Attenuation of 6-OHDA-induced neurotoxicity in glutathione peroxidase transgenic mice.
Normal cellular metabolism produces oxidants which are neutralized within cells by antioxidant enzymes and other antioxidants. An imbalance between oxidants and antioxidants has been postulated to lead to the degeneration of specific populations of neurons in neurodegenerative diseases, e.g. Parkinson's disease. The present study investigates whether overexpression of glutathione peroxidase, the enzyme which metabolizes hydrogen peroxide to water, can prevent or slow down neuronal injury in an animal model of Parkinson's disease. Transgenic mice overexpressing the human glutathione peroxidase gene under the control of the mouse hydroxymethylglutaryl-coenzyme A promoter and genetically matched control mice were injected intracerebroventricularly with the dopaminergic neurotoxin 6-hydroxydopamine. Seven days after injection, the number of tyrosine hydroxylase-positive nigral dopaminergic neurons was decreased by 52.4% and 20.5% in 6-hydroxydopamine-injected control and glutathione peroxidase transgenic mice, respectively. Similarly, 3 days after injection of the neurotoxin, striatal dopamine was decreased by 71.2% and 56.5%, respectively. Overexpression of glutathione peroxidase therefore partially protects dopaminergic neurons against 6-hydroxydopamine-induced toxicity.
Bensadoun
J C
JC
Gene Therapy Center and Division of Surgical Research, Lausanne University Medical School, Switzerland.
Mirochnitchenko
O
O
Inouye
M
M
Aebischer
P
P
Zurn
A D
AD
D000214:Acyl Coenzyme A / Q000235:genetics; D000818:Animals; D002452:Cell Count / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D003342:Corpus Striatum / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010084:Oxidation-Reduction; D016627:Oxidopamine / Q000008:administration & dosage / Q000633:toxicity*; D010300:Parkinson Disease; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D000214:Acyl Coenzyme A; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D016627:Oxidopamine; D005979:Glutathione Peroxidase; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine