s-adenosylhomocysteine and Seizures

Protein L-isoaspartyl (D-aspartyl) O-methyltransferase (PCMT1) is a protein-repair enzyme, and mice lacking this enzyme accumulate damaged proteins in multiple tissues, die at an early age from progressive epilepsy and have an increased S-adenosylmethionine (AdoMet) to S-adenosylhomocysteine (AdoHcy) ratio in brain tissue. It has been proposed that the alteration of AdoMet and AdoHcy levels might contribute to the seizure phenotype, particularly as AdoHcy has anticonvulsant properties. To investigate whether altered AdoMet and AdoHcy levels might contribute to the seizures and thus the survivability of the repair-deficient mice, a folate-deficient amino acid-based diet was administered to the mice in place of a standard chow diet. We found that the low-folate diet significantly decreases the AdoMet/AdoHcy ratio in brain tissue and results in an almost threefold extension of mean life span in the protein repair-deficient mice. These results indicate that the increased AdoMet/AdoHcy ratio may contribute to the lowered seizure threshold in young PCMT1-deficient mice. However, mean survival was also extended almost twofold for mice on a control folate-replete amino acid-based diet compared to mice on the standard chow diet. Survival after 40 days was similar in the mice on the low- and high-folate amino acid-based diets, suggesting that the survival of older PCMT1-deficient mice is not affected by the higher brain AdoMet/AdoHcy ratio. Additionally, the surviving older repair-deficient mice have a significant increase in body weight when compared to age-matched normal mice, independent of the type of diet. This weight increase was not accompanied by an increase in consumption levels, indicating that the repair-deficient mice may also have an altered metabolic state.

Topics: Animal Nutritional Physiological Phenomena; Animals; Body Weight; Brain; Eating; Folic Acid; Methionine; Mice; Mice, Mutant Strains; Protein D-Aspartate-L-Isoaspartate Methyltransferase; S-Adenosylhomocysteine; S-Adenosylmethionine; Seizures; Survival Rate

Administration of the long latency convulsant, L-methionine-d,1-sulfoximine (MSO) results in an increase in brain methylation flux. We determined the effects of the anticonvulsant, diazepam (DZ) on MSO seizures and on brain levels of S-adenosyl-L-methionine (AdoMet) and S-adenosyl-L-homocysteine (AdoHcy) to indicate possible alterations in the brain methylation pathway. We report a dose related inhibition of MSO seizures by DZ. In addition, DZ significantly increased brain levels of AdoMet and AdoHcy and reversed the MSO-induced decreases in AdoMet and AdoHcy. DZ also blocked the MSO induced increase in the methylation index (AdoMet/AdoHcy). The data indicates an inhibition of MSO induced increases in brain methylation by DZ. Possible mechanisms for the effect of DZ on the cerebral methylation pathway are discussed.

Topics: Animals; Brain Chemistry; Diazepam; Dose-Response Relationship, Drug; Homocysteine; Male; Methionine Sulfoximine; Methylation; Mice; Reaction Time; S-Adenosylhomocysteine; S-Adenosylmethionine; Seizures

Topics: Acoustic Stimulation; Animals; Brain; Chromatography, High Pressure Liquid; Methionine; Peromyscus; Polyamines; Putrescine; S-Adenosylhomocysteine; S-Adenosylmethionine; Seizures; Spermidine; Spermine