title: Sarin (GB, O-isopropyl methylphosphonofluoridate) neurotoxicity: critical review.
abstract: Sarin (GB, O-isopropyl methylphosphonoﬂuoridate) is a potent organophosphorus (OP) nerve agent that inhibits acetylcholinesterase (AChE) irreversibly. The subsequent build-up of acetylcholine (ACh) in the central nervous system (CNS) provokes seizures and, at sufficient doses, centrally-mediated respiratory arrest. Accumulation of ACh at peripheral autonomic synapses leads to peripheral signs of intoxication and overstimulation of the muscarinic and nicotinic receptors, which is described as "cholinergic crisis" (i.e. diarrhea, sweating, salivation, miosis, bronchoconstriction). Exposure to high doses of sarin can result in tremors, seizures, and hypothermia. More seriously, build-up of ACh at neuromuscular junctions also can cause paralysis and ultimately peripherally-mediated respiratory arrest which can lead to death via respiratory failure. In addition to its primary action on the cholinergic system, sarin possesses other indirect effects. These involve the activation of several neurotransmitters including gamma-amino-butyric acid (GABA) and the alteration of other signaling systems such as ion channels, cell adhesion molecules, and inflammatory regulators. Sarin exposure is associated with symptoms of organophosphate-induced delayed neurotoxicity (OPIDN) and organophosphate-induced chronic neurotoxicity (OPICN). Moreover, sarin has been involved in toxic and immunotoxic effects as well as organophosphate-induced endocrine disruption (OPIED). The standard treatment for sarin-like nerve agent exposure is post-exposure injection of atropine, a muscarinic receptor antagonist, accompanied by an oxime, an AChE reactivator, and diazepam.
authors.affiliation: a Department of Pharmacology and Cancer Biology , Duke University , Durham , NC , USA.
authors.forename: Mohamed B
authors.initials: MB
authors.lastname: Abou-Donia
authors.affiliation: a Department of Pharmacology and Cancer Biology , Duke University , Durham , NC , USA.
authors.forename: Briana
authors.initials: B
authors.lastname: Siracuse
authors.affiliation: a Department of Pharmacology and Cancer Biology , Duke University , Durham , NC , USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Gupta
authors.affiliation: a Department of Pharmacology and Cancer Biology , Duke University , Durham , NC , USA.
authors.forename: Ashly
authors.initials: A
authors.lastname: Sobel Sokol
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D009420:Nervous System / Q000187:drug effects*; D012524:Sarin / Q000633:toxicity*
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D012524:Sarin; D000110:Acetylcholinesterase
keywords: AChE; BChE; LD50; NTE; Neurotoxicity; OPICN; OPIDN; organophosphates; oximes; sarin; toxicity