Dr. Paul Greengard received the 2000 Nobel Prize in Physiology or Medicine for identifying the dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) signaling pathways in medium spiny striatal neurons. Identification of multiple phospho-sites on DARPP-32 revealed upstream effectors regulating the activation of this specific neuronal cell type. We adopted the same approach to map signaling pathways upstream of the key astrocyte damage marker, glial fibrillary acidic protein (GFAP). In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of dopaminergic neurotoxicity, we demonstrated the development of neuroinflammation (upregulation of proinflammatory cytokines/ chemokines) and activation of the janus kinase and signal transducer and activator of transcription (JAK2-STAT3) pathway preceding the up-regulation of GFAP in astrocytes in the brain. Here, we show that multiple mechanistically distinct models of neurotoxicity (MPTP, amphetamine (AMP), methamphetamine (METH), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), kainic acid (KA) and trimethyltin (TMT)) engender the same neuroinflammatory response and STAT3 activation in target brain regions of the respective neurotoxicants. Pharmacological antagonism of neurotoxic effects of MPTP, METH and KA with nomifensine, ethanol and diazepam, respectively, blocked the neuroinflammation, phosphorylation of STAT3 and GFAP induction, indicating neuronal damage as a component of the initiation of astrogliosis. Deletion of astrocytic STAT3 in conditional knockout mice prevented the induction of GFAP in MPTP-treated mice. Double immunostaining of GFAP and STAT3 showed enhanced nuclear staining localized to astrocytes in association with the induction of astrogliosis. These findings strongly implicate the STAT3 pathway in astrocytes as a key signaling pathway for astrogliosis.
The Toxicologist. Society of Toxicology 53rd Annual Meeting and ToxExpo, March 23-27, 2014, Phonex, Arizona