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Published on: December 4, 2013
Organophosphate-induced brain injuries: delayed apoptosis mediated by nitric oxide
1Biomedical Assessment Laboratory (1-3-4), Agency for Defense Development, Yuseong P.O. Box 35-1, Taejon 305-600, South Korea.
Abstract:
The features of organophosphate-induced brain injuries were investigated. Rats were poisoned intraperitoneally with 9 mg/kg (1.8 LD(50)) of diisopropylfluorophosphate. Pyridostigmine bromide (0.1 mg/kg) and atropine methylnitrate (20 mg/kg), which are centrally inactive, were pre-treated intramuscularly to reduce the mortality and eliminate peripheral signs. Diisopropylfluorophosphate induced severe limbic seizures, and early necrotic and delayed apoptotic brain injuries. The necrotic brain injury was observed to be maximal as early as 1 h after diisopropylfluorophosphate treatment predominently in hippocampus and piriform/entorhinal cortices, showing a spongiform change (malacia) of neuropils in severe cases. In contrast, typical apoptotic (TUNEL-positive) cells started to appear at 12 h in thalamus, and a mixed type 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-N(G)-nitroarginine, an inhibitor of nitric oxide synthase, reduced nitrite/nitrate content and, noteworthy, attenuated only apoptotic brain injury in all four brain regions without affecting seizure intensity and necrotic injury. Taken together, the delayed apoptotic injury of brain induced by diisopropylfluorophosphate poisoning in rats might be mediated in part through nitric oxide production.
Insights
Organophosphate poisoning causes brain injuries, including seizures and cell death. Nitric oxide may play a role in the delayed apoptotic brain injury following organophosphate exposure.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Organophosphate compounds are widely used, but their neurotoxic effects are a significant concern.
- Understanding the mechanisms of organophosphate-induced brain injury is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the characteristics of brain injuries induced by organophosphate poisoning.
- To explore the potential role of nitric oxide in the pathogenesis of these injuries.
Main Methods:
- Rats were poisoned with diisopropylfluorophosphate (an organophosphate) and treated with protective agents.
- Brain injuries were assessed for necrotic and apoptotic cell death at various time points.
- Cerebrospinal fluid nitrite/nitrate levels were measured.
- The effect of a nitric oxide synthase inhibitor on brain injury and seizures was evaluated.
Main Results:
- Diisopropylfluorophosphate induced limbic seizures, early necrotic brain injury (maximal at 1h), and delayed apoptotic brain injury (starting at 12h).
- Necrotic injury was prominent in the hippocampus and piriform/entorhinal cortices.
- Apoptotic cells appeared in the thalamus and amygdala.
- Nitrite/nitrate levels increased significantly after poisoning.
- Inhibiting nitric oxide synthase reduced nitrite/nitrate levels and attenuated apoptotic injury, but not seizure intensity or necrotic injury.
Conclusions:
- Organophosphate poisoning causes distinct patterns of necrotic and apoptotic brain injury.
- Delayed apoptotic brain injury following organophosphate exposure may be partly mediated by nitric oxide production.
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