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The M1 Muscarinic Receptor Antagonist VU0255035 Delays The 1521-0103/360/1/23–32$25.00 http://dx.doi.org/10.1124/jpet.116.236125 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 360:23–32, January 2017 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics The M1 Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala Steven L. Miller, Vassiliki Aroniadou-Anderjaska, Volodymyr I. Pidoplichko, Taiza H. Figueiredo, James P. Apland, Jishnu K. S. Krishnan, and Maria F. M. Braga Departments of Anatomy, Physiology, and Genetics (S.L.M., V.A.-A., V.I.P., T.H.F., J.K.S.K., M.F.M.B.) and Psychiatry (V.A.-A., M.F.M.B.), and Program in Neuroscience (S.L.M., V.A.-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services Downloaded from University of the Health Sciences, Bethesda, Maryland; and Neurotoxicology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland (J.P.A.) Received June 22, 2016; accepted October 27, 2016 ABSTRACT jpet.aspetjournals.org Exposure to organophosphorus toxins induces seizures that key role in seizure initiation after nerve agent exposure), progress to status epilepticus (SE), which can cause brain damage VU0255035 blocked the effects produced by bath application or death. Seizures are generated by hyperstimulation of musca- of paraoxon—namely, a brief barrage of spontaneous in- rinic receptors, subsequent to inhibition of acetylcholinesterase; hibitory postsynaptic currents, followed by a significant in- this is followed by glutamatergic hyperactivity, which sustains and crease in the ratio of the total charge transferred by reinforces seizure activity. It has been unclear which muscarinic spontaneous excitatory postsynaptic currents over that of receptor subtypes are involved in seizure initiation and the the inhibitory postsynaptic currents. Furthermore, paraoxon at ASPET Journals on September 28, 2021 development of SE in the early phases after exposure. Here, we enhanced the hyperpolarization-activated cation current Ih show that pretreatment of rats with the selective M1 receptor in basolateral amygdala principal cells, which could be one antagonist, VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin- of the mechanisms underlying the increased glutamatergic 1-yl)propyl)-benzo[c][1,2,5]thiadiazole-4 sulfonamide], significantly activity, an effect that was also blocked in the presence suppressed seizure severity and prevented the development of VU0255035. Thus, selective M1 antagonists may be an of SE for about 40 minutes after exposure to paraoxon or efficacious pretreatment in contexts in which there is risk for soman, suggesting an important role of the M1 receptor in the exposure to organophosphates, as these antagonists will early phases of seizure generation. In addition, in in vitro brain delay the development of SE long enough for medical assis- slices of the basolateral amygdala (a brain region that plays a tance to arrive. Introduction acetylcholine at cholinergic synapses. Although both nico- tinic acetylcholine receptors and mAChRs can be expected to There is ample evidence to suggest that the primary mecha- be activated by the elevated acetylcholine, it is primarily the nism by which organophosphates (OPs), used as insecticides or activation of mAChRs that elicits the generation of seizures. in chemical warfare (nerve agents), induce prolonged, severe Evidence for this has been provided by studies showing that seizures or status epilepticus (SE) involves hyperstimulation of mAChR antagonists prevent the induction of seizures if muscarinic acetylcholine receptors (mAChRs). Thus, phosphor- administered before OP exposure (Ashani and Catravas, ylation of acetylcholinesterase by these toxins inactivates 1981; McDonough et al., 1987; Capacio and Shih, 1991; the enzyme (Sirin et al., 2012), resulting in accumulation of Skovira et al., 2010) and can arrest seizures if administered shortly after exposure (McDonough et al., 1989; Anderson et al., This research was supported by the National Institutes of Health 1997), whereas nicotinic receptor antagonists do not suppress CounterACT Program, the National Institutes of Health Office of the Director, and the National Institutes of Health National Institute of Neurologic OP-induced seizures in vivo (Shih et al., 1991; Dekundy et al., Disorders and Stroke [Grant 5U01NS058162-07]. The views of the authors 2003) or epileptiform activity in vitro (Harrison et al., 2004). do not purport to reflect the position or policies of the Department of Defense or the U.S. Army. Antagonists of mAChRs are ineffective in stopping seizures if dx.doi.org/10.1124/jpet.116.236125. injected at delayed time points after OP exposure, because ABBREVIATIONS: ACSF, artificial cerebrospinal fluid; D-AP5, D(2)-2-amino-5-phosphonopentanoic acid; BLA, basolateral amygdala; DMSO, dimethylsulfoxide; LY341495, (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid; mAChR, muscarinic acetylcholine receptor; OP, organophosphate; SCH50911, (2S)-(1)-5,5-dimethyl-2-morpholineacetic acid; SE, status epilepticus; sEPSC, spontaneous excitatory postsynaptic current; sIPSC, spontaneous inhibitory postsynaptic current; VU0255035, N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)-benzo[c] [1,2,5]thiadiazole-4 sulfonamide. 23 24 Miller et al. after the initial phase of SE, glutamatergic mechanisms that and the U.S. Army Medical Research Institute of Chemical Defense have come into play are primarily responsible for reinforcing (Aberdeen Proving Ground, MD) are accredited by the Association for and sustaining seizures (McDonough and Shih, 1997; Assessment and Accreditation of Laboratory Animal Care Interna- Weissman and Raveh, 2008). It has not been clear, however, tional. All animal experiments were conducted following the Guide for which of the mAChR subtypes are involved in the initiation of the Care and Use of Laboratory Animals by the Institute of Laboratory Animal Resources and the U.S. National Research Council and were seizures, leading to and sustaining SE in the early phases approved by the Institutional Animal Care and Use Committees of postexposure. both of our institutions. – There are five subtypes of mAChRs: M1 M5. They all are G Paraoxon and Soman Exposure. Ten-week-old male rats were protein coupled; M2 and M4 are preferentially coupled to the administered 25 mg/kg (i.p.) of the selective M1 receptor antagonist Gi class of G proteins, whereas M1,M3, and M5 are coupled to VU0255035 (Tocris Bioscience, Ellisville, MO) diluted at 25 mg/ml in the Gq family (Wess, 2003; Kruse et al., 2014). Hamilton et al. dimethylsulfoxide (DMSO) (Sigma-Aldrich, St. Louis, MO), or 1 ml/kg (1997) and Bymaster et al. (2003) found that pilocarpine, a (i.p.) DMSO as the vehicle, 15 minutes before exposure to soman muscarinic agonist, induces SE in wild-type mice but not in (pinacoyl methylphosphonofluoridate; obtained from the Edgewood Chemical Biologic Center, Aberdeen Proving Ground, Edgewood, mice lacking the M1 receptor, suggesting a key role for M1 receptors in the induction of SE by pilocarpine. In addition, a MD), or 30 minutes before exposure to paraoxon (paraoxon-ethyl; Sigma-Aldrich). The concentration of VU0255035 that we used is highly selective M receptor antagonist was developed re- 1 within the range that has no significant effect on cognitive functions cently, VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1- (Sheffler et al., 2009). For the soman experiments, animals were Downloaded from yl)propyl)-benzo[c][1,2,5]thiadiazole-4 sulfonamide] (Weaver subcutaneously injected with 1.8 Â LD50 soman (198 mg/kg, diluted in et al., 2009), and was tested against seizures induced by cold physiologic saline). For the paraoxon experiments, animals were pilocarpine. Mice pretreated with VU0255035 did not develop subcutaneously injected with 4 mg/kg paraoxon; paraoxon solutions SE, at least for 40 minutes after injection of pilocarpine were prepared fresh by adding 10-ml stock solution (1.274 g/ml) to 3 ml (Sheffler et al., 2009). Because pilocarpine and OPs share ice-cold phosphate-buffered saline in a glass vial and mixing thor- the primary mechanism of seizure induction (muscarinic oughly. Soman was used because of its high toxicity and the difficulty receptor hyperstimulation), it has been suggested that in counteracting soman-induced seizures, which implies that if a drug jpet.aspetjournals.org findings in the pilocarpine model of SE may also apply to is effective in suppressing seizures induced by soman, it is likely to also be effective against other nerve agents. Paraoxon was used OP-induced SE (Tetz et al., 2006; Tang et al., 2011). Whether because it is highly potent, has similar effects to those of soman, and M1 receptor activation, which is necessary for induction of there is extensive literature on its use as a model of OP poisoning, seizures by pilocarpine, is also necessary for induction of including its use as a surrogate for chemical warfare nerve agents. The seizures by OPs was recently tested in wild-type and M1- peripheral toxic cholinergic effects of soman and paraoxon were knockout mice (Kow et al., 2015) exposed to paraoxon (O,O- controlled by intramuscular injection of either 2 mg/kg atropine diethyl O-p-nitrophenyl phosphate), which is the active methylnitrate, or 2 mg/kg atropine sulfate along with 25 mg/kg at ASPET Journals on September 28, 2021 metabolite of the insecticide
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