Inhibition of thrombin-induced microglial activation and NADPH oxidase by minocycline protects dopaminergic neurons in the substantia nigra in vivo.
The present study shows that activation of microglial NADPH oxidase and production of reactive oxygen species (ROS) is associated with thrombin-induced degeneration of nigral dopaminergic neurons in vivo. Seven days after thrombin injection in the rat substantia nigra (SN), tyrosine hydroxylase immunocytochemistry showed a significant loss of nigral dopaminergic neurons. This cell death was accompanied by localization of terminal deoxynucleotidyl transferase-mediated fluorecein UTP nick-end labelling (TUNEL) staining within dopaminergic neurons. This neurotoxicity was antagonized by the semisynthetic tetracycline derivative, minocycline, and the observed neuroprotective effects were associated with the ability of minocycline to suppress NADPH oxidase-derived ROS production and pro-inflammatory cytokine expression, including interleukin-1beta and inducible nitric oxide synthase, from activated microglia. These results suggest that microglial NADPH oxidase may be a viable target for neuroprotection against oxidative damage.
Choi
Sang H
SH
Neuroscience Graduate Program and Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
Lee
Da Y
DY
Chung
Eun S
ES
Hong
Young B
YB
Kim
Seung U
SU
Jin
Byung K
BK
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015153:Blotting, Western; D004298:Dopamine / Q000502:physiology*; D004791:Enzyme Inhibitors; D005260:Female; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007375:Interleukin-1 / Q000096:biosynthesis; D008262:Macrophage Activation / Q000187:drug effects; D017628:Microglia / Q000187:drug effects*; D008911:Minocycline / Q000494:pharmacology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013378:Substantia Nigra / Q000187:drug effects*; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; D013917:Thrombin; D008911:Minocycline; D004298:Dopamine