GDNF rescues nonpeptidergic unmyelinated primary afferents in streptozotocin-treated diabetic mice
GDNF rescues nonpeptidergic unmyelinated primary afferents in streptozotocin-treated diabetic mice
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DOI：
10.1006/exnr.2000.7547
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发表时间：
2001-01-01
影响因子：
5.3
通讯作者：
Wright, DE
中科院分区：
文献类型：
--
作者：
Akkina, SK;Patterson, CL;Wright, DE
糖尿病引起的感觉障碍通常影响小的无髓鞘多肽能和非多肽能感觉神经元。多肽能神经元对神经生长因子(NGF)产生反应，而非肽能DRG神经元在出生后将其依赖从NGF转变为神经胶质细胞源性神经营养因子(GDNF)。最近的研究表明，缺乏NGF对肽能伤害性感受器的支持与小纤维糖尿病神经病变有关。为了确定非肽能GDNF反应神经元是否同样受到高血糖的影响，用链脲佐菌素(STZ)诱导小鼠糖尿病。糖尿病诱导4周后，腰背角III层的异凝素IB4标记的非肽能无髓神经元轴突终末染色或TMP酶活性减少，尤其是在接受远端坐骨神经传入的内侧区域。相比之下，NGF反应性CG；RP免疫反应(Ir)轴突显示脊髓终末没有或仅略有减少。糖尿病小鼠的胰岛素治疗未能改善IB4/TMP中枢传入神经的缺陷。为了测试GDNF或NGF是否能恢复非肽能传入的脊髓损伤，给STZ处理的小鼠鞘内注射NGF或GDNF 2周。NGF可增强CGRP-ir的染色，但不能改善IB4/TMP的投射。GDNF治疗对CGRP-ir投射没有影响，但恢复了TMP在III板层的标记。我们的结果表明，非肽能无髓感觉神经元容易受到糖尿病的影响，GDNF的应用可以选择性地逆转糖尿病引起的IB4/TMP亚群的缺陷。(C)2001年学术出版社。
Sensory deficits induced by diabetes commonly affect small unmyelinated peptidergic and nonpeptidergic sensory neurons. The peptidergic population responds to nerve growth factor (NGF), while the nonpeptidergic DRG neurons postnatally switch their dependency from NGF to glial cell line-derived neurotrophic factor (GDNF). Recent studies have demonstrated that deficient NGF support of peptidergic nociceptors is involved in problems with small-fiber diabetic neuropathy. To determine if nonpeptidergic GDNF-responsive neurons are similarly affected by hyperglycemia, diabetes was induced in mice using streptozotocin (STZ). Four weeks following diabetes induction, staining of axon terminals of nonpeptidergic unmyelinated neurons labeled with the isolectin IB4 or enzyme activity for thiamine monophosphatase (TMP) was reduced in lamina iii of the lumbar dorsal horn, particularly in the medial region which receives distal sciatic afferents. In contrast, NGF-responsive CG;RP-immunoreactive (ir) axons showed no or only a slight decrease in spinal terminations. Insulin treatment in diabetic mice failed to improve deficits in IB4/TMP central afferents. To test whether GDNF or NGF could restore spinal deficits in nonpeptidergic afferents, STZ-treated mice were treated intrathecally for 2 weeks with NGF or GDNF. NGF administration enhanced CGRP-ir staining but failed to improve IB4/TMP projections. GDNF treatment had no effect on CGRP-ir projections but restored TMP labeling in lamina IIi. Our results demonstrate that nonpeptidergic unmyelinated sensory neurons are vulnerable to diabetes and that GDNF administration can selectively reverse deficits caused by diabetes in the IB4/TMP subpopulation. (C) 2001 Academic Press.