilepsy are described. Significance Along with the core and death‐related CRF, supplemental CRFs can help the unification of SUDEP research by systematizing various endpoints. Adoption of these data standardization tools can also enhance collaboration between teams, hasten the translatability of SUDEP research to the human condition, and ultimately help prevent SUDEP. Plain Language Summary Preclinical sudden unexpected death in epilepsy (SUDEP) research holds great promise for addressing this fatal condition; however, lack of data standardization remains an issue. Other fields have shown that the incorporation of common data elements (CDEs) can serve to harmonize data across groups, increase rigor, and improve translatability. An accompanying paper describes “Core” CDEs that could be used by all SUDEP preclinical researchers; the current manuscript describes related, supplemental CDEs applicable to researchers depending on their specific scientific question. These include neurological and physiological measures, therapeutics and pharmacology, neuroimaging, ex vivo electrophysiology, and additional phenotypes related to epilepsy.

Objective Sudden Unexpected Death in Epilepsy (SUDEP) is a fatal complication for individuals living with epilepsy and is associated with significant personal and public burden. While certain neurotransmitters and neuronal pathways have been associated with SUDEP, the exact biological mechanisms are unknown. Preclinical research has been instrumental in providing clues to the underlying pathology but is limited by a lack of standardized methodologies for describing and collecting data. A key outcome of the Basic Science working group of the 2020 SUDEP Coalition Summit was the recognition that the development of standardized tools would greatly enhance SUDEP research. Such a research infrastructure would increase experimental rigor, repeatability, reproducibility, and transparency and finally, increase the chances that preclinical SUDEP research can be translated into human SUDEP. Methods CURE Epilepsy assembled a Steering Committee and working groups consisting of experts in preclinical and clinical SUDEP research to develop Common Data Elements (CDEs) and Case Report Forms (CRFs) to enable standardization and translation of preclinical SUDEP data. Standardized methodology from the development of other epilepsy‐related CDEs was used. Results The Core and Death‐Related Information CRF constitutes the priority CRF for SUDEP preclinical studies. This CRF gives investigators CDEs to note details of animal models used, experiment‐related information, and details about triggered and spontaneous seizures. The seizure‐related death information consists of CDEs related to observations at the time of death, characteristics of fatal seizures, the posture of the animal at the time of death, diet, medications, and any adverse health conditions. Significance Systematic use of CDEs and CRFs in SUDEP preclinical research can help increase the rigor and transparency of research. Core CDEs along with supplemental CDEs described in the accompanying manuscript can aid investigators and groups working together toward a common goal of preventing SUDEP. Plain Language Summary Sudden Unexpected Death in Epilepsy (SUDEP) is a fatal complication of epilepsy. Preclinical research holds promise in understanding and preventing SUDEP, but its impacts are limited due to a lack of data standardization and translation among research groups. Common data elements (CDEs) are essential pieces of information for a certain field of study. CURE Epilepsy brought together a team of researchers to develop CDEs that could serve as a blueprint for all SUDEP preclinical researchers. This paper describes the SUDEP Core and Death‐Related CDEs to be used with data elements presented in an accompanying paper.

According to the Federal Rule of Civil Procedure 11, courts are required to impose sanctions on attorneys or represented parties who file signed papers that are not well-grounded in law and fact or are interposed for improper purposes. The fact that the government enjoys sovereign immunity from monetary sanctions under Rule 11 is uncomfortable and almost sure to be unpopular.