Inhibition of thrombin‐induced microglial activation and NADPH oxidase by minocycline protects dopaminergic neurons in the substantia nigra in vivo

• Published in: Journal of neurochemistry 2005-12, Vol.95 (6), p.1755-1765
• Main Authors: Choi, Sang H., Lee, Da Y., Chung, Eun S., Hong, Young B., Kim, Seung U., Jin, Byung K.
• Format: Article
• Language: English
• Subjects: Ageing, cell death; Animals; Anti-Bacterial Agents - pharmacology; Biochemistry; Biological and medical sciences; Blotting, Western; Cell physiology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dopamine - physiology; Enzyme Inhibitors; Female; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Immunohistochemistry; In Situ Nick-End Labeling; Inhibitor drugs; Interleukin-1 - biosynthesis; Macrophage Activation - drug effects; Medical sciences; microglia; Microglia - drug effects; minocycline; Minocycline - pharmacology; Molecular and cellular biology; NADPH oxidase; NADPH Oxidases - antagonists & inhibitors; neurodegeneration; Neurological disorders; Neurology; Neurons - drug effects; Neuroprotective Agents; Neurosciences; Nitric Oxide Synthase Type II - biosynthesis; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Reverse Transcriptase Polymerase Chain Reaction; substantia nigra; Substantia Nigra - drug effects; thrombin; Thrombin - antagonists & inhibitors
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2005.03503.x

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‐1β 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.