Subcellular alterations of protein kinase C isozymes in the rat brain after organophosphate poisoning.
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 (1x LD(50)). 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 betaII-PKC and the atypical zeta-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 zeta-PKC immunoreactivity level and betaII-PKC in the membrane fractions in the hippocampus. betaII-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.
Bloch-Shilderman
Eugenia
E
Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel. shilderman@iibr.gov.il
Kadar
Tamar
T
Levy
Aharon
A
Sahar
Rita
R
Rabinovitz
Ishai
I
Gilat
Eran
E
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D007527:Isoenzymes / Q000032:analysis*; D008297:Male; D011493:Protein Kinase C / Q000032:analysis* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012524:Sarin / Q000506:poisoning*
D007527:Isoenzymes; D012524:Sarin; D011493:Protein Kinase C