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Upregulation of phosphorylated Stat3 precedes glial induction in MPTP-mediated neurotoxicity.

Hebert-MA; O'Callaghan-JP
Toxicologist 2000 Mar; 54(1):23
STAT3 is a transcription factor that is activated by the JAK family of kinases or by the growth associated MAP kinase (MAPK). As recent studies have shown that Stat3 regulates gliogenesis in the central nervous system (CNS) and astrogliosis is a unifying effect of diverse injuries to the CNS, we are interested in elucidating the temporal relationship among alterations in Stat3, MAPK and gliosis following neurotoxic insult. At various timepoints following l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP, 12.5 mg/kg, s.c.) treatment, female C57BL/6J mice were sacrificed by focused microwave irradiation to preserve steady-state phosphorylation. Target (striatum) and nontarget (hippocampus) tissue homogenates were assayed for levels of glial fibrillary acidic protein (GFAP) and dopamine (DA), as well as alterations in Stat3 and MAPK protein phosphorylation. A 2-fold increase in striatal GFAP was measured in MPTP-treated mice, 48 hours after dosing. Striatal DA depletion occurred within hours following treatment. Alterations in activated Stat3 and MAPK, as detected by phospho-state specific antibodies, were observed as early as one hour following neurotoxic insult and persisted for weeks. The most dramatic increase in the phosphorylated form of Stat3 and MAPK (500% and 100%, respectively) was measured prior to GFAP upregulation (12 hr post-MPTP). As MPTP-induced neurotoxicity requires uptake of MPP+ into DA terminals via the dopamine transporter (OAT), OAT inhibition should block phosphorylation events linked to dopamine terminal damage. Pretreatment with the DAT inhibitor nomifensine (25 mg/kg, s.c.) completely blocked the MPTP-induced increases in GFAP and phospho-Stat3, without altering these levels in saline-treated mice. These data suggest that the activation of Stat3 and MAPK are early events in toxicant-induced glial activation. These kinase/substrate pathways may serve as potential targets for modulation of degenerative and regenerative responses to neural damage.
Neurotoxins; Neurotoxicology; Neurotoxicity; Neurotoxic-effects; Central-nervous-system; Laboratory-animals; Animals; Animal-studies
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The Toxicologist. Society of Toxicology 39th Annual Meeting, March 19-23, 2000, Philadelphia, Pennsylvania