Characterization of seizures induced by acute and repeated exposure to tetramethylenedisulfotetramine.
Tetramethylenedisulfotetramine (tetramine; TETS) is a potent convulsant poison that is considered to be a chemical threat agent. To provide a basis for the investigation of antidotes for TETS-induced seizures, we characterized the convulsant activity of TETS in mice and rats when administered by the intraperitoneal, intravenous, oral, and intraventricular routes as a single acute dose and with repeated sublethal doses. In mice, parenteral and oral TETS caused immobility, myoclonic body jerks, clonic seizures of the forelimbs and/or hindlimbs, tonic seizures, and death. The CD₅₀ values for clonic and tonic seizures after oral administration were 0.11 and 0.22 mg/kg, respectively. Intraventricular administration of TETS (5-100 μg) in rats also caused clonic-tonic seizures and death. In mice, repeated sublethal doses of TETS at intervals of 2, 24, and 48 h failed to result in the development of persistent enhanced seizure responsivity ("kindling") as was observed with repeated pentylenetetrazol treatment. In mice, sublethal doses of TETS that produced clonic seizures did not cause observable structural brain damage as assessed with routine histology and Fluoro-Jade B staining 7 days after treatment. However, 1 to 3 days after a single convulsant dose of TETS the expression of glial fibrillary acidic protein, an astrocyte marker, and ionized calcium binding adaptor molecule 1, a microglia marker, were markedly increased in cortex and hippocampus. Although TETS doses that are compatible with survival are not associated with overt evidence of cellular injury or neurodegeneration, there is transient reactive astrocytosis and microglial activation, indicating that brain inflammatory responses are provoked.
Department of Neurology, School of Medicine, University of California-Davis, Sacramento, California, USA.
Dorota
D
Zolkowska
Christopher N
CN
Banks
Ashish
A
Dhir
Bora
B
Inceoglu
James R
JR
Sanborn
Mark R
MR
McCoy
Donald A
DA
Bruun
Bruce D
BD
Hammock
Pamela J
PJ
Lein
Michael A
MA
Rogawski
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000633:toxicity*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003292:Convulsants / Q000633:toxicity*; D005121:Extremities; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D010433:Pentylenetetrazole / Q000494:pharmacology; D010852:Picrotoxin / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism*
D001952:Bridged-Ring Compounds; D002135:Calcium-Binding Proteins; D003292:Convulsants; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D010433:Pentylenetetrazole; D010852:Picrotoxin; C491049:Aif1 protein, mouse; C010349:tetramethylenedisulfotetramine