Monoacylglycerol lipase inhibitor JZL184 improves behavior and neural properties in Ts65Dn mice, a model of down syndrome.
Monoacylglycerol lipase inhibitor JZL184 improves behavior and neural properties in Ts65Dn mice, a model of down syndrome.
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DOI：
10.1371/journal.pone.0114521
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kleschevnikov AM
中科院分区：
文献类型：
--
作者：
Lysenko LV;Kim J;Henry C;Tyrtyshnaia A;Kohnz RA;Madamba F;Simon GM;Kleschevnikova NE;Nomura DK;Ezekowitz RA;Kleschevnikov AM
影响内源性大麻素信号的基因改变或药物治疗对突触和神经元特性有深远的影响，在某些条件下，可能改善高级脑功能。唐氏综合症（DS）是一种由21号染色体三倍性引起的发育障碍，其特征是认知缺陷，并在衰老过程中不可避免地发展为阿尔茨海默病（AD）型病理。本研究使用选择性单酰基甘油脂肪酶（MAGL）抑制剂JZL184，研究慢性MAGL抑制对衰老Ts65Dn小鼠（DS遗传模型）行为、生化和突触特性的影响。在Ts65Dn小鼠及其正常染色体（2N）对照中，jzl184处理增加了脑内2-花生四烯醇甘油（2-AG）的水平，降低了其代谢物如花生四烯酸、前列腺素PGD2、PGE2、PGFα和PGJ2的水平。经jzl184处理后，Ts65Dn小鼠自发运动活性的增强降低到2N小鼠的水平。长期记忆缺陷也得到了改善，而短期记忆和工作记忆则未受影响。此外，jzl184处理的Ts65Dn小鼠海马长期增强（LTP）的减少增加到2N小鼠的水平。有趣的是，在jzl184处理的2N小鼠中没有观察到突触可塑性和行为的变化，这表明该处理特异性地减轻了三体动物的缺陷。jzl184处理也降低了Ts65Dn和2N小鼠a - β40和a - β42的水平，但对全长APP和BACE1的水平没有影响。这些数据表明，慢性MAGL抑制可以改善DS模型中的行为和脑功能，这表明药物靶向MAGL可能被认为是改善DS认知的新途径。
Genetic alterations or pharmacological treatments affecting endocannabinoid signaling have profound effects on synaptic and neuronal properties and, under certain conditions, may improve higher brain functions. Down syndrome (DS), a developmental disorder caused by triplication of chromosome 21, is characterized by deficient cognition and inevitable development of the Alzheimer disease (AD) type pathology during aging. Here we used JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), to examine the effects of chronic MAGL inhibition on the behavioral, biochemical, and synaptic properties of aged Ts65Dn mice, a genetic model of DS. In both Ts65Dn mice and their normosomic (2N) controls, JZL184-treatment increased brain levels of 2-arachidonoylglycerol (2-AG) and decreased levels of its metabolites such as arachidonic acid, prostaglandins PGD2, PGE2, PGFα, and PGJ2. Enhanced spontaneous locomotor activity of Ts65Dn mice was reduced by the JZL184-treatement to the levels observed in 2N animals. Deficient long-term memory was also improved, while short-term and working types of memory were unaffected. Furthermore, reduced hippocampal long-term potentiation (LTP) was increased in the JZL184-treated Ts65Dn mice to the levels observed in 2N mice. Interestingly, changes in synaptic plasticity and behavior were not observed in the JZL184-treated 2N mice suggesting that the treatment specifically attenuated the defects in the trisomic animals. The JZL184-treatment also reduced the levels of Aβ40 and Aβ42, but had no effect on the levels of full length APP and BACE1 in both Ts65Dn and 2N mice. These data show that chronic MAGL inhibition improves the behavior and brain functions in a DS model suggesting that pharmacological targeting of MAGL may be considered as a perspective new approach for improving cognition in DS.
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影响因子：
2.5
作者：
Belichenko, PV;Masliah, E;Mobley, WC
通讯作者：
Mobley, WC
影响因子：
2.8
作者：
Counts SE;Che S;Ginsberg SD;Mufson EJ
通讯作者：
Mufson EJ
DOI：
10.1177/0269881111405366
发表时间：
2011-08
期刊：
Journal of psychopharmacology (Oxford, England)
影响因子：
--
作者：
Braudeau J;Delatour B;Duchon A;Pereira PL;Dauphinot L;de Chaumont F;Olivo-Marin JC;Dodd RH;Hérault Y;Potier MC
通讯作者：
Potier MC
DOI：
10.1124/jpet.111.180257
发表时间：
2011-07-01
影响因子：
3.5
作者：
Ahn, Kay;Smith, Sarah E.;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.
影响因子：
25
作者：
Di Marzo, Vincenzo
通讯作者：
Di Marzo, Vincenzo