Skip directly to search Skip directly to A to Z list Skip directly to page options Skip directly to site content

NIOSHTIC-2 Publications Search

Search Results

Nerve agent exposure elicits site-specific changes in protein phosphorylation in mouse brain.

Authors
Zhu-HW; O'Brien-JJ; O'Callaghan-JP; Miller-DB; Zhang-QA; Rana-M; Tsui-T; Peng-YY; Tomesch-J; Hendrick-JP; Wennogle-LP; Snyder-GL
Source
Brain Res 2010 Jun; 1342:11-23
NIOSHTIC No.
20037172
Abstract
Organophosphorus (OP) compounds cause toxic symptoms, including convulsions, coma, and death, as the result of irreversible inhibition of acetylcholinesterase (AChE). The development of effective treatments to block these effects and attenuate long-term cognitive and motor disabilities that result from OP intoxication is hampered by a limited understanding of the CNS pathways responsible for these actions. We employed a candidate method (called CNSProfile (TM)) to identify changes in the phosphorylation state of key neuronal phosphoproteins evoked by the OP compound, diisopropyl fluorophosphate (DFP). Focused microwave fixation was used to preserve the phosphorylation state of phosphoproteins in brains of DFP-treated mice; hippocampus and striatum were analyzed by immunoblotting with a panel of phospho-specific antibodies. DFP exposure elicited comparable effects on phosphorylation of brain phosphoproteins in both C57BL/6 and FVB mice. DFP treatment significantly altered phosphorylation at regulatory residues on glutamate receptors, including Serine897 (S897) of the NR1 NMDA receptor. NR1 phosphorylation was bi-directionally regulated after DFP in striatum versus hippocampus. NR1 phosphorylation was reduced in striatum, but elevated in hippocampus, compared with controls. DARPP-32 phosphorylation in striatum was selectively increased at the Cdk5 kinase substrate, Threonine75 (T75). Phencynonate hydrochloride, a muscarinic cholinergic antagonist, prevented seizure-like behaviors and the observed changes in phosphorylation induced by DFP. The data reveal region-specific effects of nerve agent exposure on intracellular signaling pathways that correlate with seizure-like behavior and which are reversed by the muscarinic receptor blockade. This approach identifies specific targets for nerve agents, including substrates for Cdk5 kinase, which may be the basis for new anticonvulsant therapies.
Keywords
Biochemical-analysis; Biohazards; Biological-effects; Biological-factors; Biological-monitoring; Brain-function; Chemical-hypersensitivity; Chemical-reactions; Chemical-synthesis; Injuries; Laboratory-animals; Laboratory-testing; Motion-studies; Nervous-system-disorders; Neurological-reactions; Neurological-system; Neuromotor-disorders; Neuromotor-function; Neuromotor-system; Neuromotor-system-disorders; Neuropathy; Neurophysiological-effects; Neurophysiology; Neurotoxic-effects Sensory-disorders; Sensory-motor-system; Author Keywords: AChE inhibitor; DARPP-32; NR1; Phospho-specific antibody; Muscarinic receptor; Phencynonate hydrochloride (PCH)
Contact
Gretchen L. Snyder, Department of Molecular Neuropharmacology, Intra-Cellular Therapies, Inc. (ITI), Audubon Business and Technology Center, 3960 Broadway, New York, NY 10032
CODEN
BRREAP
CAS No.
55-91-4
Publication Date
20100625
Document Type
Journal Article
Email Address
gsnyder@intracellulartherapies.com
Fiscal Year
2010
NTIS Accession No.
NTIS Price
ISSN
0006-8993
NIOSH Division
HELD
Priority Area
Manufacturing
Source Name
Brain Research
State
WV; NY
TOP