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.