A SUMMARY OF MECHANISTIC HYPOTHESES OF GABAPENTIN PHARMACOLOGY

Although the cellular mechanisms of pharmacological actions of gabapen tin (Neurontin(R)) remain incompletely described, several hypotheses h ave been proposed. It is possible that different mechanisms account fo r anticonvulsant, antinociceptive, anxiolytic and neuroprotective acti vity in animal models. Gabapentin is an amino acid, with a mechanism t hat differs from those of other anticonvulsant drugs such as phenytoin , carbamazepine or valproate. Radiotracer studies with [C-14]gabapenti n suggest that gabapentin is rapidly accessible to brain cell cytosol. Several hypotheses of cellular mechanisms have been proposed io expla in the pharmacology of gabapentin: 1. Gabapentin crosses several membr ane barriers in the body via a specific amino acid transporter (system L) and competes with leucine, isoleucine, valine and phenylalanine fo r transport. 2. Gabapentin increases the concentration and probably th e rate of synthesis of GABA in brain, which may enhance non-vesicular GABA release during seizures. 3. Gabapentin binds with high affinity t o a novel binding site in brain tissues that is associated with an aux iliary subunit of voltage-sensitive Ca2+ channels. Recent electrophysi ology results suggest that gabapentin may modulate certain types of Ca 2+ current. 4. Gabapentin reduces the release of several monoamine neu rotransmitters. 5. Electrophysiology suggests that gabapentin inhibits voltage-activated Na+ channels, but other results contradict these fi ndings. 6. Gabapentin increases serotonin concentrations in human whol e blood, which may be relevant to neurobehavioral actions. 7. Gabapent in prevents neuronal death in several models including those designed to mimic amyotrophic lateral sclerosis (ALS). This may occur by inhibi tion of glutamate synthesis by branched-chain amino acid aminotransfer ase (BCAA-t). (C) 1998 Elsevier Science B.V. All rights reserved.