The anticonvulsant actions of carisbamate associate with alterations in astrocyte glutamine metabolism in the lithium-pilocarpine epilepsy model

Hadera, Mussie Ghezu, Faure, Jean-Baptiste, Berggaard, Nina, Tefera, Tesfaye Wolde, Nehlig, Astrid and Sonnewald, Ursula (2015) The anticonvulsant actions of carisbamate associate with alterations in astrocyte glutamine metabolism in the lithium-pilocarpine epilepsy model. Journal of Neurochemistry, 132 5: 532-545. doi:10.1111/jnc.12977


Author Hadera, Mussie Ghezu
Faure, Jean-Baptiste
Berggaard, Nina
Tefera, Tesfaye Wolde
Nehlig, Astrid
Sonnewald, Ursula
Title The anticonvulsant actions of carisbamate associate with alterations in astrocyte glutamine metabolism in the lithium-pilocarpine epilepsy model
Journal name Journal of Neurochemistry   Check publisher's open access policy
ISSN 1471-4159
0022-3042
Publication date 2015-03
Year available 2015
Sub-type Article (original research)
DOI 10.1111/jnc.12977
Open Access Status Not Open Access
Volume 132
Issue 5
Start page 532
End page 545
Total pages 14
Place of publication Chichester, West Sussex, United Kingdom
Publisher Wiley-Blackwell Publishing
Collection year 2016
Language eng
Formatted abstract
As reported previously, in the lithium–pilocarpine model of temporal lobe epilepsy (TLE), carisbamate (CRS) produces strong neuroprotection, leads to milder absence-like seizures, and prevents behavioral impairments in a subpopulation of rats. To understand the metabolic basis of these effects, here we injected 90 mg/kg CRS or vehicle twice daily for 7 days starting 1 h after status epilepticus (SE) induction in rats. Two months later, we injected [1-13C]glucose and [1,2-13C]acetate followed by head microwave fixation after 15 min. 13C incorporation into metabolites was analyzed using 13C magnetic resonance spectroscopy. We found that SE reduced neuronal mitochondrial metabolism in the absence but not in the presence of CRS. Reduction in glutamate level was prevented by CRS and aspartate levels were similar to controls only in rats displaying absence-like seizures after treatment [CRS-absence-like epilepsy (ALE)]. Glutamine levels in CRS-ALE rats were higher compared to controls in hippocampal formation and limbic structures while unchanged in rats displaying motor spontaneous recurrent seizures after treatment (CRS-TLE). Astrocytic mitochondrial metabolism was reduced in CRS-TLE, and either enhanced or unaffected in CRS-ALE rats, which did not affect the transfer of glutamine from astrocytes to neurons. In conclusion, CRS prevents reduction in neuronal mitochondrial metabolism but its effect on astrocytes is likely key in determining outcome of treatment in this model.

To understand the metabolic basis of the strong neuroprotection and reduction in seizure severity caused by carisbamate (CRS) in the lithium–pilocarpine (Li-Pilo) model of temporal lobe epilepsy (TLE), we injected CRS for 7 days starting 1 h after status epilepticus and 2 months later [1-13C]glucose and [1,2-13C]acetate. 13C Magnetic resonance spectroscopy analysis was performed on brain extracts and we found that CRS prevented reduction in neuronal mitochondrial metabolism but its effect on astrocytes was likely key in determining outcome of treatment in this model. ALE = absence like epilepsy; acetyl CoA = acetyl coenzyme A; GS = glutamine synthetase; PAG = phosphate activated glutaminase; PC = pyruvate carboxylase; OAA = oxaloacetate; TCA cycle = tricarboxylic acid cycle.
Keyword 13C isotope
Carisbamate
lithium-pilocarpine
Neuroprotection
NMR spectroscopy
Temporal lobe epilepsy
J.Neurchem
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Biomedical Sciences Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 1 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 4 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 25 Aug 2015, 01:16:36 EST by System User on behalf of Scholarly Communication and Digitisation Service