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Publication : 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.

First Author  Miller JA Year  2011
Journal  J Neurosci Res Volume  89
Issue  3 Pages  406-17
PubMed ID  21259327 Mgi Jnum  J:286069
Mgi Id  MGI:6390511 Doi  10.1002/jnr.22549
Citation  Miller JA, et al. (2011) Low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine causes inflammatory activation of astrocytes in nuclear factor-kappaB reporter mice prior to loss of dopaminergic neurons. J Neurosci Res 89(3):406-17
abstractText  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-kappaB (NF-kappaB)-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-kappaB in primary astrocytes by expression of mutant IkappaBalpha 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-kappaB-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.
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