strychnine and pipecolic-acid

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.

Topics: 3-Mercaptopropionic Acid; Animals; Anticonvulsants; Exploratory Behavior; Hydroxyproline; Male; Mice; Motor Activity; Pentylenetetrazole; Pipecolic Acids; Proline; Strychnine

Pipecolic acid (PA) is an alicyclic amino acid and putative neurotransmitter which may modulate GABAergic transmission in the central nervous system. The present study was designed to investigate the anticonvulsant effect of intrathecally (i.t.) injected PA on picrotoxin- and bicuculline-induced convulsions which are thought to be produced by interactions with GABAergic systems. Intrathecal injections of picrotoxin and bicuculline in mice produced convulsions which were characterized by a rapid onset and short duration. Coadministration of GABA with either bicuculline or picrotoxin, but not strychnine, attenuated the severity of the convulsions. Coadministration of PA also protected against bicuculline- and picrotoxin-induced convulsions. Intrathecal injections of PA produced a dose-related increase in the latency to the onset of these convulsions as well as a decrease in their duration, however PA failed to inhibit the duration of strychnine-induced seizures. The D isomer of PA was found to be more effective than the L isomer as an anticonvulsant in this study. When administered in a high dose (500 micrograms i.t.), the D isomer produced flaccid paralysis while injection of high doses (100-500 micrograms i.t.) of the L isomer actually elicited convulsions. These results further support an interaction between PA and GABAergic activity.

Topics: Animals; Bicuculline; gamma-Aminobutyric Acid; Injections, Spinal; Male; Mice; Nipecotic Acids; Picrotoxin; Pipecolic Acids; Proline; Receptors, GABA-A; Seizures; Strychnine