Organophosphate-induced brain injuries: delayed apoptosis mediated by nitric oxide

The features of organophosphate-induced brain injuries were investigated. R ats were poisoned intraperitoneally with 9 mg/kg (1.8 LD,,) of diisopropylf luorophosphate. Pyridostigmine bromide (0.1 mg/kg) and atropine methylnitra te (20 mg/kg), which are centrally inactive, were pre-treated intramuscular ly to reduce the mortality and eliminate peripheral signs. Diisopropylfluor ophosphate induced severe limbic seizures, and early necrotic and delayed a poptotic brain injuries. The necrotic brain injury was observed to be maxim al as early as 1 h after diisopropylfluorophosphate treatment predominently in hippocampus and piriform/entorhinal cortices, showing a spongiform chan ge (malacia) of neuropils in severe cases. In contrast, typical apoptotic ( TUNEL-positive) cells started to appear at 12 h in thalamus, and a mixed ty pe in amygdala. Separately, nitrite/nitrate content in cerebrospinal fluid was found to significantly increase after 2 h, reaching a maximal level at 6 h. Pre-treatment with L-NG-nitroarginine, an inhibitor of nitric oxide sy nthase, reduced nitrite/nitrate content and, noteworthy, attenuated only ap optotic brain injury in ail four brain regions without affecting seizure in tensity and necrotic injury. Taken together, the delayed apoptotic injury o f brain induced by diisopropylfluorophosphate poisoning in rats might be me diated in part through nitric oxide production. (C) 1999 Elsevier Science B .V. All rights reserved.