The anticonvulsant activity of acetone does not depend upon its metabolites (2008)

To the Editors: Epilepsia recently published a letter (Kalapos, 2007) disputing our conclusions that the anticonvulsant activity of acetone is not mediated by its metabolites (Gasior et al., 2007). The validity of our conclusions was questioned on several grounds, the first of which is that there is a lack of evidence that acetone's metabolites cross the blood–brain barrier. Certainly, for a substance to have anticonvulsant activity, it must enter the brain. We agree with the correspondent that evidence that the metabolites cross the blood–brain barrier is scarce. However, it is certainly not nonexistent. Our own data show that intraperitoneal administration of the metabolites causes dose-dependent changes in seizure threshold and motor impairment, thus providing indirect evidence that these substances are acting on the brain. Moreover, there is direct evidence that orally administered 1,2-propanediol is absorbed and penetrates the blood–brain barrier since the compound can be shown to accumulate in brain tissue by in vivo proton magnetic resonance spectroscopy (Cady et al., 1994). There is also evidence that pyruvate can be transported into the brain by monocarboxylic acid transporters (Nakamichi et al., 2005). Indeed, intraperitoneally administered pyruvate can influence brain injury (Suh et al., 2005; Yi et al., 2007). Measurements of brain methylglyoxal are not available, but the compound is certainly absorbed after oral administration in mice as plasma levels were readily detected (Ghosh et al., 2006). We should like to emphasize, however, that whether or not the metabolites cross the blood–brain barrier is irrelevant to the conclusion of our report. Our conclusion that the metabolites do not account for the anticonvulsant activity of acetone was based primarily on the finding of a major difference between acetone and its metabolites in their relative activities on two distinct central nervous system-mediated phenomena: acetone raised seizure threshold at markedly lower doses than those that produced motor impairment, whereas this was not the case for the metabolites. This qualitative difference cannot be explained by differences in brain penetration. Related to this issue, Kalapos also questioned whether intraperitoneal administration of the metabolites was appropriate, given that they may not cross membranes. Actually, all of the metabolites we tested caused motor impairment, demonstrating that they must be absorbed. In fact, acetol, 1,2-propanediol and methylglyoxal also elevated the seizure threshold (although at higher doses than acetone). Further, Kalapos disputed our purported assertion that acetol failed to demonstrate seizure protection. In fact, we stated that acetol did produce threshold elevations in the pentylenetetrazol model (but not the 4-aminopyridine model), but only at high doses that resulted in marked behavioral impairment not seen with effective doses of acetone. A fourth issue raised was the possible contamination of commercial methylglyoxal. This is certainly a concern and we cannot exclude the possibility that an impurity contributed to the severe toxicity we observed. However, the toxicity is consistent with the known properties of the compound (Choudhary et al., 1997; Kalapos, 1999). In sum, the results of our study are wholly consistent with the conclusion that the anticonvulsant efficacy of acetone is not dependent upon its metabolites. Whereas acetone was quite potent as an anticonvulsant, equimolar doses of the metabolites did not produce anticonvulsant effects. During ketosis, low millimolar concentrations of acetone are produced, but acetol only reaches low micromolar concentrations and methylglyoxal's concentrations are in the nanomolar range (Beisswenger et al., 2005). Therefore, the metabolites cannot be responsible for the anticonvulsant properties of the ketogenic diet. To be sure, the role acetone plays in the therapeutic efficacy of the ketogenic diet remains to be determined. Nevertheless, there is now abundant evidence that acetone is an effective anticonvulsant in diverse seizure models in rodents (Likhodii & Burnham, 2002; Rho et al., 2002; Likhodii et al., 2003). Further studies are required to define the way in which acetone confers seizure protection.