Dopamine-dependent neurotoxicity of lipopolysaccharide in substantia nigra.
Intranigral injection of lipopolysaccharide (LPS), a potent inductor of inflammation, induces degeneration of dopaminergic neurons, along with an inflammatory process that features activation of microglial cells and loss of astrocytes. To test the involvement of dopamine (DA) in this degeneration induced by LPS, we treated albino Wistar rats with different concentrations of alpha-methyl-p-tyrosine (alpha-MPT), an inhibitor of tyrosine hydroxylase (TH) activity. Results showed that alpha-MPT prevented LPS-induced loss of TH immunostaining and expression of mRNA for TH and DA transporter; it also prevented substantial activation of microglial cells. Loss of the astroglial population, a marker of damage in our model, was also prevented. This protective effect resulted from inhibition of TH and the consequent decrease in DA concentration, because treatment with L-DOPA/benserazide, which bypasses TH inhibition induced by alpha-MPT, reversed the protective effect produced by this drug. These results point out the important contribution of DA to the vulnerability and degeneration of dopaminergic neurons of the substantia nigra. Knowledge about the involvement of DA in this process may lead to the possibility of new protection strategies against this important degenerative process.
De Pablos
Rocío M
RM
Departamento de Bioquímica, Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain.
Herrera
Antonio J
AJ
Villarán
Ruth F
RF
Cano
Josefina
J
Machado
Alberto
A
D000818:Animals; D004298:Dopamine / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019805:alpha-Methyltyrosine / Q000494:pharmacology
D008070:Lipopolysaccharides; D019805:alpha-Methyltyrosine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine