Down-regulation of glutaredoxin by estrogen receptor antagonist renders female mice susceptible to excitatory amino acid mediated complex I inhibition in CNS.
beta-N-oxalyl-amino-L-alanine, (L-BOAA), an excitatory amino acid, acts as an agonist of the AMPA subtype of glutamate receptors. It inhibits mitochondrial complex I in motor cortex and lumbosacral cord of male mice through oxidation of critical thiol groups, and glutaredoxin, a thiol disulfide oxido-reductase, helps maintain integrity of complex I. Since incidence of neurolathyrism is less common in women, we examined the mechanisms underlying the gender-related effects. Inhibition of complex I activity by L-BOAA was seen in male but not female mice. Pretreatment of female mice with estrogen receptor antagonist ICI 182,780 or tamoxifen sensitizes them to L-BOAA toxicity, indicating that the neuroprotection is mediated by estrogen receptors. L-BOAA triggers glutathione (GSH) loss in male mice but not in female mice, and only a small but significant increase in oxidized glutathione (GSSG) was seen in females. As a consequence, up-regulation of gamma-glutamyl cysteinyl synthase (the rate-limiting enzyme in glutathione synthesis) was seen only in male mouse CNS but not in females. Both glutathione reductase and glutaredoxin that reduce oxidized glutathione and protein glutathione mixed disulfides, respectively, were constitutively expressed at higher levels in females. Furthermore, glutaredoxin activity in female mice was down-regulated by estrogen antagonist indicating its regulation by estrogen receptor. The higher constitutive expression of glutathione reductase and glutaredoxin could potentially confer neuroprotection to female mice.
Diwakar
Latha
L
Division of Molecular and Cellular Neuroscience, National Brain Research Centre, Nainwal Mode, Manesar, 122050, India.
Kenchappa
Rajappa S
RS
Annepu
Jayasree
J
Saeed
Uzma
U
Sujanitha
Ramakrishnan
R
Ravindranath
Vijayalakshmi
V
D000599:Amino Acids, Diamino / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004347:Drug Interactions; D042967:Electron Transport Complex I / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000494:pharmacology*; D005260:Female; D054477:Glutaredoxins; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000502:physiology*; D012737:Sex Factors; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D000599:Amino Acids, Diamino; D004965:Estrogen Antagonists; D004967:Estrogens; D018846:Excitatory Amino Acids; D054477:Glutaredoxins; D011960:Receptors, Estrogen; C100126:oxalyldiaminopropionic acid; D010088:Oxidoreductases; D042967:Electron Transport Complex I; D005978:Glutathione; D019803:Glutathione Disulfide