Abstract
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.
Footnotes
This work was supported by the CounterACT Program, Office of the Director, National Institutes of Health and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R21-NS072094] (to P.J.L., M.A.R.); the National Institutes of Health National Institute of Environmental Health Sciences [Grant R01-ES002710] (to B.D.H.); the National Institutes of Health National Institute of Environmental Health Sciences Superfund Basic Research Program [Grant P42-ES004699] (to B.D.H.); a National Institutes of Health National Institute of Environmental Health Sciences postdoctoral fellowship [Grant T32-ES007059] (to C.N.B.); and a University of California Davis Academic Federation Innovative Development Award (to D.Z.). B.D.H. is a George and Judy Marcus Senior Fellow of the American Asthma Foundation.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- TETS
- tetramethylenedisulfotetramine
- HEXS
- hexamethylenetrisulfohexamine
- TBPS
- t-butylbicyclophosphorothionate
- GFAP
- glial fibrillary acidic protein
- Iba1
- ionized calcium binding adaptor molecule
- PTZ
- pentylenetetrazol
- DMSO
- dimethyl sulfoxide
- CL
- confidence limit
- PBS
- phosphate-buffered saline
- DAPI
- 4′,6-diamidino-2-phenylindole
- H&E
- hematoxylin and eosin
- ANOVA
- analysis of variance
- FJB
- Fluoro-Jade B
- DFP
- diisopropylfluorophosphate.
- Received November 29, 2011.
- Accepted February 9, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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