Induction of S100B secretion in C6 astroglial cells by the major metabolites accumulating in glutaric acidemia type I.
Glutaryl-CoA dehydrogenase deficiency or glutaric acidemia type I (GA I) is an inherited neurometabolic disorder biochemically characterized by tissue accumulation of predominantly glutaric (GA) and 3-hydroxyglutaric (3OHGA) acids and clinically by severe neurological symptoms and structural brain abnormalities, manifested as progressive cerebral atrophy and acute striatum degeneration following encephalopathic crises, whose pathophysiology is still in debate. Considering that reactive astrogliosis is a common finding in brain of GA I patients, in the present study we investigated the effects of GA and 3OHGA on glial activity determined by S100B release by rat C6-glioma cells. We also evaluated the effects of these organic acids on some parameters of oxidative stress in these astroglial cells. We observed that GA and 3OHGA significantly increased S100B secretion and thiobarbituric acid-reactive substances (lipid peroxidation), whereas GA markedly decreased reduced glutathione levels in these glioma cells. This is the first report demonstrating that the major metabolites accumulating in GA I activate S100B secretion in astroglial cells, indicating activation of these cells. We also showed that GA and 3OHGA induced oxidative stress in C6 lineage cells, confirming previous findings observed in brain fresh tissue. It is therefore presumed that reactive glial cells and oxidative damage may underlie at least in part the neuropathology of GA I.
Quincozes-Santos
André
A
Departamento de Bioquímica, Universidade Federal de Rio Grande do Sul, Porto Alegre, Brazil.
Rosa
Rafael Borba
RB
Leipnitz
Guilhian
G
de Souza
Daniela Fraga
DF
Seminotti
Bianca
B
Wajner
Moacir
M
Gonçalves
Carlos Alberto
CA
D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001284:Atrophy; D001928:Brain Diseases, Metabolic / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003342:Corpus Striatum / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005911:Gliosis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005977:Glutarates / Q000378:metabolism* / Q000494:pharmacology; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency*; D005978:Glutathione / Q000037:antagonists & inhibitors; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
C108959:3-hydroxyglutaric acid; D005977:Glutarates; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579158:S100b protein, rat; D017392:Thiobarbituric Acid Reactive Substances; D050770:Glutaryl-CoA Dehydrogenase; D005978:Glutathione; C035736:glutaric acid