Enhancing glucose metabolism via gluconeogenesis is therapeutic in a zebrafish model of a Dravet syndrome
Abstract number :
648
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2020
Submission ID :
2422989
Source :
www.aesnet.org
Presentation date :
12/7/2020 9:07:12 AM
Published date :
Nov 21, 2020, 02:24 AM
Authors :
Rajeswari Banerji, University of Colorado, Anschutz Medical Campus; Christopher Hyunh - University of Colorado, Anschutz Medical Campus; Francisco Figueroa - University of California, San Francisco; Matthew Dinday - University of California, San Francisco
Rationale:
Dravet syndrome (DS) is a catastrophic childhood epilepsy commonly associated with de novo mutations of the voltage-gated sodium channel NaV1.1 gene, SCN1A. Children affected with SCN1A mutation suffer from frequent spontaneous seizures, developmental delays, cognitive and behavioral deficits as well as increased risk of Sudden Unexpected Death in Epilepsy (SUDEP). While the role of metabolic dysfunction has emerged in acquired epilepsies, its role in genetic epilepsies is lacking. Using a zebrafish model of DS (scn1Lab) which exhibits key characteristics of DS patients, we previously showed decreased basal glycolytic rates and mitochondrial respiration accompanied by downregulation of key gluconeogenic genes, pck1 and pck2. The objective of this study was to determine if glucose regulation via gluconeogenesis mediated metabolic defects were observed in the scn1Lab zebrafish model of DS.
Method:
We performed a metabolism-based small library screen with commercially available compounds that increased gluconeogenesis via upregulation of pck gene expression (or flux) via phosphoenolpyruvate carboxykinase.
Results:
The screen identified compounds which upregulated the expression of pck1, but not pck2 more than two-fold in scn1Lab mutant larvae. Treatment with a subset of the pck1 activators normalized glucose levels, metabolic deficits and significantly decreased behavioral seizures in mutant larvae. The TSPO ligand, PK11195 was identified as our top candidate for its ability to correct the metabolic deficits, behavioral and electrographic seizures in the scn1Lab mutants.
Conclusion:
Taken together our data suggests that metabolic deficits and seizures in genetic epilepsies such as DS could be pharmacologically improved via an alternate pathway that improves metabolism without increasing glycolysis directly, thus suggesting novel avenues for therapeutic intervention. This suggests a novel metabolism-based therapeutic avenue to treat catastrophic pediatric epilepsies such as DS arising from ion channel mutations.
Funding:
:R.B. was supported by a postdoctoral fellowship from the Dravet Syndrome Foundation and R01NS039587 and R01NS086423 (M.P.).
Basic Mechanisms