title: The M1 Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala.
abstract: Exposure to organophosphorus toxins induces seizures that progress to status epilepticus (SE), which can cause brain damage or death. Seizures are generated by hyperstimulation of muscarinic receptors, subsequent to inhibition of acetylcholinesterase; this is followed by glutamatergic hyperactivity, which sustains and reinforces seizure activity. It has been unclear which muscarinic receptor subtypes are involved in seizure initiation and the development of SE in the early phases after exposure. Here, we show that pretreatment of rats with the selective M1receptor antagonist, VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)-benzo[c][1,2,5]thiadiazole-4 sulfonamide], significantly suppressed seizure severity and prevented the development of SE for about 40 minutes after exposure to paraoxon or soman, suggesting an important role of the M1receptor in the early phases of seizure generation. In addition, in in vitro brain slices of the basolateral amygdala (a brain region that plays a key role in seizure initiation after nerve agent exposure), VU0255035 blocked the effects produced by bath application of paraoxon-namely, a brief barrage of spontaneous inhibitory postsynaptic currents, followed by a significant increase in the ratio of the total charge transferred by spontaneous excitatory postsynaptic currents over that of the inhibitory postsynaptic currents. Furthermore, paraoxon enhanced the hyperpolarization-activated cation current Ihin basolateral amygdala principal cells, which could be one of the mechanisms underlying the increased glutamatergic activity, an effect that was also blocked in the presence of VU0255035. Thus, selective M1antagonists may be an efficacious pretreatment in contexts in which there is risk for exposure to organophosphates, as these antagonists will delay the development of SE long enough for medical assistance to arrive.
authors: 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 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.).
authors: Steven L
authors: SL
authors: Miller
authors: 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 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.).
authors: Vassiliki
authors: V
authors: Aroniadou-Anderjaska
authors: 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 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.).
authors: Volodymyr I
authors: VI
authors: Pidoplichko
authors: 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 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.).
authors: Taiza H
authors: TH
authors: Figueiredo
authors: 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 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.).
authors: James P
authors: JP
authors: Apland
authors: 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 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.).
authors: Jishnu K S
authors: JK
authors: Krishnan
authors: 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 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.) maria.braga@usuhs.edu.
authors: Maria F M
authors: MF
authors: Braga
mesh_terms: D000818:Animals; D066272:Basolateral Nuclear Complex / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D010261:Paraoxon / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors*; D012999:Soman / Q000633:toxicity*; D013226:Status Epilepticus / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects / Q000473:pathology; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: C542801:N-(3-oxo-3-(4-(pyridin-4-yl)piperazin-1-yl)propyl)benzo(c)(1,2,5)thiadiazole-4-sulfonamide; D043643:Receptor, Muscarinic M1; D013449:Sulfonamides; D013830:Thiadiazoles; D012999:Soman; D010261:Paraoxon