MECHANISMS OF ACTION OF GABAPENTIN

The chemical structure of gabapentin (Neurontin(R)) is derived by addi tion of a cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in an imals, including generalized tonic-clonic and partial seizures. Gabape ntin has no activity at GABA(A) or GABA(B) receptors or GABA uptake ca rriers of brain. Gabapentin interacts with a high-affinity binding sit e in brain membranes, which has recently been identified as an auxilia ry subunit of voltage-sensitive Ca2+ channels. However, the functional correlate of gabapentin binding is unclear and remains under study. G abapentin crosses several lipid membrane barriers via system L amino a cid transporters. In vitro, gabapentin modulates the action of the GAB A synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamat e synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that gabapentin in creases GABA synthesis. Gabapentin increases non-synaptic GABA respons es from neuronal tissues in vitro. In vitro, gabapentin reduces the re lease of several mono-amine neurotransmitters. Gabapentin prevents pai n responses in several animal models of hyperalgesia and prevents neur onal death in vitro and in vivo with models of the neurodegenerative d isease amyotrophic lateral sclerosis (ALS). Gabapentin is also active in models that detect anxiolytic activity. Although gabapentin may hav e several different pharmacological actions, it appears that modulatio n of GABA synthesis and glutamate synthesis may be important.