JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-hydroxydopamine Model of Parkinson's Disease.
JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-hydroxydopamine Model of Parkinson's Disease.
复制标题
DOI：
10.1021/cn1001107
复制
发表时间：
2011-04-20
影响因子：
5
通讯作者：
LoGrasso, Philip
中科院分区：
文献类型：
--
作者：
Crocker, Candice E.;Khan, Susan;Cameron, Michael D.;Robertson, Harold A.;Robertson, George S.;LoGrasso, Philip
帕金森氏病（PD）是由于位于黑质腹侧部（SNpc）的投射到纹状体的多巴胺神经元的损失而引起的。尚未确定停止这种神经变性过程的治疗剂，因此，脑渗透性小分子神经保护剂的开发将代表该疾病治疗的重大进展。为了填补这一空白，我们开发了一种氨基嘧啶JNK抑制剂（SR-3306），减少了多巴胺能细胞体的损失，在SNPC和它们的终端在纹状体产生的单侧注射6-羟基多巴胺（6-OHDA）到黑质纹状体通路。SR-3306 [10 mg/kg/天（s.c.）持续14天]使SNpc中酪氨酸羟化酶免疫反应性（TH+）神经元的数量增加6倍，并且相对于仅接受载体的6-OHDA损伤大鼠的相应侧减少纹状体中TH+末端的损失（p<0.05）。此外，SR-3306 [10 mg/kg/天（s.c.）持续14天]与给予载体的6-OHDA损伤的动物相比，使d-苯丙胺诱导的盘旋减少87%。第14天SR-3306的稳态脑水平为347 nM，约为该化合物基于细胞的IC 50的两倍。最后，磷酸-c-jun（p-c-jun）的免疫组织化学染色显示SR-3306 [10 mg/kg/天（s.c.）14天]使SNpc中免疫反应性神经元的数量相对于载体处理的大鼠减少2.3倍。总的来说，这些数据表明口服生物可利用的JNK抑制剂可能是治疗帕金森病的有用的神经保护剂。
Parkinson’s disease (PD) results from the loss of dopamine neurons located in the substantia nigra pars compacta (SNpc) that project to the striatum. A therapeutic has yet to be identified that halts this neurodegenerative process, and as such, development of a brain penetrant small molecule neuroprotective agent would represent a significant advancement in the treatment of the disease. To fill this void we developed an aminopyrimidine JNK inhibitor (SR-3306) that reduced the loss of dopaminergic cell bodies in the SNpc and their terminals in the striatum produced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the nigrostriatal pathway. Administration of SR-3306 [10 mg/kg/day (s.c.) for 14 days] increased the number of tyrosine hydroxylase immunoreactive (TH+) neurons in the SNpc by six-fold and reduced the loss of the TH+ terminals in the striatum relative to the corresponding side of 6-OHDA-lesioned rats that received only vehicle (p<0.05). In addition, SR-3306 [10 mg/kg/day (s.c.) for 14 days] decreased d-amphetamine-induced circling by 87% compared to 6-OHDA-lesioned animals given vehicle. Steady-state brain levels of SR-3306 at day 14 were 347 nM, which was approximately two-fold higher than the cell-based IC50 for this compound. Finally, immunohistochemical staining for phospho-c-jun (p-c-jun) revealed that SR-3306 [10 mg/kg/day (s.c.) for 14 days] produced a 2.3-fold reduction of the number of immunoreactive neurons in the SNpc relative to vehicle treated rats. Collectively, these data suggest that orally bioavailable JNK inhibitors may be useful neuroprotective agents for the treatment of Parkinson’s disease.
登录
查看更多内容
影响因子：
4.7
作者：
Ganguly, A;Oo, TF;Burke, RE
通讯作者：
Burke, RE
DOI：
10.1073/pnas.181182298
发表时间：
2001-08-28
影响因子：
11.1
作者：
Xia, XG;Harding, T;Schulz, JB
通讯作者：
Schulz, JB
影响因子：
3.4
作者：
Vaudano, E;Rosenblad, C;Björklund, A
通讯作者：
Björklund, A
影响因子：
5
作者：
Chambers, Jeremy W.;Pachori, Alok;Howard, Shannon;Ganno, Michelle;Hansen, Donald, Jr.;Kamenecka, Ted;Song, Xinyi;Duckett, Derek;Chen, Weimin;Ling, Yuan Yuan;Cherry, Lisa;Cameron, Michael D.;Lin, Li;Ruiz, Claudia H.;LoGrasso, Philip
通讯作者：
LoGrasso, Philip
影响因子：
2.5
作者：
Pan, Jing;Zhao, Yan-Xin;Chen, Sheng-Di
通讯作者：
Chen, Sheng-Di