Down-regulation of S-adenosylhomocysteine hydrolase in the active methyl transfer system in the brain of genetically epileptic El mice.

To study the role of cerebral methylation in epileptogenesis, we investigated the active methyl transfer pathway in the brain of genetically epileptic El mice. We examined S-adenosylhomocysteine (AdoHcy) hydrolase activity (by high performance liquid chromatography), the corresponding mRNA levels (by competitive reverse transcription-polymerase chain reaction), as well as S-adenosylmethionine (AdoMet) and AdoHcy levels in epileptic El and non-epileptic control ddY mice. The level of AdoHcy, a potent feedback inhibitor in the methyl transfer system, was relatively high throughout growth, particularly in 15 week old El mice where it was increased approximately 20% compared to control ddY mice. AdoHcy hydrolase activity in the El mice brain did not increase during growth, which was confirmed by the finding that mRNA synthesis from the hydrolase gene behaved likewise. In contrast, ddY mice exhibited a gradual increase in the mRNA synthesis up to three fold and 20% increase in the enzyme activity at 15 weeks of age compared to those of El mice in which the seizure frequency was 100%. The levels of AdoMet, a versatile methyl donor, did not change throughout growth. We concluded that the down-regulation of AdoHcy hydrolase results in the accumulation of AdoHcy, possibly inducing an unstable state including seizures in the El mouse brain. El mice predisposed to epilepsy may be characterized by disordered feedback regulation of the AdoMet-dependent methyl transfer pathway.