Beta-hydroxybutyrate alters GABA-transaminase activity in cultured astrocytes.
The ketogenic diet has long been recognized as an effective treatment for medically refractory epilepsy. Despite nearly a century of use, the mechanisms underlying its clinical efficacy remain unknown. One of the proposed hypotheses for its anti-epileptic actions involves increased GABA concentration in the brain due to ketone bodies that become elevated with a ketogenic diet. In recent years, the notion that astrocytes could play a role in the evolution of abnormal cortical excitability in chronic neurological disorders, such as epilepsy, has received renewed attention. The present study examined the effects of beta-hydroxybutyrate, a ketone body, on GABA metabolism in rat primary cultured astrocytes. When beta-hydroxybutyrate was added to culture medium, GABA-transaminase (GABA-T) mRNA expression was significantly suppressed in time- and dose-dependent manners. GABA-T enzymatic activity in beta-hydroxybutyrate-treated astrocytes was also suppressed, in accordance with its gene expression. These effects were evident after 3 days of culture, which might coincide with depleted intracellular glycogen. GABA transporter, GAT-1, gene expression was strongly suppressed in cultured astrocytes after 5 days of culture with beta-hydroxybutyrate, although other type of GABA transporters did not display significant changes. These results suggest that beta-hydroxybutyrate induced by ketogenic diet may increase GABA concentration in the epileptic brain by suppressing astrocytic GABA degradation, leading to antiepileptic effects.
Suzuki
Yuka
Y
Department of Pediatrics, Graduate School of Medicine, Ehime University, Toon, Ehime 791-0295, Japan.
Takahashi
Hisaaki
H
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime 791-0295, Japan. Electronic address: hisaaki@m.ehime-u.ac.jp.
Fukuda
Mitsumasa
M
Department of Pediatrics, Graduate School of Medicine, Ehime University, Toon, Ehime 791-0295, Japan.
Hino
Hitomi
H
Department of Pediatrics, Graduate School of Medicine, Ehime University, Toon, Ehime 791-0295, Japan.
Kobayashi
Kana
K
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime 791-0295, Japan.
Tanaka
Junya
J
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime 791-0295, Japan.
Ishii
Eiichi
E
Department of Pediatrics, Graduate School of Medicine, Ehime University, Toon, Ehime 791-0295, Japan.
D020155:3-Hydroxybutyric Acid / Q000378:metabolism* / Q000494:pharmacology*; D000612:4-Aminobutyrate Transaminase / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D020148:Butyric Acid / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D050485:GABA Plasma Membrane Transport Proteins; D012333:RNA, Messenger; C493415:Slc6a1 protein, rat; D020148:Butyric Acid; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; D005947:Glucose; D020155:3-Hydroxybutyric Acid