Gupta R P, Abdel-Rahman A, Wilmarth K W, Abou-Donia M B
Department of Pharmacology, Duke University Medical Center, Durham, NC 27708, USA.
Biochem Pharmacol. 1997 Jun 15;53(12):1799-806. doi: 10.1016/s0006-2952(97)00002-6.
Diisopropyl phosphorofluoridate (DFP) is an organophosphorus ester that produces organophosphorus ester-induced delayed neurotoxicity (OPIDN) in hens 7-14 days after a single s.c. dose of 1.7 mg/kg. In this study, hens were treated with a single dose of DFP (1.7 mg/kg, s.c.) 24 hr after [35S]methionine injection into the sacrolumbar region of their spinal cord, and killed 3, 7, 14, or 27 days post-DFP treatment. The rates of transport of labeled high (NF-H), medium (NF-M), and low (NF-L) molecular weight neurofilaments, and tubulin were faster in DFP-treated birds than in controls after 3 days. Subsequently, the rate of transport of these proteins started falling, so that the peaks of labeled proteins in control and DFP-treated hens were overlapping after 7 days. At 14 days, the peaks of NF-H, NF-M, and NF-L in treated hens were distinctly behind the corresponding peaks in control hens. This was again followed by an increase in transport of NF-H and NF-L, but not of NF-M, so that the labeled NF-H and NF-L showed the same pattern in control and treated hens after 27 days. The transient decrease in NF-H and NF-L axonal transport rate, and recovery correlated in a temporal manner with the previously reported increase of Ca2+/calmodulin-dependent protein kinase-mediated phosphorylation of neurofilament proteins and inhibition of calpain activity in the sciatic nerve in OPIDN. Proteinase inhibition has been reported recently to result in enhanced phosphorylation of neurofilaments in some cells. The present study suggests that the enhanced phosphorylation of neurofilaments by DFP-increased Ca2+/calmodulin-dependent protein kinase activity may be contributing toward alteration in NF axonal transport and the development of OPIDN.
二异丙基氟磷酸酯（DFP）是一种有机磷酸酯，单次皮下注射1.7mg/kg剂量后7 - 14天，可在母鸡中引发有机磷酸酯诱导的迟发性神经毒性（OPIDN）。在本研究中，母鸡在向其脊髓腰骶部注射[35S]甲硫氨酸24小时后，单次给予DFP（1.7mg/kg，皮下注射），并在DFP处理后3、7、14或27天处死。3天后，与对照组相比，DFP处理组鸡中标记的高分子量（NF - H）、中等分子量（NF - M）和低分子量（NF - L）神经丝以及微管蛋白的运输速率更快。随后，这些蛋白质的运输速率开始下降，以至于7天后对照组和DFP处理组母鸡中标记蛋白质的峰值出现重叠。在14天时，处理组母鸡中NF - H、NF - M和NF - L的峰值明显落后于对照组母鸡中的相应峰值。随后，NF - H和NF - L的运输再次增加，但NF - M没有，因此27天后对照组和处理组母鸡中标记的NF - H和NF - L呈现相同模式。NF - H和NF - L轴突运输速率的短暂下降以及恢复在时间上与先前报道的OPIDN中坐骨神经中钙调蛋白依赖性蛋白激酶介导的神经丝蛋白磷酸化增加和钙蛋白酶活性抑制相关。最近有报道称蛋白酶抑制会导致某些细胞中神经丝磷酸化增强。本研究表明，DFP增加的钙调蛋白依赖性蛋白激酶活性导致的神经丝磷酸化增强可能有助于改变神经丝轴突运输以及OPIDN的发展。
