Journal
NEUROBIOLOGY OF DISEASE
Volume 26, Issue 1, Pages 36-46Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2006.11.012
Keywords
Parkinson's disease; neuroinflammation; microglia; TNF-alpha; IL-1 beta; minocycline; endothelial cells
Categories
Funding
- NIEHS NIH HHS [R21 ES010776-02, R21 ES012307-02, R21 ES012307-03] Funding Source: Medline
- NINDS NIH HHS [NS045316, R01 NS045316, R01 NS045316-04] Funding Source: Medline
- PHS HHS [012307] Funding Source: Medline
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Following intraparenchymal injection of the dopamine (DA) neurotoxin 6-hydroxydopamine, we previously demonstrated passage of fluoresceinisothiocyanate-labeled albumin (FITC-LA) from blood into the substantia nigra (SN) and striatum suggesting damage to the blood-brain barrier (BBB). The factors contributing to the BBB leakage could have included neuroinflammation, loss of DA neuron control of barrier function, or a combination of both. In order to determine which factor(s) was responsible, we assessed BBB integrity using the FITC-LA technique in wild-type (WT), tumor necrosis factor alpha (TNF-alpha) knockout (KO), and minocycline (an inhibitor of microglia activation) treated mice 72 h following treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Compared with WT mice, TNF-alpha KO mice treated with MPTP showed reduced FITC-LA leakage, decreased numbers of activated microglia, and reduced proinflammatory cytokines (TNF-alpha and interleukin 1 beta) associated with significant MPTP-induced DA neuron loss. In contrast, minocycline treated animals did not exhibit significant MPTP-induced DA neuron loss although their FITC-LA leakage, numbers of activated microglia, and MPTP-induced cytokines were markedly attenuated. Since both TNF-alpha KO and minocycline treatment attenuated MPTP-induced BBB dysfunction, microglial activation, and cytokine increases, but had differential effects on DA neuron loss, it appears that neuroinflammation and not DA neuron loss was responsible for disrupting the blood-brain barrier integrity. (c) 2006 Elsevier Inc. All rights reserved.
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