Abstracts

We have previously shown that a four week course of BHB added to the drinking water of young adult rats reduced acute seizure activity. In these new experiments we studied, in more detail, the time dependency of this effect. Male Wistar rats, age 7-8 weeks, were split into one of three groups: regular water, water containing 3 gm/L racemic sodium [beta]-Hydroxybutyrate (rBHB), or water with 2 gm/L (D)-sodium [beta]-Hydroxybutyrate (dBHB). Ketone administration lasted 3, 7 or 14 days, at which point the rats were given a 70 mg/kg IP injection of pentylenetetrazol (PTZ). Seizure activity was monitored after the injection. Onset, duration and frequency of class 5 seizures (tonic-clonic seizures with loss of posture) were measured. Blood ketone and glucose levels were monitored multiple times throughout the trials, using Precision Xtra hand held unit (Medisense) and Ketosite machine (Stanbio Labs). Final levels were taken 24 hours before the convulsant injection. Rats given BHB water for less than one week showed no difference from controls in terms of seizure onset, duration, frequency, or mortality. Rats given the ketone water for [ge]7 days had less seizure activity compared to controls after PTZ injection. In control rats (n=11), a brief seizure at 1 minute after injection was usually followed at 2.5 minutes by a second prolonged seizure. In the control group (n=11), [gt]70% had 2 seizure episodes after a single injection. In contrast, only 1/8 in the 7 day dBHB group had a second seizure. An intermediate effect was observed in the 14 day rBHB-fed rats (n=8) half of whom had a second seizure. In most, this second seizure lasted only a few seconds compared to the control group in whom the second seizure lasted [gt]1 minute. The average total seizure time per rat was [gt]3x longer in controls (1.25 min) than either rBHB (0.39 min) or dBHB (0.39 min) rats. Mortality rate was 2-3x higher in the controls (6/11) compared to the rBHB group (2/8) or the dBHB group (1/8). No significant difference was measured in the pre-seizure blood ketone levels among the three groups (control=0.13 mM, rBHB=0.14 mM, dBHB=0.15 mM). Blood ketone levels showed little variation throughout the course of administration. BHB kinetics and glucose levels are discussed in a separate abstract at this meeting. Chronic administration of BHB isomers for 7 days or more reduced PTZ-induced seizure activity compared to controls. This anti-seizure effect was achieved in the absence of elevated blood BHB levels. This suggests that the action of BHB may be cumulative or persistant and may not reflect the actual BHB concentration. Also, a more critical factor may be the BHB level in neuronal tissue which was not measured in these experiments. (Supported by private donations.)