Protective effects of cyclooxygenase-2 gene inactivation against peripheral nerve dysfunction and intraepidermal nerve fiber loss in experimental diabetes
Protective effects of cyclooxygenase-2 gene inactivation against peripheral nerve dysfunction and intraepidermal nerve fiber loss in experimental diabetes
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DOI：
10.2337/db07-0740
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发表时间：
2007-12-01
期刊：
影响因子：
7.7
通讯作者：
Pop-Busui, Rodica
中科院分区：
文献类型：
--
作者：
Kellogg, Aaron P.;Wiggin, Tim D.;Pop-Busui, Rodica
环氧合酶（考克斯）通路的激活与继发性神经血管缺陷在实验性糖尿病周围神经病变（DPN）的发病机制中有牵连。本研究的目的是探讨高血糖、考克斯-2通路的激活、氧化应激和炎症在介导外周神经功能障碍中的相互关系，以及考克斯-2基因失活是否减轻长期实验性糖尿病中的神经纤维损失。6个月后，在对照和糖尿病考克斯-2缺陷（考克斯-2（-/-））和同窝野生型（考克斯-2（+/+））小鼠中测量炎症标志物和表皮内神经纤维（IENF）密度。选择性考克斯-2抑制剂塞来昔布对这些标记物的影响也在糖尿病大鼠中进行了研究。结论-在正常条件下，考克斯-2（+/+）和考克斯-2（-/-）小鼠之间的血糖、外周神经电生理、氧化应激标记物、炎症和IENF密度没有差异。6个月后，与非糖尿病小鼠相比，糖尿病考克斯-2（+/+）小鼠的神经传导速度和IENF密度显著恶化，并出现氧化应激和炎症增加的重要体征。糖尿病考克斯-2（-/-）小鼠对实验性DPN的功能和生化缺陷以及对神经纤维损失具有保护作用。在糖尿病大鼠中，选择性考克斯-2抑制复制了这种保护作用。结论-这些数据表明，选择性考克斯-2抑制可能有助于预防或延迟DPN。
OBJECTIVE-Activation of the cyclooxygenase (COX) pathway with secondary neurovascular deficits are implicated in the pathogenesis of experimental diabetic peripheral neuropathy (DPN). The aim of this study was to explore the interrelationships between hyperglycemia, activation of the COX-2 pathway, and oxidative stress and inflammation in mediating peripheral nerve dysfunction and whether COX-2 gene inactivation attenuates nerve fiber loss in long-term experimental diabetes.RESEARCH DESIGN AND METHODS-Motor and sensory digital nerve conduction velocities, sciatic nerve indexes of oxidative stress, prostaglandin content, markers of inflammation, and intraepidermal nerve fiber (IENF) density were measured after 6 months in control and diabetic COX-2-deficient (COX-2(-/-)) and littermate wild-type (COX-2(+/+)) mice. The effects of a selective COX-2 inhibitor, celecoxib, on these markers were also investigated in diabetic rats.RESULTS-Under normal conditions, there were no differences in blood glucose, peripheral nerve electrophysiology, markers of oxidative stress, inflammation, and IENF density between COX-2(+/+) and COX-2(-/-) mice. After 6 months, diabetic COX-2(+/+) mice experienced significant deterioration in nerve conduction velocities and IENF density and developed important signs of increased oxidative stress and inflammation compared with nondiabetic mice. Diabetic COX-2(-/-) mice were protected against functional and biochemical deficits of experimental DPN and against nerve fiber loss. In diabetic rats, selective COX-2 inhibition replicated this protection.CONCLUSIONS-These data suggest that selective COX-2 inhibition may be useful for preventing or delaying DPN.