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

• Published in: Brain research Vol. 1128; no. 1; pp. 1 - 11
• Main Authors: Kalkonde, Yogeshwar V, Morgan, William W, Sigala, Jose, Maffi, Shivani K, Condello, Carlo, Kuziel, William, Ahuja, Seema S, Ahuja, Sunil K
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 12.01.2007; Amsterdam Elsevier; New York, NY
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacology; Adult and adolescent clinical studies; Animals; Biological and medical sciences; Catecholamines - metabolism; CCL2; CCR2; Chemokine CCL2 - deficiency; Chemokines; Chemokines - metabolism; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; glia; Glial Fibrillary Acidic Protein - metabolism; Male; Medical sciences; Mice; Mice, Knockout; MPTP; MPTP Poisoning - metabolism; MPTP Poisoning - pathology; MPTP Poisoning - physiopathology; Neurology; Organic mental disorders. Neuropsychology; Parkinson’s disease; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors, CCR2; Receptors, Chemokine - deficiency; Time Factors; Tumor Necrosis Factor-alpha - metabolism; Tyrosine 3-Monooxygenase - metabolism; MCP-1; RPA; cysteine-X-cysteine chemokine ligand 10; RNase protection assay; CC chemokine receptor-2; 3,4-dihydroxyphenylacetic acid; monocyte chemoattractant protein-1; DM; interferon inducible protein-10; glia; Untx; ventral midbrain; MIP-1α; CCL3; CCL2; CCL2 CCR2 double knockout; SN; CCR2; untreated; substantia nigra; DOPAC; DKO; IP-10; macrophage inflammatory protein-1α; CXCL10; dorsal midbrain; PD; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; VM; MPTP; cysteine–cysteine chemokine Ligand 3; DA; dopamine; Parkinson’s disease; Chemokines; cysteine–cysteine chemokine Ligand 2; Parkinson's disease; Central nervous system; Parkinson disease; Degenerative disease; Degeneration; Nervous system diseases; Rodentia; CCR2 chemokine receptor; Basal ganglion; Corpus striatum; Cerebral disorder; Chemokine; Toxin; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Neurotoxin; Models; Extrapyramidal syndrome
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2006.08.041

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-1α), 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-α 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.