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The targeting treatment for prevention and restoration in patients with neuro-degenerative disease

神经退行性疾病患者预防和康复的靶向治疗

基本信息

批准号：
20592374
负责人：
ISHIKAWA Toshizo
金额：
$ 3.16万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

项目摘要

The neuro-glia activation in the spinal cord may mediate neuropathic pain. However, little is known about the roles of brain-derived neurotrophic factor (BDNF) and mitogen-activated protein kinase (MAPKs) in chronic pain. Although it is well documented that MAPK pathways can increase pain sensitivity via peripheral mechanisms, the present study focused on central mechanisms of MAPKs, especially ERK. In the present study, we characterized neuro-glia and evaluated pERK and c-FOS immunoreactivity after administration of 4-methylcatechol (4-MC), a BDNF inducer, can modify these derangements in relation to chronic pain. A chronic constriction injury (CCI) model as for neuropathic pain model was prepared in SD rats and pain was assessed by a reduction in paw withdrawal latency (PWL) to heat stimuli. 4-MC was injected chronically after CCI. On day 14, k252a (Trk-B receptor inhibitor) or SP600125 (JNK-1 inhibitor) was injected to determine if the analgesic effects of 4-MC could be reversed. The animals were perfused with 4% paraformaldehyde followed by fixation for immunohistochemistry (c-FOS, pERK). The rats showed a persistent decrease in PWL after CCI. On day 14, there was increase in pERK and c-FOS in regions related to pain pathways and regions associated with emotion. 4-MC reduced the decrease in PWL and this effect was reversed by k252a and SP600125, but not by minocyclin, microglial inactivator.These results suggest that the derangement of neuro-glia associated with pERK in pain-emotion system are responsible for chronic pain Neurotrophic factor related compound ameliorates chronic pain by preventing abnormal intracellular signaling via induction of BDNF and normalization of cell responses.

脊髓中的神经胶质细胞激活可能介导神经性疼痛。然而，人们对脑源性神经营养因子（BDNF）和丝裂原激活蛋白激酶（MAPK）在慢性疼痛中的作用知之甚少。尽管有充分证据表明 MAPK 通路可以通过外周机制提高疼痛敏感性，但本研究重点关注 MAPK，尤其是 ERK 的中枢机制。在本研究中，我们对神经胶质细胞进行了表征，并评估了给予 4-甲基儿茶酚 (4-MC)（一种 BDNF 诱导剂）后的 pERK 和 c-FOS 免疫反应性，可以改变与慢性疼痛相关的这些紊乱。在SD大鼠中制备用于神经性疼痛模型的慢性压迫性损伤(CCI)模型，并通过热刺激的缩爪潜伏期(PWL)的减少来评估疼痛。 CCI 后长期注射 4-MC。第14天，注射k252a（Trk-B受体抑制剂）或SP600125（JNK-1抑制剂）以确定是否可以逆转4-MC的镇痛作用。用 4% 多聚甲醛灌注动物，然后固定进行免疫组织化学（c-FOS、pERK）。 CCI 后大鼠的 PWL 持续下降。第 14 天，与疼痛通路相关的区域和与情绪相关的区域的 pERK 和 c-FOS 有所增加。 4-MC 减少了 PWL 的下降，并且这种作用被 k252a 和 SP600125 逆转，但不能被小胶质细胞灭活剂米诺环素逆转。这些结果表明，疼痛情绪系统中与 pERK 相关的神经胶质细胞的紊乱是慢性疼痛的原因。神经营养因子相关化合物通过诱导 BDNF 和细胞反应正常化。