BDNF may play a differential role in the protective effect of the mGluR2/3 agonist LY379268 on striatal projection neurons in R6/2 Huntington's disease mice.
BDNF may play a differential role in the protective effect of the mGluR2/3 agonist LY379268 on striatal projection neurons in R6/2 Huntington's disease mice.
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DOI：
10.1016/j.brainres.2012.07.026
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发表时间：
2012-09-14
期刊：
影响因子：
2.9
通讯作者：
Deng YP
中科院分区：
文献类型：
--
作者：
Reiner A;Wang HB;Del Mar N;Sakata K;Yoo W;Deng YP
我们已经发现，从第4周开始每天皮下注射最大耐受剂量（MTD）的mGluR 2/3激动剂LY 379268（20 mg/kg）显著改善了R6/2小鼠的表型。例如，我们观察到运动功能在运动距离、速度、暂停频率和直线运动能力方面的正常化，以及在10周时挽救了15-20%的纹状体神经元损失。由于已知急性LY 379268治疗可增加皮质BDNF的产生，并且已知BDNF对纹状体神经元有益，因此我们研究了R6/2小鼠中每日LY 379268对纹状体投射神经元的益处是否与皮质纹状体BDNF的增加相关，并在10周龄时从出生后第四周开始每日MTD治疗后进行评估。我们发现，LY 379268增加BDNF的表达在运动皮层的第5层神经元，这项目到纹状体，部分挽救了优先损失的脑啡肽能纹状体神经元，并增强P物质（SP）纹状体投射神经元的表达。纹状体脑啡肽能神经元存活率的增加与皮质BDNF的增加有关，而纹状体SP能神经元SP表达的增加与此无关。因此，LY 379268可能通过不同的机制保护两种主要的纹状体投射神经元类型，通过BDNF的营养益处保护脑啡肽能神经元，并且通过不涉及BDNF的机制保护SP神经元。SP神经元益处可能反而涉及mGluR 2/3受体激动剂的抗兴奋毒性作用。
We have found that daily subcutaneous injection with a maximum tolerated dose (MTD) of the mGluR2/3 agonist LY379268 (20mg/kg) beginning at 4 weeks dramatically improves the phenotype in R6/2 mice. For example, we observed normalization of motor function in distance traveled, speed, the infrequency of pauses, and the ability to locomote in a straight line, and a rescue of a 15–20% striatal neuron loss at 10 weeks. As acute LY379268 treatment is known to increase cortical BDNF production, and BDNF is known to be beneficial for striatal neurons, we investigated if the benefit of daily LY379268 in R6/2 mice for striatal projection neurons was associated with increases in corticostriatal BDNF, with assessments done at 10 weeks of age after daily MTD treatment since the fourth week of life. We found that LY379268 increased BDNF expression in layer 5 neurons in motor cortex, which project to striatum, partly rescued a preferential loss of enkephalinergic striatal neurons, and enhanced substance P (SP) expression by SP striatal projection neurons. The enhanced survival of enkephalinergic striatal neurons was correlated with the cortical BDNF increase, but the enhanced SP expression by SP striatal neurons was not. Thus, LY379268 may protect the two main striatal projection neuron types by different mechanisms, enkephalinergic neurons by the trophic benefit of BDNF, and SP neurons by a mechanism not involving BDNF. The SP neuron benefit may perhaps instead involve the anti-excitotoxic action of mGluR2/3 receptor agonists.
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DOI：
10.1073/pnas.1004744108
发表时间：
2011-01-25
影响因子：
11.1
作者：
Baydyuk, Maryna;Russell, Theron;Xu, Baoji
通讯作者：
Xu, Baoji
影响因子：
5.3
作者：
Canals, JM;Pineda, JR;Alberch, J
通讯作者：
Alberch, J
影响因子：
3
作者：
Drai, D;Benjamini, Y;Golani, I
通讯作者：
Golani, I
影响因子：
3.4
作者：
Cozzi, A;Attucci, S;Moroni, F
通讯作者：
Moroni, F
影响因子：
5.3
作者：
FIGUEREDOCARDENAS, G;ANDERSON, KD;REINER, A
通讯作者：
REINER, A