Targeting the Glutamatergic System to Counteract Soman Toxicity in Immature Rats



 DESCRIPTION (provided by applicant): Nerve agents are potent, organophosphorus toxins that act primarily by inhibiting the activity of acetylcholinesterase. The resulting accumulation o acetylcholine at synaptic junctions produces peripheral cholinergic crisis, and, in the brain, induces seizures and status epilepticus (SE). Without timely pharmacological intervention, death will ensue, or if death is prevented but the SE is not controlled, brain damage will result, with long-term neurological and behavioral consequences. The devastating effects of the sarin attack in Syria, in August of 2013, where 1,400 civilians were killed, 426 of which were children, brought again to the forefront the question of readiness and whether the existing medical countermeasures can save lives and protect against the long-term health consequences of exposure. Although the American Academy of Pediatrics have pointed out the reasons that children are more vulnerable to nerve agent toxicity, there is very little information on the appropriate countermeasures to protect the pediatric population, as data in immature animals are lacking. Here, we propose to test the combination of LY293558, an AMPA/GluR5(GluK1) receptor antagonist, with caramiphen (CRM), an antimuscarinic with NMDA receptor antagonistic properties, against soman-induced seizures, brain damage, behavioral deficits, and pathophysiological alterations in brain regions that underlie these deficits, in 12-day-old and 21-day-old rats. We have previously found that LY293558 and CRM are efficacious anticonvulsant treatments in adult rats, with the LY293558 having a faster seizure- suppressing action and greater neuroprotective effects. Recently, we discovered that when LY293558 and CRM are administered in combination, the results are far superior to those obtained when each drug is given alone; seizures are terminated in less than 10 min, neuronal degeneration is completely prevented, and the rats appear absolutely healthy the next day and have no weight loss. Targeting the glutamatergic system in immature rats to prevent nerve agent toxicity, with the use of a combination therapy that adds an NMDA antagonist to LY293558, is likely to be a most efficacious treatment, considering the high NMDA receptor activity in the developing brain, and its role in excitotoxicity.