Abstract
The protein kinase C (PKC) signaling pathway has been associated with modulation of N-metyl-d-aspartate receptor activity, motor behavior, learning, and memory, all of which are severely impaired in organophosphate (OP) intoxication. Nevertheless, the role of PKC in OP intoxication is largely unknown. The present study attempted to characterize alterations in the immunoreactivity levels of PKC isozymes expressed in different brain areas in the rat following exposure to the nerve agent sarin (1× LD50). Furthermore, possible neuroprotective effect of selective PKC regulating peptide after such insult was evaluated. The results indicated that a significant reduction in the immunoreactivity level of the conventional βII-PKC and the atypical ζ-PKC was observed in frontal cortex up to 24 h postsarin and in the striatum up to 5 days postsarin exposure. This reduction was in contrast to the increase in the immuno-reactivity level of both isozymes seen in the hippocampus or thalamus. Treatment with the anticonvulsant midazolam (0.5 mg/kg) 10 min postsarin exposure markedly reduced ζ-PKC immunoreactivity level and βII-PKC in the membrane fractions in the hippocampus. βII-PKC peptide (380 ng/kg), known to inhibit PKC translocation and activation, attenuated sarin-induced neuropathology. These observations suggest a role for both conventional and atypical PKC isozymes in OP-induced neuropathy in the rat and further support their involvement in cell death.
Footnotes
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Part of this work was presented at the following meetings: 13th Annual Meetings of the American Summer Neuropeptide Conference and the European Neuropeptide Club, New York, New York, 2003; 11th annual Meeting of the Israel Society for Neurosciences, Eilat, Israel 2003; and Bioscience 2004 U.S. Army Medical Defense Meeting, Hunt Valley, MD, 2004.
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doi:10.1124/jpet.105.083469.
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ABBREVIATIONS: ChE, cholinesterase; DAG, diacylglycerol; PKC, protein kinase C; NMDA, N-methyl-d-aspartate; KA, kainic acid; OP, organophosphate; OD, optical density; TS, tris-sodium chloride.
- Received January 11, 2005.
- Accepted February 14, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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