Proline and proline derivatives as anticonvulsants.

1. The anticonvulsant properties of L-proline, of proline derivatives (trans-4-hydroxy-L-proline, cis-4-hydroxy-D-proline, 3,4-dehydro-D,L-proline) and of D- and L-pipecolic acid were studied alone and in combination with vigabatrin (R/S-4-aminohex-5-enoic acid). 3-Mercaptopropionic acid and pentylenetetrazol-induced convulsions in mice were used as animal models of epilepsy. 2. Proline and proline derivatives are weak anticonvulsants if given alone in doses up to 10 mmol/kg, however, they are capable of potentiating the anticonvulsant effects of vigabatrin, in a manner similar to that reported previously for glycine, and some glycine derivatives. Among the compounds tested, trans-4-hydroxy-L-proline was the most potent anticonvulsant in combination with the indirect GABA agonist vigabatrin. 3. A potential explanation for the synergistic anticonvulsant effect of the combination of the GABA agonist and proline is the presumed role of proline as inhibitory neurotransmitter, and/or its glutamate antagonistic effects. 4. The current study points out the lack of basic knowledge on the neurochemistry and pharmacology of proline and hydroxyproline.