Chemokines in the MPTP model of Parkinson's disease: absence of CCL2 and its receptor CCR2 does not protect against striatal neurodegeneration

Brain Res. 2007 Jan 12;1128(1):1-11. doi: 10.1016/j.brainres.2006.08.041. Epub 2006 Nov 28.

Abstract

Recent studies have invoked inflammation as a major contributor to the pathogenesis of Parkinson's disease (PD). We determined the role of members of the chemokine system, key inflammatory mediators, in PD pathogenesis. In the MPTP model of murine PD, several chemokines, including CC chemokine ligand 2 (CCL2, Monocyte Chemoattractant Protein-1) and CCL3 (Macrophage Inflammatory Protein-1alpha), were upregulated in the striatum and the ventral midbrain. Astrocytes were the predominant source of CCL2 and CCL3 in the striatum and the substantia nigra, and dopaminergic neurons in the substantia nigra constitutively expressed these two chemokines. MPTP treatment resulted in decreased CCL2 expression and increased CCL3 expression in the surviving dopaminergic neurons. Because we found that CCL2 induced production of TNF-alpha in microglial cells, a cytokine known to play a detrimental role in PD, we anticipated that deletion of the genes encoding CCL2 and CCR2, its major receptor, would confer a protective phenotype. However, MPTP-induced striatal dopamine depletion was comparable in double knockout and wild-type mice. Our results demonstrate that chemokines such as CCL2 are induced following MPTP treatment, but that at least within the context of this PD model, the absence of CCL2 and CCR2 does not protect against striatal dopamine loss.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Animals
  • Catecholamines / metabolism
  • Chemokine CCL2 / deficiency*
  • Chemokines / metabolism*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • MPTP Poisoning / metabolism*
  • MPTP Poisoning / pathology
  • MPTP Poisoning / physiopathology*
  • Male
  • Mice
  • Mice, Knockout
  • Receptors, CCR2
  • Receptors, Chemokine / deficiency*
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Catecholamines
  • Ccl2 protein, mouse
  • Ccr2 protein, mouse
  • Chemokine CCL2
  • Chemokines
  • Glial Fibrillary Acidic Protein
  • Receptors, CCR2
  • Receptors, Chemokine
  • Tumor Necrosis Factor-alpha
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Tyrosine 3-Monooxygenase