Stat3 activation in MPTP-induced reactive gliosis: temporal delineation and pharmacological manipulation.
Abstr - Soc Neurosci 2000 Nov; 26:146
We sought to delineate signaling cascades which may initiate reactive gliosis. Down-stream effectors of cytokines and growth factors implicated in gliosis include the Janus kinase-signal transducer and activator of transcription (STAT) and mitogen-activated (MAP) kinases. We used the dopaminergic neurotoxicant, l-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) to injure the striatum and assessed the phosphorylation of Stat3 and MAP kinases relative to the onset of astrogliosis. Following MPTP-(12.5 mg/kg, s.c.) treatment, female C57BU6J mice were sacrificed by focused microwave irradiation to preserve steady-state phosphorylation. Striatal homogenates were assayed for levels of glial fibrillary acidic protein (GF AP) as an index of gliosis; tyrosine hydroxylase (TH) levels were used to confirm terminal damage; activation of Stat3 and MAP kinases were assessed by immunoblots using phospho-specific antibodies. A 2fold increase in GF AP was measured 48h following MPTP, TH depletion occurred within hours, and significant increases in activated Stat3 and MAP kinases, were observed early and persisted for weeks. The most dramatic increase in phospho-Stat3 (500%) preceded MPTP-induced GFAP up-regulation (12h). Antagonism of the dopamine transporter (DAT) with nomifensine pretreatment (25 mg/kg, s.c.), blocked the MPTP-induced increase in GFAP neurotoxicity and completely inhibited the activated forms of Stat3 and MAP kinases. Activation of Stat3 and MAP kinases appear to be early events in toxicant-induced gliosis, can be modulated upon inhibition of neurotoxicant-induced GF AP induction, and may serve as potential targets for modulation of astrocytic responses to neural damage.
Pharmacology; Growth-factors; Neurotoxins; Neurotoxic-effects; Neurotoxicity
Abstract; Conference/Symposia Proceedings
Abstracts - Society for Neuroscience. Society for Neuroscience's 30th Annual Meeting, New Orleans, LA, November 4 - 9, 2000