Beneficial effects of TCP on soman intoxication in guinea pigs: seizures, brain damage and learning behaviour.
Poisoning with the potent nerve agent soman produces a cascade of central nervous system (CNS) effects characterized by severe convulsions and eventually death. In animals that survive a soman intoxication, lesions in the amygdala, piriform cortex, hippocampus and thalamus can be observed. In order to examine the mechanisms involved in the effects of soman and to evaluate possible curative interventions, a series of behavioural, electrophysiological and neuropathological experiments were carried out in the guinea pig using the NMDA antagonist N-[1-(2-thienyl)cyclohexyl] piperidine (TCP) in conjunction with atropine and pyridostigmine. The NMDA antagonist TCP appeared to be very effective in the treatment of casualties who suffered from soman-induced seizures for 30 min: (i)Seizures were arrested within minutes after the TCP injection, confirmed by quantitative electroencephalogram (EEG), after fast Fourier analysis. Three hours after TCP the quantitative EEGs were completely normal in all frequency bands and remained normal during the entire 3-week intoxication period. The power shift to the lower (delta) frequency bands, indicative for neuropathology and found in control animals intoxicated only by soman, was not observed in the soman-TCP group. (ii)The gross neuropathology found in soman control animals within 48 h after soman was prevented in soman-TCP animals and was still absent in 3-week survivors. Instead, ultrastructural changes were observed, indicative of defense mechanisms of the cell against toxic circumstances. (iii)Twenty-four hours after soman, soman-TCP animals were able to perform in the shuttle box and Morris water maze. The beneficial effects of TCP on the performance in these tests during the 3-week intoxication period were very impressive, notwithstanding (minor) deficits in memory and learning. (iv)The increase in excitability after TCP was confirmed by an increase in the acoustic startle response. Taken together, these results confirmed the involvement of NMDA receptors in the maintenance of soman-induced seizures and the development of brain damage. They underline the current hypothesis that cholinergic mechanisms are responsible for eliciting seizure activity after soman and that, most likely, the subsequent recruitment of other excitatory neurotransmitters and loss of inhibitory control are responsible for the maintenance of seizures and the development of subsequent brain damage.
de Groot
D M
DM
TNO Nutrition and Food Research, PO Box 360, 3700 AJ Zeist, The Netherlands.
Bierman
E P
EP
Bruijnzeel
P L
PL
Carpentier
P
P
Kulig
B M
BM
Lallement
G
G
Melchers
B P
BP
Philippens
I H
IH
van Huygevoort
A H
AH
D000818:Animals; D001285:Atropine / Q000008:administration & dosage; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D002619:Chemical Warfare Agents / Q000506:poisoning*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage; D004193:Discrimination Learning; D004569:Electroencephalography; D006168:Guinea Pigs; D008297:Male; D018727:Muscarinic Antagonists / Q000008:administration & dosage; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011729:Pyridostigmine Bromide / Q000008:administration & dosage; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy*; D012999:Soman / Q000506:poisoning*
D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D001285:Atropine; C012058:tenocyclidine; D012999:Soman; D010622:Phencyclidine; D011729:Pyridostigmine Bromide