Potential treatment of amyotrophic lateral sclerosis with gabapentin: a hypothesis.
OBJECTIVE
To provide the biochemical rationale for the use of the new anticonvulsant agent gabapentin as a treatment for amyotrophic lateral sclerosis (ALS).


BACKGROUND
ALS is a neuropathologic disorder of the central nervous system characterized by a progressive loss of upper and lower motor neurons. Although the etiopathology of ALS is incompletely known, it is hypothesized that glutamatergic neurotransmission is related to neuropathology. Glutamate is an excitatory amino acid neurotransmitter that is cytotoxic when overexpressed at synaptic terminals, probably through a calcium-related mechanism. The concentration of glutamate in cerebrospinal fluid is increased in patients with ALS. The increased extracellular concentrations of glutamate may be caused by a decreased capacity of glutamate transport in brain tissue and/or abnormal glutamate metabolism. Recent success with the glutamate release inhibitor riluzole in well-controlled clinical trials supports the excitotoxic mechanism of neuropathology in patients with ALS. POTENTIAL TREATMENT FOR ALS: Gabapentin has demonstrated neuroprotective properties in a model of chronic glutamate toxicity in vitro. Although the neuroprotective mechanism of action of gabapentin is currently unknown, it is hypothesized here that gabapentin decreases the rate of formation of glutamate derived from the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. The proposed decrease in formation of glutamate from BCAAs may decrease the pool of releasable glutamate and therefore compensate for diminished glutamate uptake capacity and/or abnormal glutamate metabolism in patients with ALS.


CONCLUSIONS
Based on this rationale, it is proposed that gabapentin may provide a beneficial effect in the treatment of patients with ALS.
Welty
D F
DF
Department of Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research Division, Warner-Lambert, Ann Arbor, MI 48105, USA.
Schielke
G P
GP
Rothstein
J D
JD
D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use*; D000588:Amines; D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D000077206:Gabapentin; D005971:Glutamates / Q000378:metabolism; D006801:Humans; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000597:Amino Acids, Branched-Chain; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin