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The Journal of Neuroscience, December 15, 1998, 18(24):10287-10296

Thiol Oxidation and Loss of Mitochondrial Complex I Precede Excitatory Amino Acid-Mediated Neurodegeneration

Krishnan Sriram¹, Susarla K. Shankar², Michael R. Boyd³, and Vijayalakshmi Ravindranath¹

Departments of ¹ Neurochemistry and ² Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore 560 029, India, and ³ Laboratory of Drug Discovery Research and Development, Developmental Therapeutics Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201

Human ingestion of "chickling peas" from the plant Lathyrus sativus, which contains an excitatory amino acid, L-BOAA (L--N-oxalylamino-L-alanine), leads to a progressive corticospinal neurodegenerative disorder, neurolathyrism. Exposure to L-BOAA, but not its optical enantiomer D-BOAA, causes mitochondrial dysfunction as evidenced by loss of complex I activity in vitro in male mouse brain slices and in vivo in selected regions of mouse CNS (lumbosacral cord and motor cortex). Loss of complex I activity in lumbosacral cord after L-BOAA administration to mice was accompanied by concurrent loss of glutathione. The inhibited complex I activity in mitochondria isolated from lumbosacral cord of animals treated with L-BOAA rebounded after incubation with the thiol-reducing agent dithiothreitol, indicating that oxidation of protein thiols to disulfides was responsible for enzyme inhibition. The inhibition of complex I could be abolished by pretreatment with antioxidant thiols such as glutathione ester and -lipoic acid. Chronic treatment of male mice, but not female mice, with L-BOAA resulted in loss of complex I activity and vacuolation and dendritic swelling of neurons in the motor cortex and lumbar cord, paralleling the regionality of the aforementioned biochemical effects on CNS mitochondria. These results support the view that thiol oxidation and concomitant mitochondrial dysfunction (also implicated in other neurodegenerative disorders), occurring downstream of glutamate receptor activation by L-BOAA, are primary events leading to neurodegeneration. Maintenance of protein thiol homeostasis by thiol delivery agents could potentially offer protection against excitotoxic insults such as those seen with L-BOAA.

Key words: excitatory amino acids; mitochondrial electron transport; NADH ubiquinone-1 oxidoreductase (complex I); brain; L-BOAA; oxidative stress; glutathione; protein thiol oxidation

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Copyright © 1998 Society for Neuroscience  0270-6474/98/182410287-10$05.00/0

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