Characterization of the origins of astrocyte response to injury using the dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
We used the dopaminergic neurotoxicant, 1-methyl-1,2,3,6-tetrahydropyridine (MPTP), as a tool to characterize the origins of astroglial response to injury. Radioimmunoassay of the astrocyte protein, glial fibrillary acidic protein (GFAP), was used to quantify the astrocyte reaction to MPTP. Assays of neuron-localized proteins and of dopamine were used to assess neuronal damage caused by MPTP. A single administration of MPTP (12.5 mg/kg, s.c.) to the C57BL/6J mouse resulted in more than a 3-fold increase in striatal GFAP within 48 h, followed by a decline to baseline at 3 weeks. A decrease in the amount of striatal tyrosine hydroxylase (TH), a marker of dopaminergic neurons, preceded the rise in GFAP. The concentration of striatal DARPP-32, a phosphoprotein enriched in neurons receiving dopaminergic input, was not affected by MPTP. Protecting the dopaminergic neurons from the neurotoxic metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+), either by blocking its formation or by preventing its uptake into dopaminergic neurons, completely blocked the increase in GFAP. MPTP did not appear to disrupt the blood-brain barrier, therefore, blood-borne elements probably did not mediate the increase in GFAP. In addition, immunoblot data indicated that brain-derived interleukin 1, an astrocyte growth factor, also did not play a role in MPTP-induced gliosis. Together, these findings suggest that diffusible factors derived from damaged dopaminergic neurons initiate the astrocyte response to MPTP and that large increases in GFAP can be induced without the participation of serum-derived growth factor.(ABSTRACT TRUNCATED AT 250 WORDS)
O'Callaghan
J P
JP
Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.
Miller
D B
DB
Reinhard
J F
JF
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D007279:Injections, Subcutaneous; D020267:MPTP Poisoning; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010750:Phosphoproteins; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005904:Glial Fibrillary Acidic Protein; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D010750:Phosphoproteins; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine