Altered glutamate metabolism in amyotrophic lateral sclerosis and treatment with branched chain amino acids

Abstract

Recent studies have shown that a generalized defect in glutamate metabolism and widespread alterations in the central nervous system (CNS) levels of glutamate occur in amyotrophic lateral sclerosis, a disorder with a dismal prognosis. Present data support the hypothesis that altered presynaptic glutamatergic mechanisms, may be responsible for a neuroexcitotoxic cell loss in this disorder. In these glutamatergic mechanisms glutamate dehydrogenase (GDH) may play an important role, probably involved in the oxidation of transmitter glutamate.

We have accordingly reasoned that stimulation of GDH could increase the rate of oxidation of transmitter glutamate thus correcting the hypothesized malfunction of this amino acid in ALS. We have tested this hypothesis by performing a randomized, double-blind, placebo-controlled trial on 22 ALS patients using branched chain amino acids (BCAA) which can stimulate human brain GDH activity at physiological concentrations. During the one-year trial, patients treated with the BCAA showed a significant benefit as compared to control-treated group in terms of maintenance of extremity muscle strength and continued ability to ambulate.

Supported by NIH Grants NS-16871 and NS-11631, The Clinical Center for Research in Parkinson’s and Allied Diseases, and RR-71, Div. of Research Resources, General Clinical Research Center Branch.