Minocycline reduces the lipopolysaccharide-induced inflammatory reaction, peroxynitrite-mediated nitration of proteins, disruption of the blood-brain barrier, and damage in the nigral dopaminergic system.
We have evaluated the potential neuroprotectant activity of minocycline in an animal model of Parkinson's disease induced by intranigral injection of lipopolysaccharide. Minocycline treatment was very effective in protecting number of nigral dopaminergic neurons and loss of reactive astrocytes at 7 days postlesion. Evaluation of microglia revealed that minocycline treatment highly prevented the lipopolysaccharide-induced activation of reactive microglia as visualized by OX-42 and OX-6 immunohistochemistry. Short-term RT-PCR analysis demonstrated that minocycline partially prevented the lipopolysaccharide-induced increases of mRNA levels for interleukin-1alpha and tumor necrosis factor-alpha. In addition, lipopolysaccharide highly induced protein nitration as seen by 3-nitrotyrosine immunoreactivity in the ventral mesencephalon. Minocycline treatment strongly diminished the extent of 3-nitrotyrosine immunoreactivity. We also found a direct correlation between location of IgG immunoreactivity-a marker of blood-brain barrier disruption-and neurodegenerative processes including death of nigral dopaminergic cells and reactive astrocytes. There was also a precise spatial correlation between disruption of blood-brain barrier and 3-nitrotyrosine immunoreactivity. We discuss potential involvement of lipopolysaccharide-induced formation of peroxynitrites and cytokines in the pathological events in substantia nigra in response to inflammation. If inflammation is proved to be involved in the ethiopathology of Parkinson's disease, our data support the use of minocycline in parkinsonian patients.
Tomás-Camardiel
Mayka
M
Departamento de Bioquímica, Bromatología, Toxicología y Medicina Legal Facultad de Farmacia, Universidad de Sevilla, E-41012-Seville, Spain.
Rite
Inmaculada
I
Herrera
Antonio J
AJ
de Pablos
Rocio M
RM
Cano
Josefina
J
Machado
Alberto
A
Venero
José L
JL
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D008070:Lipopolysaccharides; D030421:Peroxynitrous Acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D008911:Minocycline; D004298:Dopamine