Low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine causes inflammatory activation of astrocytes in nuclear factor-κB reporter mice prior to loss of dopaminergic neurons

• Published in: Journal of neuroscience research Vol. 89; no. 3; pp. 406 - 417
• Main Authors: Miller, James A., Trout, Briana R., Sullivan, Kelly A., Bialecki, Russell A., Roberts, Ruth A., Tjalkens, Ronald B.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-03-2011
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacology; Analysis of Variance; Animals; Apoptosis; astrocyte; Astrocytes; Astrocytes - drug effects; Cell Death - drug effects; Central nervous system; Coculture Techniques - methods; Data processing; Disease Models, Animal; Dopamine; Dopamine - metabolism; Dose-Response Relationship, Drug; Fibers; Glial cells; Glial Fibrillary Acidic Protein - metabolism; Green fluorescent protein; Green Fluorescent Proteins - genetics; Hindlimb - physiopathology; Inflammation; Inflammation - chemically induced; Inflammation - pathology; Injuries; Locomotor activity; Male; Mice; Mice, Transgenic; Motor Activity - drug effects; MPTP; Neostriatum; Nervous system; neurodegeneration; neuroinflammation; Neurons; Neurons - drug effects; Neurons - metabolism; Neurotoxins - pharmacology; NF- Kappa B protein; NF-kappaB-Inducing Kinase; NF-κB; Nitration; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Stress; Substantia nigra; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Substantia Nigra - pathology; Transgenic mice; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0360-4012; 1097-4547; 1097-4547
• DOI: 10.1002/jnr.22549

Neuroinflammation is implicated in the progression of numerous disease states of the CNS, but early inflammatory signaling events in glial cells that may predispose neurons to injury are not easily characterized in vivo. To address this question, we exposed transgenic mice expressing a nuclear factor‐κB (NF‐κB)‐driven enhanced green fluorescent protein (EGFP) reporter construct to low doses of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and examined inflammatory activation of astrocytes in relation to neurobehavioral and neuropathological outcomes. The highest dose of MPTP (60 mg/kg total dose) caused a decrease in locomotor activity and a reduction in stride length. No significant loss of dopaminergic neurons in the substantia nigra was apparent at any dose. In contrast, expression of tyrosine hydroxylase in striatal fibers was reduced at 60 mg/kg MPTP, as were levels of dopamine and DOPAC. Colocalized expression of EGFP and inducible nitric oxide synthase (NOS2) occurred in astrocytes at 30 and 60 mg/kg MPTP and was associated with increased protein nitration in nigral dopaminergic neurons. Inhibition of NF‐κB in primary astrocytes by expression of mutant IκBα suppressed expression of NOS2 and protected cocultured neurons from astrocyte‐mediated apoptosis. These data indicate that inflammatory activation of astrocytes and enhanced nitrosative stress occurs at low doses of MPTP prior to loss of dopaminergic neurons. NF‐κB‐mediated expression of NOS2 appears to be a sensitive indicator of neuroinflammation that correlates with MPTP‐induced neurochemical and neurobehavioral deficits prior to loss of dopaminergic neurons in the subtantia nigra. © 2011 Wiley‐Liss, Inc.