The Efficacy of LY293558 in Blocking Seizures and Associated Morphological, and Behavioral Alterations Induced by Soman in Immature Male Rats and the Role of the M1 Muscarinic Acetylcholine Receptor in Organophosphate Induced Seizures

Abstract

Abstract : Poisoning by organophosphorous compounds (OPs) can produce severe symptoms including seizures or status epilepticus (SE), and if left untreated results in long-term brain damage and neuropsychiatric symptoms or death. OPs produce their toxic effects by irreversibly inhibiting the enzyme acetyl cholinesterase (AChE), which subsequently causes a hyper stimulation of the muscarinic acetylcholine receptors (mAChRs) and the nicotinic acetylcholine receptors (nAChRs). The use of OP nerve agents in attacks in Syria recently highlighted the importance of developing treatments for all ages, but specifically, this attack highlighted the importance of developing treatments for seizures induced by OP intoxication for children. We developed an immature rat model appropriate for testing novel anticonvulsants against the nerve agent soman. Using postnatal day 21 male rats (P21), we found them to be highly susceptible to seizure induction and mortality induced by soman exposure. Soman exposure in P21 rats produced profound reduction in the activity of AChE in numerous brain regions but suggested that this reduction must occur specifically in the basolateral amygdala (BLA) to produce seizures as animals that did not experience seizures still retained higher Ache activity within the BLA. Seizures, if treated within 20 min or 60 min post-soma exposure could be arrested with the administration of atropine sulfate (ATS) or theGluK1-subunit containing Kainate (GluK1KR)/-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist LY293558, respectively. We also found an additional GluK1KR antagonist, UBP302 to be efficacious in arresting soman induced seizures when treatment was administered at 60 min post-exposure. Delayed post treatment with LY293558 blocked volumetric reductions in the amygdala and hippocampus induced by soman exposure that was observed 30 or 90 days post-soma exposure in rats that did not receive LY293558 treatment.