title: β-Hydroxybutyrate attenuates NMDA-induced spasms in rats with evidence of neuronal stabilization on MR spectroscopy.
abstract: BACKGROUND
  Infantile spasms (IS) is a devastating epileptic encephalopathy. The ketogenic diet (KD) has been successfully used as a treatment for IS. This study was designed to test whether beta-hydroxybutyrate (BHB), a major metabolite of the KD, is effective in an animal model of IS.
  
  
  METHODS
  Pregnant rats received betamethasone on gestational day 15. The offspring received either single [30min prior to NMDA-triggered spasms on postnatal day (P) 15] or prolonged (three per day from P12 to P15) i.p. BHB. An additional experiment used repeated bouts of spasms on P12, P13, and P15 with randomized prolonged BHB treatment initiated after the first spasms. We determined the latency to onset of spasms and the number of spasms after the NMDA injection on P15. The rats that received randomized BHB treatment were also monitored with open field, sociability, and fear-conditioning tests and underwent in vivo (1)H MR imaging on a 9.4T MR system after NMDA-induced spasms. The acquired (1)H MR spectra were quantified using LC model.
  
  
  RESULTS
  Single-dose BHB pretreatment had no effect on spasms. In contrast, prolonged pretreatment with BHB significantly delayed the onset and decreased the frequency of spasms. In addition, randomized prolonged BHB treatment resulted in a significant reduction in number of spasms at P15. BHB treatment had no significant effect on motor activities, but significantly decreased the interactions with strangers and increased the contextual memory. On MR spectroscopic analysis of randomized prolonged BHB-treated rats at 24h after the cluster of spasms, the elevation of GABA, glutamine, glutamate, total creatine, macromolecule-plus lipids, and N-acetylaspartate levels after spasms were significantly attenuated by randomized BHB treatment (p<0.05).
  
  
  CONCLUSIONS
  Prolonged administration of BHB directly suppresses development of spasms in a rat model of IS with acute stabilization of brain metabolites. Additionally, BHB appears to decrease the interests to other rats and improve memory responses.
authors.affiliation: Department of Pediatrics, Asan Medical Center, College of Medicine Ulsan University, Seoul, South Korea. Electronic address: yumyum99@hanmail.net.
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Yum
authors.affiliation: Department of Pediatrics, Asan Medical Center, College of Medicine Ulsan University, Seoul, South Korea. Electronic address: woyeaita@hanmail.net.
authors.forename: Minyoung
authors.initials: M
authors.lastname: Lee
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, South Korea. Electronic address: dcwoo@amc.seoul.kr.
authors.forename: Dong-Cheol
authors.initials: DC
authors.lastname: Woo
authors.affiliation: Department of Pediatrics, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, South Korea. Electronic address: dwkim@paik.ac.kr.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Asan Medical Center, College of Medicine Ulsan University, Seoul, South Korea. Electronic address: tsko@amc.seoul.kr.
authors.forename: Tae-Sung
authors.initials: TS
authors.lastname: Ko
authors.affiliation: Departments of Cell Biology & Anatomy, Pediatrics and Neurology, New York Medical College, Valhalla, NY, United States. Electronic address: Libor_Velisek@nymc.edu.
authors.forename: Libor
authors.initials: L
authors.lastname: Velíšek
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D007231:Infant, Newborn; D009682:Magnetic Resonance Spectroscopy; D016202:N-Methylaspartate; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D013036:Spasms, Infantile / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D016202:N-Methylaspartate; D020155:3-Hydroxybutyric Acid
keywords: Animal model; Infantile spasms; Ketogenic diet; Ketone body; β-Hydroxybutyrate