title: Propagation of damage in the rat brain following sarin exposure: Differential progression of early processes.
abstract: Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic warfare agent. Following the overt, dose-dependent signs (e.g. tremor, hyper secretion, seizures, respiratory depression and eventually death), brain damage is often reported. The goal of the present study was to characterize the early histopathological and biochemical events leading to this damage. Rats were exposed to 1LD50 of sarin (80μg/kg, i.m.). Brains were removed at 1, 2, 6, 24 and 48h and processed for analysis. Results showed that TSPO (translocator protein) mRNA increased at 6h post exposure while TSPO receptor density increased only at 24h. In all brain regions tested, bax mRNA decreased 1h post exposure followed by an increase 24h later, with only minor increase in bcl2 mRNA. At this time point a decrease was seen in both anti-apoptotic protein Bcl2 and pro-apoptotic Bax, followed by a time and region specific increase in Bax. An immediate elevation in ERK1/2 activity with no change in JNK may indicate an endogenous "first response" mechanism used to attenuate the forthcoming apoptosis. The time dependent increase in the severity of brain damage included an early bi-phasic activation of astrocytes, a sharp decrease in intact neuronal cells, a time dependent reduction in MAP2 and up to 15% of apoptosis. Thus, neuronal death is mostly due to necrosis and severe astrocytosis. The data suggests that timing of possible treatments should be determined by early events following exposure. For example, the biphasic changes in astrocytes activity indicate a possible beneficial effects of delayed anti-inflammatory intervention.
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Shlomi
authors.initials: S
authors.lastname: Lazar
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Egoz
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Brandeis
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Chapman
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Bloch-Shilderman
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel. Electronic address: ettieg@iibr.gov.il.
authors.forename: Ettie
authors.initials: E
authors.lastname: Grauer
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012524:Sarin / Q000633:toxicity*
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D012524:Sarin
keywords: Apoptosis; Brain Damage; Inflammation; Necrosis; Sarin