Delayed tezampanel and caramiphen treatment but not midazolam protects against long-term neuropathology after soman exposure

• Published in: Experimental biology and medicine (Maywood, N.J.) Vol. 248; no. 7; pp. 612 - 623
• Main Authors: Figueiredo, Taiza H, Aroniadou-Anderjaska, Vassiliki, Apland, James P, Rossetti, Katia, Braga, Maria FM
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01-04-2023
• Subjects: Animals; Anticonvulsants - adverse effects; Brain - pathology; Brain Injuries - drug therapy; Female; Male; Midazolam - pharmacology; Midazolam - therapeutic use; Nerve Agents - adverse effects; Original Research; Rats; Seizures - chemically induced; Seizures - drug therapy; Seizures - pathology; Soman - therapeutic use; Soman - toxicity; Status Epilepticus - chemically induced; Status Epilepticus - drug therapy; Status Epilepticus - pathology; status epilepticus; tezampanel; midazolam; soman; neuroprotection; LY293558; caramiphen; Nerve agents
• ISSN: 1535-3702; 1535-3699; 1535-3699
• DOI: 10.1177/15353702231171911

Prolonged status epilepticus (SE) can cause brain damage; therefore, treatment must be administered promptly after seizure onset to limit SE duration and prevent neuropathology. Timely treatment of SE is not always feasible; this would be particularly true in a mass exposure to an SE-inducing agent such as a nerve agent. Therefore, the availability of anticonvulsant treatments that have neuroprotective efficacy even if administered with a delay after SE onset is an imperative. Here, we compared the long-term neuropathology resulting from acutely exposing 21-day-old male and female rats to the nerve agent soman, and treating them with midazolam (3 mg/kg) or co-administration of tezampanel (10 mg/kg) and caramiphen (50 mg/kg), at 1 h postexposure (~50 min after SE onset). Midazolam-treated rats had significant neuronal degeneration in limbic structures, mainly at one month postexposure, followed by neuronal loss in the basolateral amygdala and the CA1 hippocampal area. Neuronal loss resulted in significant amygdala and hippocampal atrophy, deteriorating from one to six months postexposure. Rats treated with tezampanel–caramiphen had no evidence of neuropathology, except for neuronal loss in the basolateral amygdala at the six-month timepoint. Anxiety was increased only in the midazolam-treated rats, at one, three, and six months postexposure. Spontaneous recurrent seizures appeared only in midazolam-treated rats, at three and six months postexposure in males and only at six months in females. These findings suggest that delayed treatment of nerve agent–induced SE with midazolam may result in long-lasting or permanent brain damage, while antiglutamatergic anticonvulsant treatment consisting of tezampanel and caramiphen may provide full neuroprotection.