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The Journal of Neuroscience, July 2, 2003, 23(13):5877-5886
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Thrombin-Induced Microglial Activation Produces Degeneration of Nigral Dopaminergic Neurons In Vivo
Sang-H. Choi,1,2
Eun H. Joe,1,2,3
Seung U. Kim,1,2 and
Byung K. Jin1,2
1Brain Disease Research Center,
2Neuroscience Graduate Program, and
3Department of Pharmacology, Ajou University School of
Medicine, Suwon 442-749, Korea
The present study examined whether thrombin-induced microglial activation
could contribute to death of dopaminergic neurons in the rat substantia nigra
(SN) in vivo. Seven days after thrombin injection into the SN,
tyrosine hydroxylase immunohistochemistry showed a significant loss of nigral
dopaminergic neurons. In parallel, thrombin-activated microglia, visualized by
immunohistochemical staining using antibodies against the complement receptor
type 3 (OX-42) and the major histocompatibility complex class II antigens were
also observed in the SN, where degeneration of nigral neurons was found.
Reverse transcription PCR at various time points demonstrated that activated
microglia in vivo exhibited an early and transient expression of
inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and several
proinflammatory cytokines, including interleukin 1 (IL-1), IL-6,
and tumor necrosis factor  . Western blot analysis and double-label
immunohistochemistry showed an increase in the expression of iNOS and COX-2
and the colocalization of these proteins within microglia. The
thrombin-induced loss of SN dopaminergic neurons was partially inhibited by
NG-nitro-L-arginine methyl ester hydrochloride,
an NOS inhibitor, and by DuP-697, a COX-2 inhibitor. Additional studies
demonstrated that extracellular signal-regulated kinase 1/2 (ERK1/2) and p38
mitogen-activated protein kinase (MAPK) were activated in the SN as early as
30 min after thrombin injection, and that these kinases were localized within
microglia. Inhibition of ERK1/2 and p38 MAPK reduced iNOS and COX-2 mRNA
expression and rescued dopaminergic neurons in the SN. The present results
strongly suggest that microglial activation triggered by endogenous
compound(s) such as thrombin may be involved in the neuropathological
processes of dopaminergic neuronal cell death that occur in Parkinson's
disease.
Key words: thrombin; microglia; inducible nitric oxide synthase; cyclooxygenase-2; mitogen-activated protein kinase; proinflammatory cytokines; dopaminergic neurons; Parkinson's disease
Received Jul. 30, 2002;
revised May. 12, 2003;
accepted May. 12, 2003.
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