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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 35; pp. 14230 - 14235
• Main Authors: Deogracias, Rubén, Yazdani, Morteza, Dekkers, Martijn P. J, Guy, Jacky, Ionescu, Mihai Constantin S, Vogt, Kaspar E, Barde, Yves-Alain
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 28-08-2012; National Acad Sciences
• Subjects: agonists; animal models; Animals; Antibodies; Astrocytes; Astrocytes - cytology; Astrocytes - metabolism; Biological Sciences; blood-brain barrier; Brain; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - deficiency; Brain-Derived Neurotrophic Factor - metabolism; cell death; Cell Death - drug effects; Cell Death - physiology; Cells, Cultured; Central nervous system; death; Disease Models, Animal; drugs; Excitatory Amino Acid Agonists - toxicity; Female; Fingolimod Hydrochloride; genes; humans; Immunosuppressive Agents - pharmacology; Intellectual disability; locomotion; Locomotor activity; Lymph nodes; Lymphocytes; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Messenger RNA; Methyl-CpG-Binding Protein 2 - genetics; Mice; mitogen-activated protein kinase; Motor Activity - drug effects; Motor Activity - physiology; Multiple sclerosis; N-Methylaspartate - toxicity; Nervous system; Neurological disorders; Neurons; Neurons - cytology; Neurons - metabolism; oral administration; Organ Culture Techniques; Pharmaceuticals; phosphates; Phosphorylation; Pregnancy; Propylene Glycols - pharmacology; Receptors; Receptors, Lysosphingolipid - agonists; Rett Syndrome - drug therapy; Rett Syndrome - genetics; Rett Syndrome - metabolism; Rodents; sclerosis; Sphingosine - analogs & derivatives; Sphingosine - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1206093109

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.