TY - JOUR
T1 - Susceptibility to Soman Toxicity and Efficacy of LY293558 Against Soman-Induced Seizures and Neuropathology in 10-Month-Old Male Rats
AU - Apland, James P.
AU - Aroniadou-Anderjaska, Vassiliki
AU - Figueiredo, Taiza H.
AU - Prager, Eric M.
AU - Olsen, Cara H.
AU - Braga, Maria F.M.
N1 - Funding Information:
Acknowledgements We wish to thank Dr. Camila P. Almeida-Suhett for expert assistance in measuring acetylcholinesterase activity. This study was supported by the CounterACT Program, National Institutes of Health, Office of the Director and the National Institute of Neurologic Disorders and Stroke [Grant Number 5U01NS058162-07].
Publisher Copyright:
© 2017, US Government (outside the USA).
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Acute nerve agent exposure causes prolonged status epilepticus (SE), leading to death or long-term brain damage. We have previously demonstrated that LY293558, an AMPA/GluK1 kainate receptor antagonist, terminates SE induced by the nerve agent soman and protects from long-term brain damage, in immature rats and young-adult rats, even if administered with a relatively long latency from the time of exposure. However, susceptibility to the lethal consequences of SE increases with age, and mortality by SE induced by soman is substantially greater in older animals. Therefore, in the present study, we compared the susceptibility to soman toxicity of 10-month-old male rats with that of young-adult male rats (42 to 50 days old) and examined the protective efficacy of LY293558 in the older group. A lower percentage of the 10-month-old rats developed SE after injection of 1.2 × LD50 soman, compared to the young adults, the latency to seizure onset was longer in the older rats, and seizure intensity did not differ between the two age groups. However, mortality rate in the older rats who developed SE was higher than in the young adults. Acetylcholinesterase activity in the amygdala, hippocampus, and piriform cortex did not differ between the two age groups. Administration of LY293558 at 20 or 60 min post-exposure suppressed SE, increased 24-h survival rate, decreased the long-term risk of death, reduced neuronal degeneration in the amygdala, hippocampus, piriform, and entorhinal cortices, and facilitated recovery from body weight loss. Thus, LY293558 is an effective countermeasure against soman toxicity also in older animals.
AB - Acute nerve agent exposure causes prolonged status epilepticus (SE), leading to death or long-term brain damage. We have previously demonstrated that LY293558, an AMPA/GluK1 kainate receptor antagonist, terminates SE induced by the nerve agent soman and protects from long-term brain damage, in immature rats and young-adult rats, even if administered with a relatively long latency from the time of exposure. However, susceptibility to the lethal consequences of SE increases with age, and mortality by SE induced by soman is substantially greater in older animals. Therefore, in the present study, we compared the susceptibility to soman toxicity of 10-month-old male rats with that of young-adult male rats (42 to 50 days old) and examined the protective efficacy of LY293558 in the older group. A lower percentage of the 10-month-old rats developed SE after injection of 1.2 × LD50 soman, compared to the young adults, the latency to seizure onset was longer in the older rats, and seizure intensity did not differ between the two age groups. However, mortality rate in the older rats who developed SE was higher than in the young adults. Acetylcholinesterase activity in the amygdala, hippocampus, and piriform cortex did not differ between the two age groups. Administration of LY293558 at 20 or 60 min post-exposure suppressed SE, increased 24-h survival rate, decreased the long-term risk of death, reduced neuronal degeneration in the amygdala, hippocampus, piriform, and entorhinal cortices, and facilitated recovery from body weight loss. Thus, LY293558 is an effective countermeasure against soman toxicity also in older animals.
KW - Aging
KW - AMPA receptors
KW - GluK1-kainate receptors
KW - Nerve agents
KW - Seizures
KW - Status epilepticus
UR - http://www.scopus.com/inward/record.url?scp=85026834523&partnerID=8YFLogxK
U2 - 10.1007/s12640-017-9789-7
DO - 10.1007/s12640-017-9789-7
M3 - Article
C2 - 28776308
AN - SCOPUS:85026834523
SN - 1029-8428
VL - 32
SP - 694
EP - 706
JO - Neurotoxicity Research
JF - Neurotoxicity Research
IS - 4
ER -