Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome

被引:210
作者
Deogracias, Ruben [1 ]
Yazdani, Morteza [1 ]
Dekkers, Martijn P. J. [1 ]
Guy, Jacky [2 ]
Ionescu, Mihai Constantin S. [1 ]
Vogt, Kaspar E. [1 ]
Barde, Yves-Alain [1 ]
机构
[1] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland
[2] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland
基金
瑞士国家科学基金会;
关键词
electrophysiology; transcription; NEUROTROPHIC FACTOR; MUTANT MICE; RESPIRATORY-FUNCTION; NERVOUS-SYSTEM; FTY720; PHOSPHORYLATION; TRANSCRIPTION; MECP2; ASTROCYTES; EXPRESSION;
D O I
10.1073/pnas.1206093109
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The functional relevance of brain-derived neurotrophic factor (BDNF) is beginning to be well appreciated not only in mice, but also in humans. Because reduced levels typically correlate with impaired neuronal function, increasing BDNF levels with well-tolerated drugs diffusing into the central nervous system may help in ameliorating functional deficits. With this objective in mind, we used the sphingosine-1 phosphate receptor agonist fingolimod, a drug that crosses the blood-brain barrier. In addition, fingolimod has recently been introduced as the first oral treatment for multiple sclerosis. In cultured neurons, fingolimod increases BDNF levels and counteracts NMDA-induced neuronal death in a BDNF-dependent manner. Ongoing synaptic activity and MAPK signaling is required for fingolimod-induced BDNF increase, a pathway that can also be activated in vivo by systemic fingolimod administration. Mice lacking Mecp2, a gene frequently mutated in Rett syndrome, show decreased levels of BDNF, and fingolimod administration was found to partially rescue these levels as well as the size of the striatum, a volumetric sensor of BDNF signaling in rodents. These changes correlate with increased locomotor activity of the Mecp2-deficient animals, suggesting that fingolimod may improve the functional output of the nervous system, in addition to its well-documented effects on lymphocyte egress from lymph nodes.
引用
收藏
页码:14230 / 14235
页数:6
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