AS601245, a c-Jun NH2-terminal kinase (JNK) inhibitor, reduces axon/dendrite damage and cognitive deficits after global cerebral ischaemia in gerbils
AS601245, a c-Jun NH2-terminal kinase (JNK) inhibitor, reduces axon/dendrite damage and cognitive deficits after global cerebral ischaemia in gerbils
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DOI：
10.1038/sj.bjp.0707574
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发表时间：
2008-01-01
影响因子：
7.3
通讯作者：
Vitte, P-A
中科院分区：
文献类型：
--
作者：
Carboni, S.;Boschert, U.;Vitte, P-A
背景和目的。基于它们在中风动物模型中被证明的减少脑灰质损伤的能力，许多药物已经在临床试验中进行了测试，但没有成功。未能挽救轴突损伤和保护功能的结果已被提出作为这种缺乏成功的主要原因。我们之前已经在两种啮齿动物脑缺血模型中证明了AS 601245（1，3-苯并噻唑-2-基（2-{[2-（3-吡啶基）乙基]氨基}-4嘧啶基）乙腈），一种c-Jun NH 2-末端激酶（JNK）抑制剂，具有神经保护特性。本研究的目的是进一步研究AS 601245除了保护神经元的能力外，是否还可以保护沙土鼠脑缺血后的神经突和记忆。使用免疫组织化学技术和行为测试，我们研究了化合物AS 601245对沙土鼠全脑缺血后神经变性和认知缺陷的影响。关键结果。剂量为80 mg/kg，腹腔注射，AS 601245使神经突损伤减少67%（与对照组相比P < 0.001），星形胶质细胞活化减少84%（与对照组相比P < 0.001）。此外，AS 601245（80 mg kg（-1），i. p.）在抑制性回避任务模型中预防缺血引起的记忆损伤。结论和意义。目前的结果表明，AS 601245减少了神经突损伤，减少了全脑缺血后的星形胶质细胞增生，还改善了长期记忆，支持JNK抑制作为CNS缺血性损伤的有前景的治疗策略。
Background and purpose. Based on their proven ability, in animal models of stroke, to reduce damage to brain grey matter, many drugs have been tested in clinical trials but without success. Failure to save axons from injury and to protect functional outcome has been proposed as the major reason for this lack of success. We have previously demonstrated in two rodent models of cerebral ischaemia, that AS601245 (1,3-benzothiazol-2-yl (2-{[2-(3-pyridinyl) ethyl] amino}-4 pyrimidinyl) acetonitrile), an inhibitor of the c-Jun NH2-terminal kinase (JNK), has neuroprotective properties. The aim of the present study was to further investigate if AS601245 in addition to its ability to protect neurons also could protect neurites and preserve memory after cerebral ischaemia, in gerbils.Experimental approach. Using immunohistochemical techniques and a behavioural test, we studied the effect of the compound AS601245 on neurodegeneration and cognitive deficits after global cerebral ischaemia in gerbils.Key results. At a dose of 80 mgkg(-1), i.p., AS601245 reduced damage to neurites by 67% (P < 0.001 versus controls) and activation of astrocytes by 84% (P < 0.001 versus controls). In addition, AS601245 (80 mgkg(-1), i.p.) prevented ischaemia-induced impairment of memory in the inhibitory avoidance task model.Conclusions and implications. The present results suggest that AS601245 reduced damage to neurites and decreased astrogliosis following global ischaemia and also improved long-term memory, supporting JNK inhibition as a promising therapeutic strategy for ischaemic insults to the CNS.