title: Immunomodulation by poly-YE reduces organophosphate-induced brain damage.
abstract: Accidental organophosphate poisoning resulting from environmental or occupational exposure, as well as the deliberate use of nerve agents on the battlefield or by terrorists, remain major threats for multi-casualty events, with no effective therapies yet available. Even transient exposure to organophosphorous compounds may lead to brain damage associated with microglial activation and to long-lasting neurological and psychological deficits. Regulation of the microglial response by adaptive immunity was previously shown to reduce the consequences of acute insult to the central nervous system (CNS). Here, we tested whether an immunization-based treatment that affects the properties of T regulatory cells (Tregs) can reduce brain damage following organophosphate intoxication, as a supplement to the standard antidotal protocol. Rats were intoxicated by acute exposure to the nerve agent soman, or the organophosphate pesticide, paraoxon, and after 24 h were treated with the immunomodulator, poly-YE. A single injection of poly-YE resulted in a significant increase in neuronal survival and tissue preservation. The beneficial effect of poly-YE treatment was associated with specific recruitment of CD4(+) T cells into the brain, reduced microglial activation, and an increase in the levels of brain derived neurotrophic factor (BDNF) in the piriform cortex. These results suggest therapeutic intervention with poly-YE as an immunomodulatory supplementary approach against consequences of organophosphate-induced brain damage.
authors.affiliation: Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Arseny
authors.initials: A
authors.lastname: Finkelstein
authors.forename: Gilad
authors.initials: G
authors.lastname: Kunis
authors.forename: Tamara
authors.initials: T
authors.lastname: Berkutzki
authors.forename: Ayal
authors.initials: A
authors.lastname: Ronen
authors.forename: Amir
authors.initials: A
authors.lastname: Krivoy
authors.forename: Eti
authors.initials: E
authors.lastname: Yoles
authors.forename: David
authors.initials: D
authors.lastname: Last
authors.forename: Yael
authors.initials: Y
authors.lastname: Mardor
authors.forename: Kerry
authors.initials: K
authors.lastname: Van Shura
authors.forename: Emylee
authors.initials: E
authors.lastname: McFarland
authors.forename: Benedict A
authors.initials: BA
authors.lastname: Capacio
authors.forename: Claire
authors.initials: C
authors.lastname: Eisner
authors.forename: Mary
authors.initials: M
authors.lastname: Gonzales
authors.forename: Danise
authors.initials: D
authors.lastname: Gregorowicz
authors.forename: Arik
authors.initials: A
authors.lastname: Eisenkraft
authors.forename: John H
authors.initials: JH
authors.lastname: McDonough
authors.forename: Michal
authors.initials: M
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D001927:Brain Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D049109:Cell Proliferation; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D005434:Flow Cytometry; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010261:Paraoxon / Q000037:antagonists & inhibitors / Q000633:toxicity; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012999:Soman / Q000037:antagonists & inhibitors / Q000633:toxicity; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D007155:Immunologic Factors; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D010455:Peptides; C416504:poly(tyrosyl-glutamic acid); D012999:Soman; D010261:Paraoxon