Organophosphorus compounds (OP) are a constant problem, both in the military and in the civilian field, not only in the form of acute poisoning but also for their long-lasting consequences. No antidote has been found that satisfactorily protects against the toxic effects of organophosphates. Likewise, there is no universal cure to avert damage after poisoning. The key mechanism of organophosphate toxicity is the inhibition of acetylcholinesterase. The overstimulation of nicotinic or muscarinic receptors by accumulated acetylcholine on a synaptic cleft leads to activation of the glutamatergic system and the development of seizures. Further consequences include generation of reactive oxygen species (ROS), neuroinflammation, and the formation of various other neuropathologists. In this review, we present neuroprotection strategies which can slow down the secondary nerve cell damage and alleviate neurological and neuropsychiatric disturbance. In our opinion, there is no unequivocal approach to ensure neuroprotection, however, sooner the neurotoxicity pathway is targeted, the better the results which can be expected. It seems crucial to target the key propagation pathways, i.e., to block cholinergic and, foremostly, glutamatergic cascades. Currently, the privileged approach oriented to stimulating GABAAR by benzodiazepines is of limited efficacy, so that antagonizing the hyperactivity of the glutamatergic system could provide an even more efficacious approach for terminating OP-induced seizures and protecting the brain from permanent damage. Encouraging results have been reported for tezampanel, an antagonist of GluK1 kainate and AMPA receptors, especially in combination with caramiphen, an anticholinergic and anti-glutamatergic agent. On the other hand, targeting ROS by antioxidants cannot or already developed neuroinflammation does not seem to be very productive as other processes are also involved.

Biomedical Research Center University Hospital Hradec Kralove Sokolska 581 Hradec Kralove Czech Republic

Faculty of Military Health Sciences University of Defence Trebesska 1575 Hradec Kralove Czech Republic

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Abdel-Rahman A, Shetty AK, Abou-Donia MB (2002) Acute exposure to sarin increases blood brain barrier permeability and induces neuropathological changes in the rat brain: dose-response relationships. Neuroscience 113:721–741. https://doi.org/10.1016/s0306-4522(02)00176-8 DOI

Ahmed R, Seth V, SkG P, Banerjee B (2000) Influence of dietary Ginger (Zingiber officinales Rosc) on oxidative stress induced by malathion in rats. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc 38:443–450. https://doi.org/10.1016/S0278-6915(00)00019-3 DOI

Ahmed D, Abdel-Rahman RH, Salama M et al (2017) Malathion neurotoxic effects on dopaminergic system in mice: role of inflammation. J Biomed Sci. https://doi.org/10.4172/2254-609X.100074 DOI

Aidan N, Rajakulendran S, Walker MC (2021) Advances in the management of generalized convulsive status epilepticus: what have we learned? Brain 144:1336–1341. https://doi.org/10.1093/brain/awab049 DOI

Akhgari M, Abdollahi M, Kebriaeezadeh A et al (2003) Biochemical evidencefor free radical induced lipid peroxidation as a mechanism for subchronic toxicity of malathion in blood and liver of rats. Hum Exp Toxicol 22:205–211. https://doi.org/10.1191/0960327103ht346oa DOI

Albuquerque EX, Pereira EFR, Aracava Y et al (2006) Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents. Proc Natl Acad Sci U S A 103:13220–13225. https://doi.org/10.1073/pnas.0605370103 DOI

Allan SM, Rothwell NJ (2001) Cytokines and acute neurodegeneration. Nat Rev Neurosci 2:734–744. https://doi.org/10.1038/35094583 DOI

Allan SM, Tyrrell PJ, Rothwell NJ (2005) Interleukin-1 and neuronal injury. Nat Rev Immunol 5:629–640. https://doi.org/10.1038/nri1664 DOI

Amitai G, Adani R, Fishbein E et al (2006) Bifunctional compounds eliciting anti-inflammatory and anti-cholinesterase activity as potential treatment of nerve and blister chemical agents poisoning. J Appl Toxicol JAT 26:81–87. https://doi.org/10.1002/jat.1111 DOI

Angoa-Pérez M, Kreipke CW, Thomas DM et al (2010) Soman increases neuronal COX-2 levels: possible link between seizures and protracted neuronal damage. Neurotoxicology 31:738–746. https://doi.org/10.1016/j.neuro.2010.06.007 DOI

Anthony J, Johanson RB, Duley L (1996) Role of magnesium sulfate in seizure prevention in patients with eclampsia and pre-eclampsia. Drug Saf 15:188–199. https://doi.org/10.2165/00002018-199615030-00004 DOI

Apland JP, Aroniadou-Anderjaska V, Figueiredo TH et al (2018a) full protection against soman-induced seizures and brain damage by LY293558 and caramiphen combination treatment in adult rats. Neurotox Res 34:511–524. https://doi.org/10.1007/s12640-018-9907-1 DOI

Apland JP, Aroniadou-Anderjaska V, Figueiredo TH et al (2018b) Comparing the antiseizure and neuroprotective efficacy of LY293558, diazepam, caramiphen, and LY293558-caramiphen combination against soman in a rat model relevant to the pediatric population. J Pharm Exp Ther 365:314–326. https://doi.org/10.1124/jpet.117.245969 DOI

Aracava Y, Pereira EFR, Akkerman M et al (2009) Effectiveness of donepezil, rivastigmine, and (+/-)huperzine A in counteracting the acute toxicity of organophosphorus nerve agents: comparison with galantamine. J Pharm Exp Ther 331:1014–1024. https://doi.org/10.1124/jpet.109.160028 DOI

Aroniadou-Anderjaska V, Figueiredo TH, Apland JP, Braga MF (2020) Targeting the glutamatergic system to counteract organophosphate poisoning: a novel therapeutic strategy. Neurobiol Dis 133:104406. https://doi.org/10.1016/j.nbd.2019.02.017 DOI

Asthana S, Greig NH, Hegedus L et al (1995) Clinical pharmacokinetics of physostigmine in patients with Alzheimer’s disease. Clin Pharm Ther 58:299–309. https://doi.org/10.1016/0009-9236(95)90246-5 DOI

Atack JR (2003) Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. Curr Drug Targets CNS Neurol Disord 2:213–232. https://doi.org/10.2174/1568007033482841 DOI

Au CC, Branco RG, Tasker RC (2017) Management protocols for status epilepticus in the pediatric emergency room: systematic review article. J Pediatr (rio j) 93(Suppl 1):84–94. https://doi.org/10.1016/j.jped.2017.08.004 DOI

Auta J, Giusti P, Guidotti A, Costa E (1994) Imidazenil, a partial positive allosteric modulator of GABAA receptors, exhibits low tolerance and dependence liabilities in the rat. J Pharm Exp Ther 270:1262–1269

Auta J, Faust WB, Lambert P et al (1995) Comparison of the effects of full and partial allosteric modulators of GABA(A) receptors on complex behavioral processes in monkeys. Behav Pharm 6:323–332

Auta J, Costa E, Davis J, Guidotti A (2004) Imidazenil: a potent and safe protective agent against diisopropyl fluorophosphate toxicity. Neuropharmacology 46:397–403. https://doi.org/10.1016/j.neuropharm.2003.09.010 DOI

Bae YS, Oh H, Rhee SG, Yoo YD (2011) Regulation of reactive oxygen species generation in cell signaling. Mol Cells 32:491–509. https://doi.org/10.1007/s10059-011-0276-3 DOI

Bagchi D, Bagchi M, Hassoun EA, Stohs SJ (1995) In vitro and in vivo generation of reactive oxygen species, DNA damage and lactate dehydrogenase leakage by selected pesticides. Toxicology 104:129–140. https://doi.org/10.1016/0300-483x(95)03156-a DOI

Bajgar J (2004) Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. Adv Clin Chem 38:151–216. https://doi.org/10.1016/s0065-2423(04)38006-6 DOI

Bajgar J, Kuca K, Fusek J et al (2010) Cholinesterase reactivators as prophylactics against nerve agents. Curr Bioact Compd 6:2–8

Balali-Mood M, Saber H (2012) Recent advances in the treatment of organophosphorous poisonings. Iran J Med Sci 37:74–91

Balasaheb Nimse S, Pal D (2015) Free radicals, natural antioxidants, and their reaction mechanisms. RSC Adv 5:27986–28006. https://doi.org/10.1039/C4RA13315C DOI

Balbuena P, Li W, Ehrich M (2011) Assessments of tight junction proteins occludin, claudin 5 and scaffold proteins ZO1 and ZO2 in endothelial cells of the rat blood–brain barrier: Cellular responses to neurotoxicants malathion and lead acetate. Neurotoxicology 32:58–67. https://doi.org/10.1016/j.neuro.2010.10.004 DOI

Baltazar MT, Dinis-Oliveira RJ, de Lourdes BM et al (2014) Pesticides exposure as etiological factors of Parkinson’s disease and other neurodegenerative diseases–a mechanistic approach. Toxicol Lett 230:85–103. https://doi.org/10.1016/j.toxlet.2014.01.039 DOI

Banerjee BD, Seth V, Ahmed RS (2001) Pesticide-induced oxidative stress: perspectives and trends. Rev Environ Health 16:1–40. https://doi.org/10.1515/reveh.2001.16.1.1 DOI

Banks CN, Lein PJ (2012) A review of experimental evidence linking neurotoxic organophosphorus compounds and inflammation. Neurotoxicology 33:575–584. https://doi.org/10.1016/j.neuro.2012.02.002 DOI

Barker BS, Spampanato J, McCarren HS et al (2020) Screening for efficacious anticonvulsants and neuroprotectants in delayed treatment models of organophosphate-induced status epilepticus. Neuroscience 425:280–300. https://doi.org/10.1016/j.neuroscience.2019.11.020 DOI

Barry JD, Wills BK (2011) Neurotoxic emergencies. Neurol Clin 29:539–563. https://doi.org/10.1016/j.ncl.2011.05.006 DOI

Bartošová L, Bajgar J (2005) Vývoj a nové trendy v profylaxi otrav organofosfáty. Čs Fyziol 54:185

Bebe FN, Panemangalore M (2003) Exposure to low doses of endosulfan and chlorpyrifos modifies endogenous antioxidants in tissues of rats. J Environ Sci Health B 38:349–363. https://doi.org/10.1081/PFC-120019901 DOI

Benveniste EN (1998) Cytokine actions in the central nervous system. Cytokine Growth Factor Rev 9:259–275. https://doi.org/10.1016/s1359-6101(98)00015-x DOI

Bernard GR (1991) N-acetylcysteine in experimental and clinical acute lung injury. Am J Med 91:54S-59S. https://doi.org/10.1016/0002-9343(91)90284-5 DOI

Bitzinger DI, Zausig YA, Paech C et al (2013) Modulation of immune functions in polymorphonuclear neutrophils induced by physostigmine, but not neostigmine, independent of cholinergic neurons. Immunobiology 218:1049–1054. https://doi.org/10.1016/j.imbio.2013.01.003 DOI

Blanke ML, VanDongen AMJ (2009) Activation mechanisms of the NMDA receptor. In: Van Dongen AM (ed) Biology of the NMDA receptor. CRC Press/Taylor & Francis, Boca Raton (FL)

Block ML, Hong J-S (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 76:77–98. https://doi.org/10.1016/j.pneurobio.2005.06.004 DOI

Blohberger J, Kunz L, Einwang D et al (2015) Readthrough acetylcholinesterase (AChE-R) and regulated necrosis: pharmacological targets for the regulation of ovarian functions? Cell Death Dis 6:e1685. https://doi.org/10.1038/cddis.2015.51 DOI

Bolton SJ, Anthony DC, Perry VH (1998) Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood-brain barrier breakdown in vivo. Neuroscience 86:1245–1257. https://doi.org/10.1016/s0306-4522(98)00058-x DOI

Borovikova LV, Ivanova S, Zhang M et al (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–462. https://doi.org/10.1038/35013070 DOI

Bredt DS (1999) Endogenous nitric oxide synthesis: biological functions and pathophysiology. Free Radic Res 31:577–596. https://doi.org/10.1080/10715769900301161 DOI

Bruins J, Menezes C, Wong M (2019) Organophosphate poisoning at chris hani baragwanath academic hospital 2012–2015. Afr J Thorac Crit Care Med 25:104. https://doi.org/10.7196/SARJ.2019.v25i3.001 DOI

Brvar M, Chan MY, Dawson AH et al (2018) Magnesium sulfate and calcium channel blocking drugs as antidotes for acute organophosphorus insecticide poisoning—a systematic review and meta-analysis. Clin Toxicol Phila Pa 56:725–736. https://doi.org/10.1080/15563650.2018.1446532 DOI

Burman RJ, Selfe JS, Lee JH et al (2019) Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus. Brain J Neurol 142:3482–3501. https://doi.org/10.1093/brain/awz283 DOI

Carini M, Aldini G, Facino RM (2004) Mass spectrometry for detection of 4-hydroxy-trans-2-nonenal (HNE) adducts with peptides and proteins. Mass Spectrom Rev 23:281–305. https://doi.org/10.1002/mas.10076 DOI

Carpentier P, Foquin A, Kamenka J-M et al (2001) Effects of thienylphencyclidine (TCP) on seizure activity and brain damage produced by soman in guinea-pigs: ECoG correlates of neurotoxicity. Neurotoxicology 22:13–28. https://doi.org/10.1016/S0161-813X(00)00016-4 DOI

Carpentier DP, Foquin A, Lallement G, Dorandeu F (2004) Flunarizine: a possible adjuvant medication against soman poisoning? Drug Chem Toxicol 27:213–231. https://doi.org/10.1081/DCT-120037503 DOI

Chan AC (1993) Partners in defense, vitamin E and vitamin C. Can J Physiol Pharm 71:725–731. https://doi.org/10.1139/y93-109 DOI

Chapman S, Kadar T, Gilat E (2006) Seizure duration following sarin exposure affects neuro-inflammatory markers in the rat brain. Neurotoxicology 27:277–283. https://doi.org/10.1016/j.neuro.2005.11.009 DOI

Chen Y (2012) Organophosphate-induced brain damage: Mechanisms, neuropsychiatric and neurological consequences, and potential therapeutic strategies. NeuroToxicology 33:391–400. https://doi.org/10.1016/j.neuro.2012.03.011 DOI

Choi E-K, Park D, Yon J-M et al (2004) Protection by sustained release of physostigmine and procyclidine of soman poisoning in rats. Eur J Pharm 505:83–91. https://doi.org/10.1016/j.ejphar.2004.10.034 DOI

Choudhary S, Gill KD (2001) Protective effect of nimodipine on dichlorvos-induced delayed neurotoxicity in rat brain (1). Biochem Pharm 62:1265–1272. https://doi.org/10.1016/S0006-2952(01)00762-6 DOI

Coelho F, Birks J (2001) Physostigmine for Alzheimer’s disease. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.cd001499 DOI

Collombet J-M (2011) Nerve agent intoxication: recent neuropathophysiological findings and subsequent impact on medical management prospects. Toxicol Appl Pharm 255:229–241. https://doi.org/10.1016/j.taap.2011.07.003 DOI

Cornelissen AS, Klaassen SD, van Groningen T et al (2020) Comparative physiology and efficacy of atropine and scopolamine in sarin nerve agent poisoning. Toxicol Appl Pharm 396:114994. https://doi.org/10.1016/j.taap.2020.114994 DOI

Corps KN, Roth TL, McGavern DB (2015) Inflammation and neuroprotection in traumatic brain injury. JAMA Neurol 72:355–362. https://doi.org/10.1001/jamaneurol.2014.3558 DOI

Costa LG (2006) Current issues in organophosphate toxicology. Clin Chim Acta 366:1–13. https://doi.org/10.1016/j.cca.2005.10.008 DOI

Costa LG (2018) Organophosphorus compounds at 80: some old and new issues. Toxicol Sci 162:24–35. https://doi.org/10.1093/toxsci/kfx266 DOI

Cowan FM, Shih TM, Lenz DE et al (1996) Hypothesis for synergistic toxicity of organophosphorus poisoning-induced cholinergic crisis and anaphylactoid reactions. J Appl Toxicol JAT 16:25–33. https://doi.org/10.1002/(SICI)1099-1263(199601)16:1%3c25::AID-JAT303%3e3.0.CO;2-5 DOI

Cowan F, Broomfield C, Lenz D, Smith W (2003) Putative role of proteolysis and inflammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi-threat medical countermeasures. J Appl Toxicol 23:177–186

Cracowski J-L, Durand T, Bessard G (2002) Isoprostanes as a biomarker of lipid peroxidation in humans: physiology, pharmacology and clinical implications. Trends Pharm Sci 23:360–366. https://doi.org/10.1016/s0165-6147(02)02053-9 DOI

Damodaran TV, Bilska MA, Rahman AA, Abou-Doni MB (2002) Sarin causes early differential alteration and persistent overexpression in mRNAs coding for glial fibrillary acidic protein (GFAP) and vimentin genes in the central nervous system of rats. Neurochem Res 27:407–415. https://doi.org/10.1023/a:1015508132137 DOI

Darreh-Shori T, Hellström-Lindahl E, Flores-Flores C et al (2004) Long-lasting acetylcholinesterase splice variations in anticholinesterase-treated Alzheimer’s disease patients. J Neurochem 88:1102–1113. https://doi.org/10.1046/j.1471-4159.2003.02230.x DOI

Day B (2004) Catalytic antioxidants: a radical approach to new therapeutics. Drug Discov Today 9:557–566. https://doi.org/10.1016/S1359-6446(04)03139-3 DOI

de Araujo FM, Rossetti F, Chanda S, Yourick D (2012) Exposure to nerve agents: from status epilepticus to neuroinflammation, brain damage, neurogenesis and epilepsy. Neurotoxicology 33:1476–1490. https://doi.org/10.1016/j.neuro.2012.09.001 DOI

de Araujo FM, Aroniadou-Anderjaska V, Figueiredo TH et al (2020) Electroencephalographic analysis in soman-exposed 21-day-old rats and the effects of midazolam or LY293558 with caramiphen. Ann NY Acad Sci 1479:122–133. https://doi.org/10.1111/nyas.14331 DOI

Dey A, Kang X, Qiu J et al (2016) Anti-inflammatory small molecules to treat seizures and epilepsy: from bench to bedside. Trends Pharm Sci 37:463–484. https://doi.org/10.1016/j.tips.2016.03.001 DOI

Dhir A, Bruun DA, Guignet M et al (2020) Allopregnanolone and perampanel as adjuncts to midazolam for treating diisopropylfluorophosphate-induced status epilepticus in rats. Ann NY Acad Sci 1480:183–206. https://doi.org/10.1111/nyas.14479 DOI

Dhote F, Peinnequin A, Carpentier P et al (2007) Prolonged inflammatory gene response following soman-induced seizures in mice. Toxicology 238:166–176. https://doi.org/10.1016/j.tox.2007.05.032 DOI

Dhote F, Carpentier P, Barbier L et al (2012) Combinations of ketamine and atropine are neuroprotective and reduce neuroinflammation after a toxic status epilepticus in mice. Toxicol Appl Pharm 259:195–209. https://doi.org/10.1016/j.taap.2011.12.024 DOI

Dillman JF, Phillips CS, Kniffin DM et al (2009) Gene expression profiling of rat hippocampus following exposure to the acetylcholinesterase inhibitor soman. Chem Res Toxicol 22:633–638. https://doi.org/10.1021/tx800466v DOI

Ding Q, Fang S, Chen X et al (2017) TRPA1 channel mediates organophosphate-induced delayed neuropathy. Cell Discov 3:1–15. https://doi.org/10.1038/celldisc.2017.24 DOI

DiSabato D, Quan N, Godbout JP (2016) Neuroinflammation: the devil is in the details. J Neurochem 139:136–153. https://doi.org/10.1111/jnc.13607 DOI

Doebler JA, Shih TM, Anthony A (1985) Quantitative cytophotometric analyses of mesenteric mast cell granulation in acute soman intoxicated rats. Experientia 41:1457–1458. https://doi.org/10.1007/BF01950034 DOI

Dorandeu F, Carpentier P, Baubichon D et al (2005) Efficacy of the ketamine–atropine combination in the delayed treatment of soman-induced status epilepticus. Brain Res 1051:164–175. https://doi.org/10.1016/j.brainres.2005.06.013 DOI

Dorandeu F, Baille V, Mikler J et al (2007) Protective effects of S(+) ketamine and atropine against lethality and brain damage during soman-induced status epilepticus in guinea-pigs. Toxicology 234:185–193. https://doi.org/10.1016/j.tox.2007.02.012 DOI

Dorandeu F, Dhote F, Barbier L et al (2013) Treatment of status epilepticus with ketamine, are we there yet? CNS Neurosci Ther 19:411–427. https://doi.org/10.1111/cns.12096 DOI

Duffield JS (2003) The inflammatory macrophage: a story of Jekyll and Hyde. Clin Sci Lond Engl 1979 104:27–38

Eddleston M, Buckley NA, Eyer P, Dawson AH (2008) Management of acute organophosphorus pesticide poisoning. Lancet 371:597–607. https://doi.org/10.1016/S0140-6736(07)61202-1 DOI

Eisenkraft A, Falk A, Finkelstein A (2013) The role of glutamate and the immune system in organophosphate-induced CNS damage. Neurotox Res 24:265–279. https://doi.org/10.1007/s12640-013-9388-1 DOI

Elbarrany UM, Mohamed MA, Ibrahim SF et al (2018) Clinical benefits of magnesium sulfate in management of acute organophosphorus poisoning. Saudi J Forensic Med Sci 1:30–34. https://doi.org/10.4103/sjfms.sjfms_5_18 DOI

El-Nahhal Y (2013) Human health risks: impact of pesticide application. J Environ Earth Sci 3:199–209

Falsafi SK, Deli A, Höger H et al (2012) Scopolamine administration modulates muscarinic, nicotinic and NMDA receptor systems. PLoS ONE. https://doi.org/10.1371/journal.pone.0032082 DOI

Faria M, Prats E, Padrós F et al (2017) Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication. Arch Toxicol 91:1891–1901. https://doi.org/10.1007/s00204-016-1851-3 DOI

Fauvelle F, Carpentier P, Dorandeu F et al (2012) Prediction of neuroprotective treatment efficiency using a HRMAS NMR-based statistical model of refractory status epilepticus on mouse: a metabolomic approach supported by histology. J Proteome Res 11:3782–3795. https://doi.org/10.1021/pr300291d DOI

Fidahic M, Jelicic Kadic A, Radic M, Puljak L (2017) Celecoxib for rheumatoid arthritis. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD012095.pub2 DOI

Figueiredo T, Aroniadou-Anderjaska V, Qashu F et al (2011) Neuroprotective efficacy of caramiphen against soman and mechanisms of its action. Br J Pharmacol 164:1495–1505. https://doi.org/10.1111/j.1476-5381.2011.01427.x DOI

Fischer D, Vander Leek TK, Ellis AK, Kim H (2018) Anaphylaxis. Allergy Asthma Clin Immunol off J Can Soc Allergy Clin Immunol 14:54. https://doi.org/10.1186/s13223-018-0283-4 DOI

Flannery BM, Bruun DA, Rowland DJ et al (2016) Persistent neuroinflammation and cognitive impairment in a rat model of acute diisopropylfluorophosphate intoxication. J Neuroinflammation 13:267. https://doi.org/10.1186/s12974-016-0744-y DOI

Floyd RA, Hensley K, Forster MJ et al (2002) Nitrones as neuroprotectants and antiaging drugs. Ann NY Acad Sci 959:321–329. https://doi.org/10.1111/j.1749-6632.2002.tb02103.x DOI

Fogal B, Hewett SJ (2008) Interleukin-1beta: a bridge between inflammation and excitotoxicity? J Neurochem 106:1–23. https://doi.org/10.1111/j.1471-4159.2008.05315.x DOI

Fradley RL, Guscott MR, Bull S et al (2007) Differential contribution of GABA(A) receptor subtypes to the anticonvulsant efficacy of benzodiazepine site ligands. J Psychopharmacol Oxf Engl 21:384–391. https://doi.org/10.1177/0269881106067255 DOI

Friguet B (2006) Oxidized protein degradation and repair in ageing and oxidative stress. FEBS Lett 580:2910–2916. https://doi.org/10.1016/j.febslet.2006.03.028 DOI

Fritschy J-M, Brünig I (2003) Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications. Pharmacol Ther 98:299–323. https://doi.org/10.1016/s0163-7258(03)00037-8 DOI

Gao ZG, Liu BY, Cui WY et al (1998) Anti-nicotinic properties of anticholinergic antiparkinson drugs. J Pharm Pharmacol 50:1299–1305. https://doi.org/10.1111/j.2042-7158.1998.tb03349.x DOI

Garcia GE, Campbell AJ, Olson J et al (2010) Novel oximes as blood–brain barrier penetrating cholinesterase reactivators. Chem Biol Interact 187:199–206. https://doi.org/10.1016/j.cbi.2010.02.033 DOI

Gerretsen P, Pollock BG (2011) Drugs with anticholinergic properties: a current perspective on use and safety. Expert Opin Drug Saf 10:751–765. https://doi.org/10.1517/14740338.2011.579899 DOI

Geyer BC, Evron T, Soreq H, Leket-Mor T (2009) Organophosphate intoxication: Molecular consequences, mechanisms and solutions. Handb Toxicol Chem Warf Agents. https://doi.org/10.1016/B978-012374484-5.00046-8 DOI

Ghiani CA, Serra M, Motzo C et al (1994) Chronic administration of an anticonvulsant dose of imidazenil fails to induce tolerance of GABAA receptor function in mice. Eur J Pharmacol 254:299–302. https://doi.org/10.1016/0014-2999(94)90470-7 DOI

Ghossein N, Kang M, Lakhkar AD (2021) Anticholinergic medications. In: StatPearls. StatPearls Publishing, Treasure Island (FL)

Giebelen IAJ, van Westerloo DJ, LaRosa GJ et al (2007) Local stimulation of alpha7 cholinergic receptors inhibits LPS-induced TNF-alpha release in the mouse lung. Shock Augusta Ga 28:700–703. https://doi.org/10.1097/shk.0b013e318054dd89 DOI

Giordano G, Afsharinejad Z, Guizzetti M et al (2007) Organophosphorus insecticides chlorpyrifos and diazinon and oxidative stress in neuronal cells in a genetic model of glutathione deficiency. Toxicol Appl Pharm 219:181–189. https://doi.org/10.1016/j.taap.2006.09.016 DOI

Giovannoni F, Quintana FJ (2020) The role of astrocytes in CNS inflammation. Trends Immunol 41:805–819. https://doi.org/10.1016/j.it.2020.07.007 DOI

Giusti P, Ducić I, Puia G et al (1993) Imidazenil: a new partial positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors. J Pharm Exp Ther 266:1018–1028

Glauser T, Shinnar S, Gloss D et al (2016) Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society. Epilepsy Curr 16:48–61. https://doi.org/10.5698/1535-7597-16.1.48 DOI

Goffe B, Cather JC (2003) Etanercept: an overview. J Am Acad Dermatol 49:S105-111. https://doi.org/10.1016/mjd.2003.554 DOI

Golime R, Palit M, Acharya J, Dubey DK (2018) Neuroprotective effects of galantamine on nerve agent-induced neuroglial and biochemical changes. Neurotox Res 33:738–748. https://doi.org/10.1007/s12640-017-9815-9 DOI

Goodkin HP, Kapur J (2009) The impact of diazepam’s discovery on the treatment and understanding of status epilepticus. Epilepsia 50:2011–2018. https://doi.org/10.1111/j.1528-1167.2009.02257.x DOI

Gore A, Neufeld-Cohen A, Egoz I et al (2021) Neuroprotection by delayed triple therapy following sarin nerve agent insult in the rat. Toxicol Appl Pharm 419:115519. https://doi.org/10.1016/j.taap.2021.115519 DOI

Gorecki L, Soukup O, Korabecny J (2022) Countermeasures in organophosphorus intoxication: pitfalls and prospects. Trends Pharm Sci. https://doi.org/10.1016/j.tips.2022.04.008 DOI

Gray SL, Soma KK, Duncan KA (2022) Steroid profiling in brain and plasma of adult zebra finches following traumatic brain injury. J Neuroendocrinol. https://doi.org/10.1111/jne.13151 DOI

Guignet M, Lein PJ (2018) Neuroinflammation in organophosphate-induced neurotoxicity. Advances in Neurotoxicology. Academic Press, Cambridge, pp 35–79

Guignet M, Lein PJ (2019) Chapter two—neuroinflammation in organophosphate-induced neurotoxicity. In: Aschner M, Costa LG (eds) Advances in neurotoxicology. Academic Press, pp 35–79

Gultekin F, Delibas N, Yasar S, Kilinc I (2001) In vivo changes in antioxidant systems and protective role of melatonin and a combination of vitamin C and vitamin E on oxidative damage in erythrocytes induced by chlorpyrifos-ethyl in rats. Arch Toxicol 75:88–96. https://doi.org/10.1007/s002040100219 DOI

Guo F, Yi L, Zhang W et al (2021) Association between Z drugs use and risk of cognitive impairment in middle-aged and older patients with chronic insomnia. Front Hum Neurosci 15:775144. https://doi.org/10.3389/fnhum.2021.775144 DOI

Gupta A, Agarwal R, Shukla GS (1999) Functional impairment of blood-brain barrier following pesticide exposure during early development in rats. Hum Exp Toxicol 18:174–179. https://doi.org/10.1177/096032719901800307 DOI

Gupta RC, Milatovic D, Dettbarn WD (2001) Depletion of energy metabolites following acetylcholinesterase inhibitor-induced status epilepticus: protection by antioxidants. Neurotoxicology 22:271–282. https://doi.org/10.1016/s0161-813x(01)00013-4 DOI

Halliwell GJMC (2015) Free radicals in biology and medicine, 5th edn. Oxford University Press, Oxford

Harris RE, Beebe-Donk J, Doss H, Burr Doss D (2005) Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). Oncol Rep 13:559–583

Harrison NL, Majewska MD, Harrington JW, Barker JL (1987) Structure-activity relationships for steroid interaction with the gamma-aminobutyric acidA receptor complex. J Pharm Exp Ther 241:346–353

Harrison PK, Sheridan RD, Green AC et al (2004) A guinea pig hippocampal slice model of organophosphate-induced seizure activity. J Pharm Exp Ther 310:678–686. https://doi.org/10.1124/jpet.104.065433 DOI

Haug KH, Myhrer T, Fonnum F (2007) The combination of donepezil and procyclidine protects against soman-induced seizures in rats. Toxicol Appl Pharm 220:156–163. https://doi.org/10.1016/j.taap.2006.12.023 DOI

Heath AJ. (2002) Atropine (International programme on chemical safety evaluation, 2002). http://www.inchem.org/documents/antidote/antidote/atropine.htm . Accessed 30 Apr 2021

Henderson RF, Barr EB, Blackwell WB et al (2002) Response of rats to low levels of sarin. Toxicol Appl Pharm 184:67–76

Hilmas CJ, Poole MJ, Finneran K et al (2009) Galantamine is a novel post-exposure therapeutic against lethal VX challenge. Toxicol Appl Pharm 240:166–173

Hirani A, Lee WH, Kang S et al (2007) Chlorpyrifos induces pro-inflammatory environment in discrete regions of mouse brain. FASEB J 21:A988–A988. https://doi.org/10.1096/fasebj.21.6.A988-b DOI

Hirbec H, Gaviria M, Vignon J (2001) Gacyclidine: a new neuroprotective agent acting at the N-methyl-D-aspartate receptor. CNS Drug Rev 7:172–198. https://doi.org/10.1111/j.1527-3458.2001.tb00194.x DOI

Holmuhamedov EL, Kholmoukhamedova GL, Baimuradov TB (1996) Non-cholinergic toxicity of organophosphates in mammals: interaction of ethaphos with mitochondrial functions. J Appl Toxicol JAT 16:475–481. https://doi.org/10.1002/(SICI)1099-1263(199611)16:6%3c475::AID-JAT376%3e3.0.CO;2-S DOI

Hou X, Yang F, Li A et al (2021) The Pin1-CaMKII-AMPA receptor axis regulates epileptic susceptibility. Cereb Cortex NYN 1991 31:3082–3095. https://doi.org/10.1093/cercor/bhab004 DOI

Hudkins RL, Stubbins JF, DeHave-Hudkins DL. (1993) Caramiphen, iodocaramiphen and nitrocaramiphen are potent, competitive, muscarinic M1 receptor-selective agents—PubMed. https://pubmed.ncbi.nlm.nih.gov/8449241/ . Accessed 14 May 2021

Ishizawa Y, Furuya K, Yamagishi S, Dohi S (1997) Non-GABAergic effects of midazolam, diazepam and flumazenil on voltage-dependent ion currents in NG108-15 cells. NeuroReport 8:2635–2638. https://doi.org/10.1097/00001756-199707280-00042 DOI

Jacob RA, Sotoudeh G (2002) Vitamin C function and status in chronic disease. Nutr Clin Care off Publ Tufts Univ 5:66–74. https://doi.org/10.1046/j.1523-5408.2002.00005.x DOI

Jamshidi F, Yazdanbakhsh A, Jamalian M et al (2018) Therapeutic effect of adding magnesium sulfate in treatment of organophosphorus poisoning. Open Access Maced J Med Sci 6:2051–2056. https://doi.org/10.3889/oamjms.2018.350 DOI

Jett DA, Spriggs SM (2020) Translational research on chemical nerve agents. Neurobiol Dis 133:104335. https://doi.org/10.1016/j.nbd.2018.11.020 DOI

Jha MK, Jo M, Kim J-H, Suk K (2019) Microglia-astrocyte crosstalk: an intimate molecular conversation. Neurosci Rev J Bringing Neurobiol Neurol Psychiatry 25:227–240. https://doi.org/10.1177/1073858418783959 DOI

Jiang J, Yang M-S, Quan Y et al (2015) Therapeutic window for cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus. Neurobiol Dis 76:126–136. https://doi.org/10.1016/j.nbd.2014.12.032 DOI

Johnson EA, Kan RK (2010) The acute phase response and soman-induced status epilepticus: temporal, regional and cellular changes in rat brain cytokine concentrations. J Neuroinflammation 7:40. https://doi.org/10.1186/1742-2094-7-40 DOI

Johnson EA, Dao TL, Guignet MA et al (2011) Increased expression of the chemokines CXCL1 and MIP-1α by resident brain cells precedes neutrophil infiltration in the brain following prolonged soman-induced status epilepticus in rats. J Neuroinflammation 8:41. https://doi.org/10.1186/1742-2094-8-41 DOI

Johnstone TBC, McCarren HS, Spampanato J et al (2019) Enaminone modulators of extrasynaptic α4β3δ γ-aminobutyric AcidA receptors reverse electrographic status epilepticus in the rat after acute organophosphorus poisoning. Front Pharmacol 10:560. https://doi.org/10.3389/fphar.2019.00560 DOI

Jokanović M (2009) Medical treatment of acute poisoning with organophosphorus and carbamate pesticides. Toxicol Lett 190:107–115. https://doi.org/10.1016/j.toxlet.2009.07.025 DOI

Jokanović M, Prostran M (2009) Pyridinium oximes as cholinesterase reactivators. Structure-activity relationship and efficacy in the treatment of poisoning with organophosphorus compounds. Curr Med Chem 16:2177–2188. https://doi.org/10.2174/092986709788612729 DOI

Jones DP, Sies H (2015) The redox code. Antioxid Redox Signal 23:734–746. https://doi.org/10.1089/ars.2015.6247 DOI

Joó F (1996) Endothelial cells of the brain and other organ systems: some similarities and differences. Prog Neurobiol 48:255–273. https://doi.org/10.1016/0301-0082(95)00046-1 DOI

Joosen MJA, Vester SM, Hamelink J et al (2016) Increasing nerve agent treatment efficacy by P-glycoprotein inhibition. Chem Biol Interact 259:115–121. https://doi.org/10.1016/j.cbi.2016.06.012 DOI

Jung YJ, Tweedie D, Scerba MT, Greig NH (2019) Neuroinflammation as a factor of neurodegenerative disease: thalidomide analogs as treatments. Front Cell Dev Biol 7:313. https://doi.org/10.3389/fcell.2019.00313 DOI

Kabir MT, Sufian MA, Uddin MS et al (2019) NMDA receptor antagonists: repositioning of memantine as a multitargeting agent for Alzheimer’s therapy. Curr Pharm Des 25:3506–3518. https://doi.org/10.2174/1381612825666191011102444 DOI

Kadriu B, Guidotti A, Costa E, Auta J (2009) Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage. Toxicology 256:164–174. https://doi.org/10.1016/j.tox.2008.11.021 DOI

Kadriu B, Gocel J, Larson J et al (2011a) Absence of tolerance to the anticonvulsant and neuroprotective effects of imidazenil against DFP-induced seizure and neuronal damage. Neuropharmacology 61:1463–1469. https://doi.org/10.1016/j.neuropharm.2011.08.043 DOI

Kadriu B, Guidotti A, Costa E et al (2011b) Acute imidazenil treatment after the onset of DFP-induced seizure is more effective and longer lasting than midazolam at preventing seizure activity and brain neuropathology. Toxicol Sci off J Soc Toxicol 120:136–145. https://doi.org/10.1093/toxsci/kfq356 DOI

Kalyanam B, Narayana S, Kamarthy P (2013) A rare neurological complication of acute organophosphorous poisoning. Toxicol Int 20:189–191. https://doi.org/10.4103/0971-6580.117270 DOI

Kassa J. (2006) Therapeutic and neuroprotective efficacy of pharmacological pretreatment and antidotal treatment of acute tabun or soman poisoning with the emphasis on pretreatment drug PANPAL. Arh Hig Rada Toksikol

Kassa J, Pohanka M, Timperley CM et al (2016) Evaluation of the benefit of the bispyridinium compound MB327 for the antidotal treatment of nerve agent-poisoned mice. Toxicol Mech Methods 26:334–339. https://doi.org/10.3109/15376516.2016.1162249 DOI

Katalan S, Lazar S, Brandeis R et al (2013) Magnesium sulfate treatment against sarin poisoning: dissociation between overt convulsions and recorded cortical seizure activity. Arch Toxicol 87:347–360. https://doi.org/10.1007/s00204-012-0916-1 DOI

Kaur S, Singh S, Chahal KS, Prakash A (2014) Potential pharmacological strategies for the improved treatment of organophosphate-induced neurotoxicity. Can J Physiol Pharm 92:893–911. https://doi.org/10.1139/cjpp-2014-0113 DOI

Kemp JA, Marshall GR, Wong EHF, Woodruff GN (1987) The affinities, potencies and efficacies of some benzodiazepine-receptor agonists, antagonists and inverse-agonists at rat hippocampal GABAA-receptors. Br J Pharm 91:601–608. https://doi.org/10.1111/j.1476-5381.1987.tb11253.x DOI

Kennedy KAM, Sandiford SDE, Skerjanc IS, Li SS-C (2012) Reactive oxygen species and the neuronal fate. Cell Mol Life Sci CMLS 69:215–221. https://doi.org/10.1007/s00018-011-0807-2 DOI

Ketchum JS, Sidell FR, Crowell EB et al (1973) Atropine, scopolamine, and ditran: comparative pharmacology and antagonists in man. Psychopharmacologia 28:121–145. https://doi.org/10.1007/BF00421398 DOI

Kim W-S, Cho Y, Kim J-C et al (2005) Protection by a transdermal patch containing physostigmine and procyclidine of soman poisoning in dogs. Eur J Pharmacol 525:135–142. https://doi.org/10.1016/j.ejphar.2005.09.052 DOI

Kirkland AE, Sarlo GL, Holton KF (2018) The role of magnesium in neurological disorders. Nutrients. https://doi.org/10.3390/nu10060730 DOI

Konar A, Gupta R, Shukla RK et al (2019) M1 muscarinic receptor is a key target of neuroprotection, neuroregeneration and memory recovery by i-Extract from Withania somnifera. Sci Rep 9:13990. https://doi.org/10.1038/s41598-019-48238-6 DOI

Koplovitz I, Schulz S (2010) Perspectives on the use of scopolamine as an adjunct treatment to enhance survival following organophosphorus nerve agent poisoning. Mil Med 175:878–882. https://doi.org/10.7205/MILMED-D-10-00089 DOI

Kosta P, Mehta AK, Sharma A et al (2013) Effect of piracetam and vitamin E on phosphamidon-induced impairment of memory and oxidative stress in rats. Drug Chem Toxicol. https://doi.org/10.3109/01480545.2011.649093 DOI

Koster R (1946) Synergisms and antagonisms between physostigmine and di-isopropyl fluorophosphate in cats. J Pharm Exp Ther 88(1):39–46

Kostrzewa RM (2017) Neurotoxins☆. In: Reference module in neuroscience and biobehavioral psychology. Elsevier, Amsterdam

Kovacic P (2003) Mechanism of organophosphates (nerve gases and pesticides) and antidotes: electron transfer and oxidative stress. Curr Med Chem 10:2705–2709. https://doi.org/10.2174/0929867033456314 DOI

Kovacic P, Somanathan R (2010) Clinical physiology and mechanism of dizocilpine (MK-801). Oxid Med Cell Longev 3:13–22

Kozhemyakin M, Rajasekaran K, Kapur J (2010) Central cholinesterase inhibition enhances glutamatergic synaptic transmission. J Neurophysiol 103:1748–1757. https://doi.org/10.1152/jn.00949.2009 DOI

Kraft AD, Harry GJ (2011) Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. Int J Environ Res Public Health 8:2980–3018. https://doi.org/10.3390/ijerph8072980 DOI

Kreft M, Zorec R (2008) Truth about a plant with many names. Nature 452:934–934. https://doi.org/10.1038/452934d DOI

Kuruba R, Wu X, Reddy DS (2018) Benzodiazepine-refractory status epilepticus, neuroinflammation, and interneuron neurodegeneration after acute organophosphate intoxication. Biochim Biophys Acta Mol Basis Dis 1864:2845–2858. https://doi.org/10.1016/j.bbadis.2018.05.016 DOI

Kurutas EB (2016) The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state. Nutr J 15:71. https://doi.org/10.1186/s12937-016-0186-5 DOI

Kutsuna S, Tsuruta R, Fujita M et al (2010) Cholinergic agonist physostigmine suppresses excessive superoxide anion radical generation in blood, oxidative stress, early inflammation, and endothelial injury in rats with forebrain ischemia/reperfusion. Brain Res 1313:242–249. https://doi.org/10.1016/j.brainres.2009.11.077 DOI

Kventsel I, Berkovitch M, Reiss A et al (2005) Scopolamine treatment for severe extra-pyramidal signs following organophosphate (chlorpyrifos) ingestion. Clin Toxicol Phila Pa 43:877–879. https://doi.org/10.1080/15563650500357636 DOI

Lallement G, Veyret J, Masqueliez C et al (1997) Efficacy of huperzine in preventing soman-induced seizures, neuropathological changes and lethality. Fundam Clin Pharm 11:387–394. https://doi.org/10.1111/j.1472-8206.1997.tb00200.x DOI

Lallement G, Baubichon D, Clarençon D et al (1999) Review of the value of gacyclidine (GK-11) as adjuvant medication to conventional treatments of organophosphate poisoning: primate experiments mimicking various scenarios of military or terrorist attack by soman. Neurotoxicology 20:675–684

Lallement G, Baille V, Baubichon D et al (2002) Review of the value of huperzine as pretreatment of organophosphate poisoning. Neurotoxicology 23:1–5. https://doi.org/10.1016/s0161-813x(02)00015-3 DOI

Lane M, Carter D, Pescrille JD et al (2020) Oral pretreatment with galantamine effectively mitigates the acute toxicity of a supra-lethal dose of soman in cynomolgus monkeys post-treated with conventional antidotes. J Pharm Exp Ther. https://doi.org/10.1124/jpet.120.265843 DOI

Laney J, Clark MG. (2018) FDA Approval of anti-seizure drug provides a new tool for protecting americans during a chemical attack. In: JPEO-CBRND. https://www.jpeocbrnd.osd.mil/Media/News/Article/2594007/fda-approval-of-anti-seizure-drug-provides-a-new-tool-for-protecting-americans/ . Accessed 21 Apr 2022

Lemaire-Hurtel A-S, Alvarez J-C (2014) Chapter 3—Drugs involved in drug-facilitated crime—pharmacological aspects. In: Kintz P (ed) Toxicological aspects of drug-facilitated crimes. Academic Press, Oxford, pp 47–91

Levy A, Chapman S, Cohen G et al (2004) Protection and inflammatory markers following exposure of guinea pigs to sarin vapour: comparative efficacy of three oximes. J Appl Toxicol JAT 24:501–504. https://doi.org/10.1002/jat.1008 DOI

Lewine JD, Weber W, Gigliotti A et al (2018) Addition of ketamine to standard-of-care countermeasures for acute organophosphate poisoning improves neurobiological outcomes. Neurotoxicology 69:37–46. https://doi.org/10.1016/j.neuro.2018.08.011 DOI

Li W, Ehrich M (2013) Transient alterations of the blood-brain barrier tight junction and receptor potential channel gene expression by chlorpyrifos. J Appl Toxicol JAT 33:1187–1191. https://doi.org/10.1002/jat.2762 DOI

Li P, Eaton MM, Steinbach JH, Akk G (2013) The benzodiazepine diazepam potentiates responses of α1β2γ2L γ-aminobutyric acid type a receptors activated by either γ-aminobutyric acid or allosteric agonists. Anesthesiology 118:1417–1425. https://doi.org/10.1097/ALN.0b013e318289bcd3 DOI

Li Y, Lein PJ, Ford GD et al (2015a) Neuregulin-1 inhibits neuroinflammatory responses in a rat model of organophosphate-nerve agent-induced delayed neuronal injury. J Neuroinflammation 12:64. https://doi.org/10.1186/s12974-015-0283-y DOI

Li Y, Lein PJ, Ford GD et al (2015b) Neuregulin-1 inhibits neuroinflammatory responses in a rat model of organophosphate-nerve agent-induced delayed neuronal injury. J Neuroinflammation 12:1–13

Li Q, Zhang J, Chen LZ et al (2018) New pentadienone oxime ester derivatives: synthesis and anti-inflammatory activity. J Enzyme Inhib Med Chem 33:130–138

Liang L-P, Pearson-Smith JN, Huang J et al (2018) Neuroprotective effects of AEOL10150 in a rat organophosphate model. Toxicol Sci off J Soc Toxicol 162:611–621. https://doi.org/10.1093/toxsci/kfx283 DOI

Liang L-P, Pearson-Smith JN, Huang J et al (2019) Neuroprotective effects of a catalytic antioxidant in a rat nerve agent model. Redox Biol 20:275–284. https://doi.org/10.1016/j.redox.2018.10.010 DOI

Lilienfeld S (2002) Galantamine–a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer’s disease. CNS Drug Rev 8:159–176. https://doi.org/10.1111/j.1527-3458.2002.tb00221.x DOI

Lim KL, Tay A, Nadarajah VD, Mitra NK (2011) The effect of consequent exposure of stress and dermal application of low doses of chlorpyrifos on the expression of glial fibrillary acidic protein in the hippocampus of adult mice. J Occup Med Toxicol Lond Engl 6:4. https://doi.org/10.1186/1745-6673-6-4 DOI

Lipp JA (1972) Effect of diazepam upon soman-induced seizure activity and convulsions. Electroencephalogr Clin Neurophysiol 32:557–560. https://doi.org/10.1016/0013-4694(72)90065-X DOI

Liu Z-H, Ma Y-F, Wu J-S et al (2010) Effect of cholinesterase inhibitor galanthamine on circulating tumor necrosis factor alpha in rats with lipopolysaccharide-induced peritonitis. Chin Med J (engl) 123:1727–1730

Liu C, Li Y, Lein PJ, Ford BD (2012) Spatiotemporal patterns of GFAP upregulation in rat brain following acute intoxication with diisopropylfluorophosphate (DFP). Curr Neurobiol 3:90–97

Liu C, Tang X, Zhang W et al (2019) 6-Bromoindirubin-3′-oxime suppresses LPS-induced inflammation via inhibition of the TLR4/NF-κB and TLR4/MAPK signaling pathways. Inflammation 42:2192–2204

Loane DJ, Kumar A, Stoica BA et al (2014) Progressive neurodegeneration after experimental brain trauma: association with chronic microglial activation. J Neuropathol Exp Neurol 73:14–29. https://doi.org/10.1097/NEN.0000000000000021 DOI

Lochner M, Thompson AJ (2016) The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT3 receptors. Neuropharmacology 108:220–228. https://doi.org/10.1016/j.neuropharm.2016.04.027 DOI

Lorke DE, Hasan MY, Nurulain SM et al (2011) Pretreatment for acute exposure to diisopropylfluorophosphate: in vivo efficacy of various acetylcholinesterase inhibitors. J Appl Toxicol JAT 31:515–523. https://doi.org/10.1002/jat.1589 DOI

Lotti M, Moretto A (2005) Organophosphate-induced delayed polyneuropathy. Toxicol Rev 24:37–49. https://doi.org/10.2165/00139709-200524010-00003 DOI

Lukaszewicz-Hussain A (2010) Role of oxidative stress in organophosphate insecticide toxicity–short review. Pestic Biochem Physiol 98:145–150. https://doi.org/10.1016/j.pestbp.2010.07.006 DOI

Lumley LA, Marrero-Rosado B, Rossetti F et al (2021) Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman-induced epileptogenesis and brain pathology in rats. Epilepsia Open 6:757–769. https://doi.org/10.1002/epi4.12552 DOI

MacDonald JF, Bartlett MC, Mody I et al (1991) Actions of ketamine, phencyclidine and MK-801 on NMDA receptor currents in cultured mouse hippocampal neurones. J Physiol 432:483–508. https://doi.org/10.1113/jphysiol.1991.sp018396 DOI

Marrero-Rosado B, de Furtado MA, Schultz CR et al (2018) Soman-induced status epilepticus, epileptogenesis, and neuropathology in carboxylesterase knockout mice treated with midazolam. Epilepsia 59:2206–2218. https://doi.org/10.1111/epi.14582 DOI

Massaad CA, Klann E (2011) Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid Redox Signal 14:2013–2054. https://doi.org/10.1089/ars.2010.3208 DOI

Mayhan WG (2002) Cellular mechanisms by which tumor necrosis factor-alpha produces disruption of the blood-brain barrier. Brain Res 927:144–152. https://doi.org/10.1016/s0006-8993(01)03348-0 DOI

McDonough JH, Shih T-M (1993) Pharmacological modulation of soman-induced seizures. Neurosci Biobehav Rev 17:203–215. https://doi.org/10.1016/S0149-7634(05)80151-4 DOI

McDonough JH, Shih T-M (1997) Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neurosci Biobehav Rev 21:559–579. https://doi.org/10.1016/S0149-7634(96)00050-4 DOI

McDonough JH, McLeod CG, Nipwoda MT (1987) Direct microinjection of soman or VX into the amygdala produces repetitive limbic convulsions and neuropathology. Brain Res 435:123–137. https://doi.org/10.1016/0006-8993(87)91593-9 DOI

McDonough JH, Shih TM, Adams N (1993) Forebrain areas sensitive to the convulsant effects of the anticholinesterase agent VX. Neurosci Abs 19:1630

McDonough JH, Zoeffel LD, McMonagle J et al (1999) Anticonvulsant treatment of nerve agent seizures: anticholinergics versus diazepam in soman-intoxicated guinea pigs. Epilepsy Res 38:1–14. https://doi.org/10.1016/S0920-1211(99)00060-1 DOI

McGrath M, Hoyt H, Pence A et al (2021) Selective actions of benzodiazepines at the transmembrane anaesthetic binding sites of the GABAA receptor: In vitro and in vivo studies. Br J Pharmacol 178:4842–4858. https://doi.org/10.1111/bph.15662 DOI

McLendon K, Preuss CV (2021) Atropine. In: StatPearls. StatPearls Publishing, Treasure Island (FL)

Mehta SK, Gowder SJT. (2015) Members of antioxidant machinery and their functions. IntechOpen

Mense SM, Sengupta A, Lan C et al (2006) The common insecticides cyfluthrin and chlorpyrifos alter the expression of a subset of genes with diverse functions in primary human astrocytes. Toxicol Sci off J Soc Toxicol 93:125–135. https://doi.org/10.1093/toxsci/kfl046 DOI

Mesiano S, DeFranco E, Muglia LJ (2015) Chapter 42—Parturition. In: Plant TM, Zeleznik AJ (eds) Knobil and Neill’s physiology of reproduction, 4th edn. Academic Press, San Diego, pp 1875–1925

Migirov A, Datta AR (2021) Physiology anticholinergic, reaction. In: StatPearls. StatPearls Publishing, Treasure Island (FL)

Milatovic D, Jokanović M (2009) Chapter 65—Pyridinium oximes as cholinesterase reactivators in the treatment of OP poisoning. In: Gupta RC (ed) Handbook of toxicology of chemical warfare agents. Academic Press, San Diego, pp 985–996

Milatovic D, Radic Z, Zivin M, Dettbarn WD (2000a) Atypical effect of some spin trapping agents: reversible inhibition of acetylcholinesterase. Free Radic Biol Med 28:597–603. https://doi.org/10.1016/s0891-5849(99)00270-1 DOI

Milatovic D, Zivin M, Hustedt E, Dettbarn W-D (2000b) Spin trapping agent phenyl-N-tert-butylnitrone prevents diisopropylphosphorofluoridate-induced excitotoxicity in skeletal muscle of the rat. Neurosci Lett 278:25–28. https://doi.org/10.1016/S0304-3940(99)00904-0 DOI

Milatovic D, Gupta RC, Aschner M (2006) Anticholinesterase toxicity and oxidative stress. Sci World J 6:295–310. https://doi.org/10.1100/tsw.2006.38 DOI

Miller SA, Blick DW, Kerenyi SZ, Murphy MR (1993) Efficacy of physostigmine as a pretreatment for organophosphate poisoning. Pharm Biochem Behav 44:343–347. https://doi.org/10.1016/0091-3057(93)90472-6 DOI

Miller SL, Aroniadou-Anderjaska V, Pidoplichko VI et al (2017) The M1 muscarinic receptor antagonist VU0255035 delays the development of status epilepticus after organophosphate exposure and prevents hyperexcitability in the basolateral amygdala. J Pharm Exp Ther 360:23–32. https://doi.org/10.1124/jpet.116.236125 DOI

Millis RM, Archer PW, Whittaker JA, Trouth CO (1988) The role of hypoxia in organophosphorus nerve agent intoxication. Neurotoxicology 9:273–285

Mirakhur RK (1979) Anticholinergic drugs. Br J Anaesth 51:671–679. https://doi.org/10.1093/bja/51.7.671 DOI

Miyajima T, Kotake Y (1995) Spin trapping agent, phenyl N-tert-butyl nitrone, inhibits induction of nitric oxide synthase in endotoxin-induced shock in mice. Biochem Biophys Res Commun 215:114–121. https://doi.org/10.1006/bbrc.1995.2440 DOI

Miyaki K, Nishiwaki Y, Maekawa K et al (2005) Effects of sarin on the nervous system of subway workers seven years after the Tokyo subway sarin attack. J Occup Health 47:299–304. https://doi.org/10.1539/joh.47.299 DOI

Mohassab AM, Hassan HA, Abdelhamid D et al (2017) Novel quinoline incorporating 1, 2, 4-triazole/oxime hybrids: synthesis, molecular docking, anti-inflammatory, COX inhibition, ulceroginicity and histopathological investigations. Bioorganic Chem 75:242–259

Momeni HR (2011) Role of calpain in apoptosis. Cell J Yakhteh 13:65–72

Morgan JE, Wilson SC, Travis BJ et al (2021) Refractory and super-refractory status epilepticus in nerve agent-poisoned rats following application of standard clinical treatment guidelines. Front Neurosci 15:732213. https://doi.org/10.3389/fnins.2021.732213 DOI

Moshiri M, Darchini-Maragheh E, Balali-Mood M (2012) Advances in toxicology and medical treatment of chemical warfare nerve agents. DARU J Pharm Sci 20:81. https://doi.org/10.1186/2008-2231-20-81 DOI

Mosser C-A, Baptista S, Arnoux I, Audinat E (2017) Microglia in CNS development: shaping the brain for the future. Prog Neurobiol 149–150:1–20. https://doi.org/10.1016/j.pneurobio.2017.01.002 DOI

Myhrer T, Aas P (2014) Choice of approaches in developing novel medical countermeasures for nerve agent poisoning. Neurotoxicology 44:27–38. https://doi.org/10.1016/j.neuro.2014.04.011 DOI

Myhrer T, Skymoen LR, Aas P (2003) Pharmacological agents, hippocampal eeg, and anticonvulsant effects on soman-induced seizures in rats. Neurotoxicology 24:357–367. https://doi.org/10.1016/S0161-813X(03)00040-8 DOI

Myhrer T, Andersen JM, Nguyen NHT, Aas P (2005) Soman-induced Convulsions in rats terminated with pharmacological agents after 45 min: neuropathology and cognitive performance. Neurotoxicology 26:39–48. https://doi.org/10.1016/j.neuro.2004.07.011 DOI

Myhrer T, Enger S, Aas P (2006) Pharmacological therapies against soman-induced seizures in rats 30 min following onset and anticonvulsant impact. Eur J Pharm 548:83–89. https://doi.org/10.1016/j.ejphar.2006.07.001 DOI

Myhrer T et al (2008) Anticonvulsant efficacy of drugs with cholinergic and/or glutamatergic antagonism microinfused into area tempestas of rats exposed to soman. Neurochem Res 33:348–354. https://doi.org/10.1007/s11064-007-9429-3 DOI

Naylor DE, Liu H, Niquet J, Wasterlain CG (2013) Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus. Neurobiol Dis 54:225–238. https://doi.org/10.1016/j.nbd.2012.12.015 DOI

Neligan et al (2019) Epilepticus in high-income countries over time. JAMA Neurol 76:897–905. https://doi.org/10.1001/jamaneurol.2019.1268 DOI

Neligan A, Rajakulendran S, Walker MC (2021) Advances in the management of generalized convulsive status epilepticus: what have we learned? Brain 144:1336–1341. https://doi.org/10.1093/brain/awab049 DOI

Newball HH, Donlon MA, Procell LR et al (1986) Organophosphate-induced histamine release from mast cells. J Pharm Exp Ther 238:839–845

Newmark J (2007) Nerve agents. Neurologist 13:20–32. https://doi.org/10.1097/01.nrl.0000252923.04894.53 DOI

Newmark J (2019) Therapy for acute nerve agent poisoning: an update. Neurol Clin Pract. https://doi.org/10.1212/CPJ.0000000000000641 DOI

Niessen KV, Seeger T, Rappenglück S et al (2018) In vitro pharmacological characterization of the bispyridinium non-oxime compound MB327 and its 2- and 3-regioisomers. Toxicol Lett 293:190–197. https://doi.org/10.1016/j.toxlet.2017.10.009 DOI

Nikolaev MV, Magazanik LG, Tikhonov DB (2012) Influence of external magnesium ions on the NMDA receptor channel block by different types of organic cations. Neuropharmacology 62:2078–2085. https://doi.org/10.1016/j.neuropharm.2011.12.029 DOI

Niquet J, Lumley L, Baldwin R et al (2020) Rational polytherapy in the treatment of cholinergic seizures. Neurobiol Dis 133:104537. https://doi.org/10.1016/j.nbd.2019.104537 DOI

Ojha S, Sharma C, Nurulain SM (2014) Antihistamines: promising antidotes of organophosphorus poisoninG. Mil Med Sci Lett 83:97–103. https://doi.org/10.31482/mmsl.2014.019 DOI

Olivares D, Deshpande VK, Shi Y et al (2012) N-methyl D-aspartate (NMDA) receptor antagonists and memantine treatment for alzheimer’s disease, vascular dementia and Parkinson’s disease. Curr Alzheimer Res 9:746–758

Oncu M, Gultekin F, Karaöz E et al (2002) Nephrotoxicity in rats induced by chlorpryfos-ethyl and ameliorating effects of antioxidants. Hum Exp Toxicol 21:223–230. https://doi.org/10.1191/0960327102ht225oa DOI

Owunari GU, Chika IJ, Owunari GU, Chika IJ (2021) Effect of chlorpheniramine on acute dichlorvos poisoning in wistar rats. GSC Biol Pharm Sci 14:154–160. https://doi.org/10.30574/gscbps.2021.14.1.0024 DOI

Ozawa S, Kamiya H, Tsuzuki K (1998) Glutamate receptors in the mammalian central nervous system. Prog Neurobiol 54:581–618. https://doi.org/10.1016/s0301-0082(97)00085-3 DOI

Palazón J, Navarro-Ocaña A, Hernandez-Vazquez L, Mirjalili MH (2008) Application of metabolic engineering to the production of scopolamine. Mol Basel Switz 13:1722–1742. https://doi.org/10.3390/molecules13081722 DOI

Park K-K, Ko D-H, You Z et al (2006) In vitro anti-inflammatory activities of new steroidal antedrugs:[16α, 17α-d] Isoxazoline and [16α, 17α-d]-3′-hydroxy-iminoformyl isoxazoline derivatives of prednisolone and 9α-fluoroprednisolone. Steroids 71:183–188

Parran DK, Magnin G, Li W et al (2005) Chlorpyrifos alters functional integrity and structure of an in vitro BBB model: co-cultures of bovine endothelial cells and neonatal rat astrocytes. Neurotoxicology 26:77–88. https://doi.org/10.1016/j.neuro.2004.07.003 DOI

Patel M (2016) Targeting oxidative stress in central nervous system disorders. Trends Pharm Sci 37:768–778. https://doi.org/10.1016/j.tips.2016.06.007 DOI

Patocka J, Honegr J, Soukup O (2015) Gulf war syndrome–a syndrome or not? Toxin Rev 34:43–52. https://doi.org/10.3109/15569543.2014.994131 DOI

Pavlov VA, Tracey KJ (2005) The cholinergic anti-inflammatory pathway. Brain Behav Immun 19:493–499. https://doi.org/10.1016/j.bbi.2005.03.015 DOI

Pavlov V et al. (2007). The anti-inflammatory efficacy of galantamine is dependent on the integrity of the cholinergic anti-inflammatory pathway. In: Shock. 530 Walnut St, Philadelphia, PA 19106–3621 USA: Lippincott Williams & Wilkins. p. 23–23. Accessed 28 Sep 2021

Pazdernik T, Emerson M, Cross R et al (2001) Soman-induced seizures: limbic activity, oxidative stress and neuroprotective proteins. J Appl Toxicol. https://doi.org/10.1002/JAT.818 DOI

Pearson JN, Rowley S, Liang L-P et al (2015) Reactive oxygen species mediate cognitive deficits in experimental temporal lobe epilepsy. Neurobiol Dis 82:289–297. https://doi.org/10.1016/j.nbd.2015.07.005 DOI

Pearson-Smith JN, Patel M (2020) Antioxidant drug therapy as a neuroprotective countermeasure of nerve agent toxicity. Neurobiol Dis 133:104457. https://doi.org/10.1016/j.nbd.2019.04.013 DOI

Pearson-Smith JN, Liang L-P, Rowley SD et al (2017) Oxidative stress contributes to status epilepticus associated mortality. Neurochem Res 42:2024–2032. https://doi.org/10.1007/s11064-017-2273-1 DOI

Peña-Llopis S (2005) Antioxidants as potentially safe antidotes for organophosphorus poisoning. Curr Enzyme Inhib 1:147–156. https://doi.org/10.2174/1573408054022243 DOI

Peña-Llopis S, Ferrando MD, Peña JB (2003) Fish tolerance to organophosphate-induced oxidative stress is dependent on the glutathione metabolism and enhanced by N-acetylcysteine. Aquat Toxicol Amst Neth 65:337–360. https://doi.org/10.1016/s0166-445x(03)00148-6 DOI

Petras JM (1994) Neurology and neuropathology of soman-induced brain injury: an overview. J Exp Anal Behav 61:319–329. https://doi.org/10.1901/jeab.1994.61-319 DOI

Petroianu G, Toomes LM, Petroianu A et al (1998) Control of blood pressure, heart rate and haematocrit during high-dose intravenous paraoxon exposure in mini pigs. J Appl Toxicol JAT 18:293–298. https://doi.org/10.1002/(sici)1099-1263(199807/08)18:4%3c293::aid-jat509%3e3.0.co;2-p DOI

Philippens I, Jongsma M, Joosen M et al. (2007) Prophylaxis against nerve agent toxicity: physiological, behavioral, and neuroprotection of current and novel treatments. In: InHFM-149 symposium defense against the effects of chemical hazards: toxicology, diagnosis and medical countermeasures. Edinburgh, Scotland. pp 8–10

Pibiri F, Kozikowski AP, Pinna G et al (2008) The combination of huperzine A and imidazenil is an effective strategy to prevent diisopropyl fluorophosphate toxicity in mice. Proc Natl Acad Sci USA 105:14169–14174. https://doi.org/10.1073/pnas.0807172105 DOI

Pohanka M (2014) Inhibitors of acetylcholinesterase and butyrylcholinesterase meet immunity. Int J Mol Sci 15:9809–9825. https://doi.org/10.3390/ijms15069809 DOI

Pohanka M, Musilek K, Kuca K (2009) Progress of biosensors based on cholinesterase inhibition. Curr Med Chem 16:1790–1798. https://doi.org/10.2174/092986709788186129 DOI

Pollak Y, Gilboa A, Ben-Menachem O et al (2005) Acetylcholinesterase inhibitors reduce brain and blood interleukin-1beta production. Ann Neurol 57:741–745. https://doi.org/10.1002/ana.20454 DOI

Price ME, Whitmore CL, Tattersall JEH et al (2018) Efficacy of the antinicotinic compound MB327 against soman poisoning—importance of experimental end point. Toxicol Lett 293:167–171. https://doi.org/10.1016/j.toxlet.2017.11.006 DOI

Rambabu L, Megson IL, Eddleston M (2020) Does oxidative stress contribute to toxicity in acute organophosphorus poisoning? A systematic review of the evidence. Clin Toxicol Phila Pa 58:437–452. https://doi.org/10.1080/15563650.2019.1693589 DOI

Ramírez BG, Blázquez C, Gómez del Pulgar T et al (2005) Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci off J Soc Neurosci 25:1904–1913. https://doi.org/10.1523/JNEUROSCI.4540-04.2005 DOI

Raveh L, Brandeis R, Gilat E et al (2003) Anticholinergic and antiglutamatergic agents protect against soman-induced brain damage and cognitive dysfunction. Toxicol Sci 75:108–116. https://doi.org/10.1093/toxsci/kfg166 DOI

Raveh L, Rabinovitz I, Gilat E et al (2008) Efficacy of antidotal treatment against sarin poisoning: the superiority of benactyzine and caramiphen. Toxicol Appl Pharm 227:155–162. https://doi.org/10.1016/j.taap.2007.10.020 DOI

Raveh L, Eisenkraft A, Weissman BA (2014) Caramiphen edisylate: an optimal antidote against organophosphate poisoning. Toxicology 325:115–124. https://doi.org/10.1016/j.tox.2014.09.005 DOI

Reddy SD, Reddy DS (2015) Midazolam as an anticonvulsant antidote for organophosphate intoxication–a pharmacotherapeutic appraisal. Epilepsia 56:813–821. https://doi.org/10.1111/epi.12989 DOI

Reji KK, Mathew V, Zachariah A et al (2016) Extrapyramidal effects of acute organophosphate poisoning. Clin Toxicol Phila Pa 54:259–265. https://doi.org/10.3109/15563650.2015.1126841 DOI

Ricaurte GA, Langston JW, McCANN UD (2008) Chapter 38—Neuropsychiatric complications of substance abuse. In: Aminoff MJ (ed) Neurology and general medicine, 4th edn. Churchill Livingstone, Philadelphia, pp 735–747

Richards MH (1991) Pharmacology and second messenger interactions of cloned muscarinic receptors. Biochem Pharm 42:1645–1653. https://doi.org/10.1016/0006-2952(91)90498-T DOI

Richardson RJ, Hein ND, Wijeyesakere SJ et al (2013) Neuropathy target esterase (NTE): overview and future. Chem Biol Interact 203:238–244. https://doi.org/10.1016/j.cbi.2012.10.024 DOI

Rodgers K, Xiong S (1997) Effect of acute administration of malathion by oral and dermal routes on serum histamine levels. Int J Immunopharmacol 19:437–441. https://doi.org/10.1016/S0192-0561(97)00098-2 DOI

Rohlman DS, Anger WK, Lein PJ (2011) Correlating neurobehavioral performance with biomarkers of organophosphorous pesticide exposure. Neurotoxicology 32:268–276. https://doi.org/10.1016/j.neuro.2010.12.008 DOI

Rojas A, Ganesh T, Lelutiu N et al (2015) Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus. Neuropharmacology 93:15–27. https://doi.org/10.1016/j.neuropharm.2015.01.017 DOI

Rojas A, McCarren HS, Wang J et al (2021) Comparison of neuropathology in rats following status epilepticus induced by diisopropylfluorophosphate and soman. Neurotoxicology 83:14–27. https://doi.org/10.1016/j.neuro.2020.12.010 DOI

Rosas-Ballina M, Goldstein RS, Gallowitsch-Puerta M et al (2009) The selective alpha7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE. Mol Med Camb Mass 15:195–202. https://doi.org/10.2119/molmed.2009.00039 DOI

Rosati A, De Masi S, Guerrini R (2018) Ketamine for refractory status epilepticus: a systematic review. CNS Drugs 32:997–1009. https://doi.org/10.1007/s40263-018-0569-6 DOI

Rump S, Kowalczyk M, Antkowiak O et al. (2001) Use and risks of anticonvulsant therapy in nerve agents poisonings in combat conditions. Vojen Zdr LISTY 4

Sánchez-Santed F, Colomina MT, Herrero Hernández E (2016) Organophosphate pesticide exposure and neurodegeneration. Cortex J Devoted Study Nerv Syst Behav 74:417–426. https://doi.org/10.1016/j.cortex.2015.10.003 DOI

Scheffel C, Niessen KV, Rappenglück S et al (2018) Counteracting desensitization of human α7-nicotinic acetylcholine receptors with bispyridinium compounds as an approach against organophosphorus poisoning. Toxicol Lett 293:149–156. https://doi.org/10.1016/j.toxlet.2017.12.005 DOI

Schmeller T, Sporer F, Sauerwein M, Wink M (1995) Binding of tropane alkaloids to nicotinic and muscarinic acetylcholine receptors. Pharm 50:493–495

Schultz MK, Wright LKM, de Araujo FM et al (2014) Caramiphen edisylate as adjunct to standard therapy attenuates soman-induced seizures and cognitive deficits in rats. Neurotoxicol Teratol 44:89–104. https://doi.org/10.1016/j.ntt.2014.06.002 DOI

Seeger T, Eichhorn M, Lindner M et al (2012) Restoration of soman-blocked neuromuscular transmission in human and rat muscle by the bispyridinium non-oxime MB327 in vitro. Toxicology 294:80–84. https://doi.org/10.1016/j.tox.2012.02.002 DOI

Sharma Y, Bashir S, Irshad M et al (2005) Effects of acute dimethoate administration on antioxidant status of liver and brain of experimental rats. Toxicology 206:49–57. https://doi.org/10.1016/j.tox.2004.06.062 DOI

Sharma AK, Bhattacharya SK, Khanna N et al (2011) Effect of progesterone on phosphamidon-induced impairment of memory and oxidative stress in rats. Hum Exp Toxicol 30:1626–1634. https://doi.org/10.1177/0960327110396522 DOI

Sheridan RD, Smith AP, Turner SR, Tattersall JEH (2005) nicotinic antagonists in the treatment of nerve agent intoxication. J R Soc Med 98:114–115. https://doi.org/10.1177/014107680509800307 DOI

Shih TM, Koviak TA, Capacio BR (1991) Anticonvulsants for poisoning by the organophosphorus compound soman: pharmacological mechanisms. Neurosci Biobehav Rev 15:349–362. https://doi.org/10.1016/s0149-7634(05)80028-4 DOI

Sigalapalli DK, Rangaswamy R, Tangellamudi ND (2020) Novel huperzine A based NMDA antagonists: insights from molecular docking, ADME/T and molecular dynamics simulation studies. RSC Adv 10:25446–25455. https://doi.org/10.1039/D0RA00722F DOI

Skovira JW, McDonough JH, Shih T-M (2010) Protection against sarin-induced seizures in rats by direct brain microinjection of Scopolamine, Midazolam or MK-801. J Mol Neurosci 40:56–62. https://doi.org/10.1007/s12031-009-9253-0 DOI

Sodhi S, Sharma A, Brar RS (2006) A protective effect of vitamin E and selenium in ameliorating the immunotoxicity of malathion in chicks. Vet Res Commun 30:935–942. https://doi.org/10.1007/s11259-006-2503-5 DOI

Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647. https://doi.org/10.1016/j.tins.2009.08.002 DOI

Sofroniew MV (2015) Astrogliosis. Cold Spring Harb Perspect Biol 7:a020420. https://doi.org/10.1101/cshperspect.a020420 DOI

Somani SM, Dube SN (1989) Physostigmine, an overview as pretreatment drug for organophosphate intoxication. Physostigmine Overv Pretreat Drug Organophosphate Intox 27:367–387

Song YJ (2020) Transdermal patch containing physostigmine and procyclidine protects rhesus monkeys against VX intoxication. bioRxiv. https://doi.org/10.1101/2020.10.16.343434 DOI

Song X, Pope C, Murthy R et al (2004) Interactive effects of paraoxon and pyridostigmine on blood-brain barrier integrity and cholinergic toxicity. Toxicol Sci off J Soc Toxicol 78:241–247. https://doi.org/10.1093/toxsci/kfh076 DOI

Soukup O, Jun D, Tobin G, Kuca K (2013) The summary on non-reactivation cholinergic properties of oxime reactivators: the interaction with muscarinic and nicotinic receptors. Arch Toxicol 87:711–719. https://doi.org/10.1007/s00204-012-0977-1 DOI

Spradling KD, Lumley LA, Robison CL et al (2011a) Transcriptional responses of the nerve agent-sensitive brain regions amygdala, hippocampus, piriform cortex, septum, and thalamus following exposure to the organophosphonate anticholinesterase sarin. J Neuroinflammation 8:84. https://doi.org/10.1186/1742-2094-8-84 DOI

Spradling KD, Lumley LA, Robison CL et al (2011b) Transcriptional analysis of rat piriform cortex following exposure to the organophosphonate anticholinesterase sarin and induction of seizures. J Neuroinflammation 8:83. https://doi.org/10.1186/1742-2094-8-83 DOI

Steindl D, Boehmerle W, Körner R et al (2021) Novichok nerve agent poisoning. Lancet Lond Engl 397:249–252. https://doi.org/10.1016/S0140-6736(20)32644-1 DOI

Stevenson M, Archer R, Tosh J et al (2016) Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with disease-modifying antirheumatic drugs and after the failure of conventional disease-modifying antirheumatic drugs only: systematic review and economic evaluation. Health Technol Assess Winch Engl 20:1–610. https://doi.org/10.3310/hta20350 DOI

Stojiljković MP, Jokanović M, Lončar-Stojiljković D, Škrbić R (2020) Chapter 65—Prophylactic and therapeutic measures in nerve agents poisonings. In: Gupta RC (ed) Handbook of toxicology of chemical warfare agents, 3rd edn. Academic Press, Boston, pp 1103–1119

Sugimoto H, Ogura H, Arai Y et al (2002) Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor. Jpn J Pharmacol 89:7–20. https://doi.org/10.1254/jjp.89.7 DOI

Sugimoto H, Matsumoto S, Tachibana M et al (2011) Establishment of in vitro P-glycoprotein inhibition assay and its exclusion criteria to assess the risk of drug-drug interaction at the drug discovery stage. J Pharm Sci 100:4013–4023. https://doi.org/10.1002/jps.22652 DOI

Sun L, Zhang G, Zhang X et al (2012) Combined administration of anisodamine and neostigmine produces anti-shock effects: involvement of α7 nicotinic acetylcholine receptors. Acta Pharm Sin 33:761–766. https://doi.org/10.1038/aps.2012.26 DOI

Supasai S, González EA, Rowland DJ et al (2020) Acute administration of diazepam or midazolam minimally alters long-term neuropathological effects in the rat brain following acute intoxication with diisopropylfluorophosphate. Eur J Pharm 886:173538. https://doi.org/10.1016/j.ejphar.2020.173538 DOI

Svensson I, Waara L, Johansson L et al (2001) Soman-induced interleukin-1 beta mRNA and protein in rat brain. Neurotoxicology 22:355–362. https://doi.org/10.1016/s0161-813x(01)00022-5 DOI

Svensson I, Waara L, Cassel G (2005) Effects of HI 6, diazepam and atropine on soman-induced IL-1 beta protein in rat brain. Neurotoxicology 26:173–181. https://doi.org/10.1016/j.neuro.2004.11.004 DOI

Takada-Takatori Y, Kume T, Sugimoto M et al (2006) Acetylcholinesterase inhibitors used in treatment of Alzheimer’s disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology 51:474–486. https://doi.org/10.1016/j.neuropharm.2006.04.007 DOI

Takata K, Kitamura Y, Saeki M et al (2010) Galantamine-induced amyloid-β clearance mediated via stimulation of microglial nicotinic acetylcholine receptors. J Biol Chem 285:40180–40191. https://doi.org/10.1074/jbc.M110.142356 DOI

Tao Y, Li L, Jiang B et al (2016) Cannabinoid receptor-2 stimulation suppresses neuroinflammation by regulating microglial M1/M2 polarization through the cAMP/PKA pathway in an experimental GMH rat model. Brain Behav Immun 58:118–129. https://doi.org/10.1016/j.bbi.2016.05.020 DOI

Tashma Z, Raveh L, Liani H et al (2001) Bretazenil, a benzodiazepine receptor partial agonist, as an adjunct in the prophylactic treatment of OP poisoning. J Appl Toxicol JAT 21(Suppl 1):S115-119. https://doi.org/10.1002/jat.810 DOI

Tayyaba K, Hasan M (1985) Vitamin E protects against metasystox-induced adverse effect on lipid metabolism in the rat brain and spinal cord. Acta Pharm Toxicol (copenh) 57:190–196. https://doi.org/10.1111/bcpt.1985.57.3.190 DOI

Thiel VE, Audus KL (2001) Nitric oxide and blood-brain barrier integrity. Antioxid Redox Signal 3:273–278. https://doi.org/10.1089/152308601300185223 DOI

Tocco G, Freire-Moar J, Schreiber SS et al (1997) Maturational regulation and regional induction of cyclooxygenase-2 in rat brain: implications for Alzheimer’s disease. Exp Neurol 144:339–349. https://doi.org/10.1006/exnr.1997.6429 DOI

Tracey KJ (2002) The inflammatory reflex. Nature 420:853–859. https://doi.org/10.1038/nature01321 DOI

Traynelis SF, Wollmuth LP, McBain CJ et al (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62:405–496. https://doi.org/10.1124/pr.109.002451 DOI

Tyagi E, Agrawal R, Nath C, Shukla R (2010) Cholinergic protection via alpha7 nicotinic acetylcholine receptors and PI3K-Akt pathway in LPS-induced neuroinflammation. Neurochem Int 56:135–142. https://doi.org/10.1016/j.neuint.2009.09.011 DOI

Ullrich SF, Hagels H, Kayser O (2017) Scopolamine: a journey from the field to clinics. Phytochem Rev 16:333–353. https://doi.org/10.1007/s11101-016-9477-x DOI

van Helden HP, Busker RW, Melchers BP, Bruijnzeel PL (1996) Pharmacological effects of oximes: how relevant are they? Arch Toxicol 70:779–786

van Steveninck AL, Gieschke R, Schoemaker RC et al (1996) Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol. Br J Clin Pharm 41:565–573. https://doi.org/10.1046/j.1365-2125.1996.38514.x DOI

Váňová N, Pejchal J, Herman D et al (2018) Oxidative stress in organophosphate poisoning: role of standard antidotal therapy. J Appl Toxicol. https://doi.org/10.1002/jat.3605 DOI

Veleiro AS, Burton G (2009) Structure-activity relationships of neuroactive steroids acting on the GABAA receptor. Curr Med Chem 16:455–472. https://doi.org/10.2174/092986709787315522 DOI

Verma RS, Srivastava N (2001) Chlorpyrifos induced alterations in levels of thiobarbituric acid reactive substances and glutathione in rat brain. Indian J Exp Biol 39:174–177

Vezzani A, Aronica E, Mazarati A, Pittman QJ (2013) Epilepsy and brain inflammation. Exp Neurol 244:11–21. https://doi.org/10.1016/j.expneurol.2011.09.033 DOI

Vijayakumar HN, Kannan S, Tejasvi C et al (2017) Study of effect of magnesium sulphate in management of acute organophosphorous pesticide poisoning. Anesth Essays Res 11:192–196. https://doi.org/10.4103/0259-1162.194585 DOI

Viviani B, Boraso M, Marchetti N, Marinovich M (2014) Perspectives on neuroinflammation and excitotoxicity: a neurotoxic conspiracy? Neurotoxicology 43:10–20. https://doi.org/10.1016/j.neuro.2014.03.004 DOI

Voorhees JR, Rohlman DS, Lein PJ, Pieper AA (2017) Neurotoxicity in preclinical models of occupational exposure to organophosphorus compounds. Front Neurosci. https://doi.org/10.3389/fnins.2016.00590 DOI

Wang M (2011) Neurosteroids and GABA-A receptor function. Front Endocrinol 2:44. https://doi.org/10.3389/fendo.2011.00044 DOI

Wang Y, Qin Z-H (2010) Molecular and cellular mechanisms of excitotoxic neuronal death. Apoptosis Int J Program Cell Death 15:1382–1402. https://doi.org/10.1007/s10495-010-0481-0 DOI

Wang Y-A, Zhou W-X, Li J et al (2005) Anticonvulsant effects of phencynonate hydrochloride and other anticholinergic drugs in soman poisoning: Neurochemical mechanisms. Life Sci 78:210–223. https://doi.org/10.1016/j.lfs.2005.04.071 DOI

Wani WY, Gudup S, Sunkaria A et al (2011) Protective efficacy of mitochondrial targeted antioxidant MitoQ against dichlorvos induced oxidative stress and cell death in rat brain. Neuropharmacology 61:1193–1201. https://doi.org/10.1016/j.neuropharm.2011.07.008 DOI

Webster L, McKenzie G, Moriarty H (2002) Organophosphate-based pesticides and genetic damage implicated in bladder cancer. Cancer Genet Cytogenet. https://doi.org/10.1016/S0165-4608(01)00576-3 DOI

Weissman BA, Raveh L (2008) Therapy against organophosphate poisoning: the importance of anticholinergic drugs with antiglutamatergic properties. Toxicol Appl Pharm 232:351–358. https://doi.org/10.1016/j.taap.2008.07.005 DOI

Wetherell J, Price M, Mumford H et al (2007) Development of next generation medical countermeasures to nerve agent poisoning. Toxicology 233:120–127. https://doi.org/10.1016/j.tox.2006.07.028 DOI

White RP, Rinaldi F, Himwich HE (1956) Central and peripheral nervous effects of atropine sulfate and mepiperphenidol bromide (darstine) on human subjects. J Appl Physiol 8:635–642. https://doi.org/10.1152/jappl.1956.8.6.635 DOI

Williams AJ, Berti R, Yao C et al (2003) Central neuro-inflammatory gene response following soman exposure in the rat. Neurosci Lett 349:147–150. https://doi.org/10.1016/s0304-3940(03)00818-8 DOI

Wink DA, Mitchell JB (1998) Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med 25:434–456. https://doi.org/10.1016/s0891-5849(98)00092-6 DOI

Wong-Ekkabut J, Xu Z, Triampo W et al (2007) Effect of lipid peroxidation on the properties of lipid bilayers: a molecular dynamics study. Biophys J 93:4225–4236. https://doi.org/10.1529/biophysj.107.112565 DOI

Worek F, Jenner J, Thiermann H (2016) Chemical warfare toxicology: management of poisoning, vol 2. Royal Society of Chemistry, London

Xu H-Y, Sun Y-J, Sun Y-Y et al (2021) Lapatinib alleviates TOCP-induced axonal damage in the spinal cord of mouse. Neuropharmacology 189:108535. https://doi.org/10.1016/j.neuropharm.2021.108535 DOI

Yanagisawa N, Morita H, Nakajima T (2006) Sarin experiences in Japan: acute toxicity and long-term effects. J Neurol Sci 249:76–85. https://doi.org/10.1016/j.jns.2006.06.007 DOI

Zaja-Milatovic S, Gupta RC, Aschner M, Milatovic D (2009) Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist. Toxicol Appl Pharm 240:124–131. https://doi.org/10.1016/j.taap.2009.07.006 DOI

Zeferino-Díaz R, Olivera-Castillo L, Dávalos A et al (2019) 22-Oxocholestane oximes as potential anti-inflammatory drug candidates. Eur J Med Chem 168:78–86

Zepeda-Arce R, Rojas A, Benitez-Trinidad A et al (2017) Oxidative stress and genetic damage among workers exposed primarily to organophosphate and pyrethroid pesticides. Environ Toxicol. https://doi.org/10.1002/tox.22398 DOI

Zhang J-M, An J (2007) Cytokines, inflammation and pain. Int Anesthesiol Clin 45:27–37. https://doi.org/10.1097/AIA.0b013e318034194e DOI

Zhang X, Zhou W, Zhang Y (2018) Improvements in SOD mimic AEOL-10150, a potent broad-spectrum antioxidant. Mil Med Res 5:30. https://doi.org/10.1186/s40779-018-0176-3 DOI

Zimmer LA, Ennis M, Shipley MT (1997) Soman-induced seizures rapidly activate astrocytes and microglia in discrete brain regions. J Comp Neurol 378:482–492. https://doi.org/10.1002/(sici)1096-9861(19970224)378:4%3c482::aid-cne4%3e3.0.co;2-z DOI

Zwart R, Vijverberg HP (1997) Potentiation and inhibition of neuronal nicotinic receptors by atropine: competitive and noncompetitive effects. Mol Pharm 52(5):886–895. https://doi.org/10.1124/mol.52.5.886 DOI

A-series agent A-234: initial in vitro and in vivo characterization

Strategies for enhanced bioavailability of oxime reactivators in the central nervous system

A-agents, misleadingly known as "Novichoks": a narrative review

Differentiated SH-SY5Y neuroblastoma cells as a model for evaluation of nerve agent-associated neurotoxicity