A summary of mechanistic hypotheses of gabapentin pharmacology.
Although the cellular mechanisms of pharmacological actions of gabapentin (Neurontin) remain incompletely described, several hypotheses have been proposed. It is possible that different mechanisms account for anticonvulsant, antinociceptive, anxiolytic and neuroprotective activity in animal models. Gabapentin is an amino acid, with a mechanism that differs from those of other anticonvulsant drugs such as phenytoin, carbamazepine or valproate. Radiotracer studies with [14C]gabapentin suggest that gabapentin is rapidly accessible to brain cell cytosol. Several hypotheses of cellular mechanisms have been proposed to explain the pharmacology of gabapentin: 1. Gabapentin crosses several membrane barriers in the body via a specific amino acid transporter (system L) and competes with leucine, isoleucine, valine and phenylalanine for transport. 2. Gabapentin increases the concentration and probably the rate of synthesis of GABA in brain, which may enhance non-vesicular GABA release during seizures. 3. Gabapentin binds with high affinity to a novel binding site in brain tissues that is associated with an auxiliary subunit of voltage-sensitive Ca2+ channels. Recent electrophysiology results suggest that gabapentin may modulate certain types of Ca2+ current. 4. Gabapentin reduces the release of several monoamine neurotransmitters. 5. Electrophysiology suggests that gabapentin inhibits voltage-activated Na+ channels, but other results contradict these findings. 6. Gabapentin increases serotonin concentrations in human whole blood, which may be relevant to neurobehavioral actions. 7. Gabapentin prevents neuronal death in several models including those designed to mimic amyotrophic lateral sclerosis (ALS). This may occur by inhibition of glutamate synthesis by branched-chain amino acid aminotransferase (BCAA-t).
Taylor
C P
CP
Department of Neuroscience Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., Ann Arbor, MI 48105, USA.
Gee
N S
NS
Su
T Z
TZ
Kocsis
J D
JD
Welty
D F
DF
Brown
J P
JP
Dooley
D J
DJ
Boden
P
P
Singh
L
L
D000085:Acetates / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D000588:Amines; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000502:physiology; D015220:Calcium Channels / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D003509:Cyclohexanecarboxylic Acids; D000077206:Gabapentin; D006801:Humans; D008959:Models, Neurological; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D018377:Neurotransmitter Agents / Q000502:physiology; D010146:Pain; D015222:Sodium Channels / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D014018:Tissue Distribution; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000085:Acetates; D000588:Amines; D000700:Analgesics; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D015222:Sodium Channels; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin