NeuropharmacologyMicrotubule-associated targets in chlorpyrifos oxon hippocampal neurotoxicity
Section snippets
Organotypic hippocampal slice preparations
Complete brains from 8-day-old male and female Sprague–Dawley rat pups were aseptically extracted and transferred to dissection medium (4 °C), consisting of Minimum Essential Medium (MEM) plus 25 mM Hepes, 2 mM l-glutamine, and 50 μM streptomycin/penicillin. Bilateral hippocampi were dissected out and placed into chilled culture medium. Culture medium consisted of dissection medium with the addition of sterile H2O, 36 mM glucose, 25% Hanks’ balanced salt solution (HBSS), and 25%
AChE activity
Following 1 day of exposure to the two highest concentrations of CPO (1.0 and 10.0 μM), AChE activity in the slice cultures was reduced by approximately 50% [F(3,206)=107.86, P<0.001], though no marked differences in AChE activity between these two groups were noted (post hoc=P<0.05 vs. control and 0.1 μM). Exposure to the 0.1 μM concentration of CPO did not reduce AChE activity at this time point. In contrast, 3 days of exposure to CPO, at each concentration, markedly reduced AChE activity [F
Discussion
The present studies were designed to examine the effects of prolonged exposure to CPO on AChE activity, as well as, the bioavailability of microtubule-related proteins α-tubulin and MAP-2a/b in a neonatal rat slice culture preparation. Further, these studies examined effects of CPO exposure on these proteins in parallel with the time course of cytotoxicity. Lastly, effects of CPO exposure on polymerization of purified and MAP-rich bovine tubulin were assessed to examine whether CPO affected
Conclusion
In conclusion, the present findings are consistent with previous work and extend our understanding of the means by which CPF and CPO produce neuronal injury that is independent of AChE inhibition and may involve degradation of microtubules, possibly mediated by interactions with MAP-2 proteins. Thus, it is possible that prolonged CPF exposure in vivo may significantly impact not only early CNS development but neurogenesis in the adult brain.
Acknowledgments
This work was supported by NIEHS (ES012241).
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