Effect of beta-Hydroxybutyrate on Flurothyl-Induced Seizure Susceptibility

PURPOSE: The ketogenic diet (KD) remains a therapy in search of explanation although it is an established treatment for patients with intractable seizures. It was designed to mimic the biochemical changes seen upon fasting, specifically the formation of ketone bodies: acetoacetate (ACA), beta-hydroxybutyrate (BHB), and to a lesser extent, acetone. The present study was designed to investigate the protective effect of BHB on flurothyl-induced seizures in rats. METHODS: Thirty-four male Sprague-Dawley rats were divided into two equal groups. Experimental rats (n=17) were injected intraperitoneally with BHB (20 mmol/kg), while control animals (n=17) with normal saline. Fifteen minutes later, seizures were chemically induced by flurothyl infusion (40 mL/min). Seizure susceptibility was defined as the latency from the start of flurothyl infusion to the onset of a generalized seizure. Shorter latencies reflected greater seizure susceptibility. RESULTS: The mean (+/- SEM) latency to the onset of a generalized seizure in the experimental animals treated with BHB was 476.5 +/- 13.9 seconds, which was significantly longer (P < 0.05) than the control (438.0 +/- 10.5 seconds). CONCLUSION: This study demonstrated the significant decrease in flurothyl-induced seizure susceptibility in rats treated with BHB. Our results suggest that BHB may be directly anticonvulsant.

The Protective Effect of Chlorpromazine on Flurothyl-Induced Seizure

PURPOSE: Chlorpromazine(CPZ) is known to inhibit glutamate ehydrogenase(GDH). Reductive amination of alpha-ketoglutarate is catalyzed by GDH and forms glutamate, a major excitatory neurotransmitter. Thus, I hypothesized that CPZ might have a seizure- protective effect by inhibiting glutamate release from the excitatory presynaptic nerve terminal. The present study was designed to investigate the protective effect of CPZ on flurothyl-induced seizure in rats. METHODS: Twenty-eight male Sprague-Dawley rats were equally divided into 2 groups. CPZ(20 mg/kg) was administered to experimental animals by subcutaneous injection, while normal saline to control animals. Twenty minutes later, seizures were chemically induced by flurothyl infusion(40 microL/min). Seizure susceptibility was defined as the latency from the start of flurothyl infusion to the onset of a generalized seizure(loss of posture with bilateral hindlimb tonic extension). Shorter latency reflects greater seizure susceptibility. RESULTS: The mean(+/-SEM) seizure latency in the experimental group was 539.2 (+/-17.5) seconds, and it was significantly longer than 432.4(+/-21.9) seconds in the control group(P<0.001). CONCLUSION: This study demonstrates that CPZ decrease flurothyl-induced seizure susceptibility in rats. This result suggests that CPZ may have a seizure-protective effect. I hope that further studies on this issue should be performed in a near future.

Effect of the Ketogenic Diet on Flurothyl-Induced Seizure Susceptibility / 대한간질학회지

PURPOSE: Despite decades of clinical experience with the ketogenic diet (KD), its efficacy and mechanisms of action have been examined in few animal studies. The present study was designed to investigate the effect of a KD on flurothyl-induced seizure susceptibility in rats. METHODS: Twenty male Sprague-Dawley rats were divided into two equal groups. Dietary treatment was initiated at P39. The experimental group was fasted for a day and then fed a KD consisting of [fat] : [protein + carbohydrate] ratio of 4.3 : 1, while the control group was fed a standard rodent chow. On treatment day 21, blood beta-hydroxybutyrate (BHB) levels were assayed and seizures were chemically induced by flurothyl (40 micro l/min). Seizure susceptibility was defined as the latency from the start of flurothyl infusion to the onset of a generalized seizure (loss of posture with bilateral hindlimb tonic extension). Shorter latencies reflect greater seizure susceptibility. RESULTS: Blood BHB levels in the KD-treated group were significantly higher than those of the control group (4.75+/-0.38 [n=10] vs. 0.19+/-0.02 [n=10] mM, respectively ; p<0.01). The latencies to the onset of a generalized seizure were 673.2+/-32.95 [n=10] and 523.0+/-31.11 [n=10] seconds for the KD-treated and control groups, respectively (p<0.01). CONCLUSION: This study demonstrates the significant decrease in the susceptibility of flurothyl-induced seizure in the KD-treated rats. Furthermore, we have established a working animal model from which future mechanistic studies can be based.