Mechanisms by which acyclovir reduces the oxidative neurotoxicity and biosynthesis of quinolinic acid.
The concentration of the endogenous neurotoxin quinolinic acid (QA) is increased in the central nervous system of mice with herpes simplex encephalitis. We have previously shown that the antiherpetic agent acyclovir (AC) has the ability to reduce QA-induced neuronal damage in rat brain, by attenuating lipid peroxidation. The mechanism by which QA induces lipid peroxidation includes the enhancement of the iron (Fe)-mediated Fenton reaction and the generation of free radicals, such as the superoxide anion (O(2)(-)). Thus, the present study determined whether AC has the ability to reduce Fe(2+)-induced lipid peroxidation, O(2)(-) generation and QA-induced superoxide anion generation, and to bind free Fe. O(2)(-) and Fe(2+) are also cofactors of the enzymes, indoleamine-2,3-dioxygenase (IDO) and 3-hydroxyanthranilate-3,4-dioxygenase (3-HAO) respectively. These enzymes catalyse steps in the biosynthesis of QA; thus, the effect of AC on their activity was also investigated. AC significantly attenuates Fe(2+)-induced lipid peroxidation and O(2)(-) generation. AC reduces O(2)(-) generation in the presence of QA and strongly binds Fe(2+) and Fe(3+). It also reduces the activity of both IDO and 3-HAO, which could be attributed to the superoxide anion scavenging and iron binding properties, respectively, of this drug.
Müller
Adrienne C
AC
Division of Pharmacology, Faculty of Pharmacy, Rhodes University, 6140, Grahamstown, South Africa.
Dairam
Amichand
A
Limson
Janice L
JL
Daya
Santy
S
D050561:3-Hydroxyanthranilate 3,4-Dioxygenase / Q000378:metabolism; D000212:Acyclovir / Q000494:pharmacology*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D004563:Electrochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology; D007501:Iron / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D010084:Oxidation-Reduction; D017378:Quinolinic Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism
D000963:Antimetabolites; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D013481:Superoxides; D007501:Iron; D050561:3-Hydroxyanthranilate 3,4-Dioxygenase; D017378:Quinolinic Acid; D000212:Acyclovir