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.

Midazolam-Resistant Seizures and Brain Injury after Acute Intoxication of Diisopropylfluorophosphate, an Organophosphate Pesticide and Surrogate for Nerve Agents

“…Pittel et al, 2006Pittel et al, , 2018. Acute exposure to OPs results in cholinergic hyperactivation and causes a set of predictable and well-documented toxic signs: hypersecretion, miosis, headache, fasciculations, tremors, convulsions, respiratory distress, and death (Bakry et al, 1988;Bajgar, 1997;McDonough and Shih, 1997;Shih et al, 1991Shih et al, , 2003Hájek et al, 2004;Bajgar et al, 2008;Sirin et al, 2012;Abou-Donia et al, 2016;Reddy and Colman, 2017;Pittel et al, 2018).…”

Dorsoventral-Specific Effects of Nerve Agent Surrogate Diisopropylfluorophosphate on Synaptic Transmission in the Mouse Hippocampus

“…Our results are consistent with these prior reports indicating acute DFP exposure inhibits CA1 glutamatergic transmission and that a substantial component of this inhibition is mediated via cholinergic receptors. More specifically, following irreversible inhibition of AChE, enhanced synaptic ACh leads to hyperactivation of mAChRs, a well-established mechanism of OP-induced neurotoxicity (Abou-Donia et al, 2016). Previous studies have shown that mAChR blockade via ATR pretreatment partially prevents DFP-induced PS1 inhibition (Ferchmin et al, 2015).…”

“…JPET # 263053 treated, acute OP-induced cholinergic hyperactivity precipitates the presentation of cholinergic crisis followed by glutamatergic-mediated persistence of seizures and ultimately death (Abou-Donia et al, 2016).…”

Solid‐Phase Synthesis of the Aged‐Nonapeptide‐Nerve‐Agent Adduct of Butyrylcholinesterase as Reference Materials for Analytical Verification

“…The reactivators show an agent‐specific effectiveness and no broadband reactivator is available today. Survivors might suffer from long‐term neuropathic effects …”

“…J = 20, 3 H) 13. C-NMR { 1 H} (100 MHz, CDCl 3 ): 136.2; 128.6; 128.4; 127.8; 127.7; 127.0; 66.5; 12.6; 11.2 31 P-NMR { 1 H} (162 MHz, CDCl 3 ): 34.65 (98%).…”