The neuroprotective antioxidant alpha-lipoic acid induces detoxication enzymes in cultured astroglial cells.
alpha-Lipoic acid (LA), an antioxidant with broad neuroprotective capacity, is thought to act by scavenging reactive oxygen species and stimulation of glutathione synthesis. LA shows structural resemblance to dithiolethiones, like anethole dithiolethione (ADT). ADT protects against oxidative damage, primarily by induction of phase II detoxication enzymes, in particular NAD(P)H:quinone oxidoreductase (NQO1) and glutathione-S-transferase (GST). Therefore, we investigated whether LA, like ADT, is capable also of inducing these protective enzymes. Our data show that LA, like ADT, induces a highly significant, time- and concentration dependent, increase in the activity of NQO1 and GST in C6 astroglial cells. The LA or ADT mediated induction of NQO1 was further confirmed by quantitative PCR and western blot analysis. This work for the first time unequivocally demonstrates LA mediated upregulation of phase II detoxication enzymes, which may highly contribute to the compounds' neuroprotective potential. Moreover, the data support the notion of a common mechanism of action of LA and ADT.
Department of Medical Pharmacology, Research Institute Neurosciences Vrije Universiteit, van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
Jacoba
J
Flier
Freek L
FL
Van Muiswinkel
Cornelis A M
CA
Jongenelen
Benjamin
B
Drukarch
D000781:Anethole Trithione / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D001254:Astrocytoma / Q000201:enzymology; D016543:Central Nervous System Neoplasms / Q000201:enzymology; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism; D008658:Inactivation, Metabolic; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010088:Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D008063:Thioctic Acid / Q000494:pharmacology*; D014166:Transferases / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D018696:Neuroprotective Agents; D008063:Thioctic Acid; D010088:Oxidoreductases; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D014166:Transferases; D005982:Glutathione Transferase; D000781:Anethole Trithione