Use of cytochrome-P450 mono-oxygenase 2 E1 isozyme inhibitors to delay seizures caused by central nervous system oxygen toxicity.
BACKGROUND
The neuronal origins and mechanisms of central nervous system oxygen toxicity are only partly understood. Oxygen free radicals are felt to play a major role in the production of CNS oxygen toxicity because of the interactions of free radicals with plasma membranes producing lipid peroxidation. The cytochrome P-450 monooxygenase system IIE1 isozyme is important in the brain. This led to trials of P450 monooxygense inhibitors for prevention of oxygen toxicity. Diethyldithiocarbonate (DDC) proved to be the most promising agent in this class; 21-aminosteroid lazeroid compounds have been successful in experimentally limiting pulmonary oxygen toxicity. This led to our trying to prevent neuronal oxygen toxicity by the use of 21-aminosteroid and six other drugs during hyperoxia.


METHODS
In our experiments, mice were placed in an oxygen-filled hyperbaric chamber in paired experiments. One pre-treated mouse and one control mouse were exposed simultaneously to assess the efficacy of drugs in preventing seizures caused by hyperbaric oxygen at 5.1 atmospheres absolute. Time to seizure was observed through a port hole in the hull of the hyperbaric chamber.


RESULTS
DDC, 21-aminosteroid and propranolol produced significant delays in the onset of seizures (p < 0.001) with no observable side effects; 1-aminobenzotriazole and disulfiram produced much shorter delays in the onset of seizures caused by hyperbaric oxygen and also had unacceptable side effects.
Whelan
H T
HT
Dept. of Neurology, Medical College of Wisconsin, Milwaukee 53226, USA.
Bajic
D M
DM
Karlovits
S M
SM
Houle
J M
JM
Kindwall
E P
EP
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects; D002490:Central Nervous System / Q000502:physiology*; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism*; D004242:Diving / Q000502:physiology; D005609:Free Radicals; D006931:Hyperbaric Oxygenation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010100:Oxygen / Q000633:toxicity*; D012640:Seizures / Q000209:etiology / Q000517:prevention & control*
D000927:Anticonvulsants; D005609:Free Radicals; D019392:Cytochrome P-450 CYP2E1; D010100:Oxygen