Abstract
Huntington's disease (HD) is themost common neurodegenerative disorder for which no effective cure is yet available. Although several agents have been identified to provide benefits so far, the number of therapeutic options remains limited with only symptomatic treatment available. Over the past few years, we have demonstrated that sphingolipid-based approachesmay open the door to newandmore targeted treatments for the disease. In this study, we investigated the therapeutic potential of stimulating sphingosine-1-phosphate (S1P) receptor 5 by the new selective agonist A-971432 (provided by AbbVie) in R6/2mice, a widely used HD animalmodel. Chronic administration of low-dose (0.1mg/kg) A-971432 slowed down the progression of the disease and significantly prolonged lifespan in symptomatic R6/2mice. Such beneficial effects were associated with activation of pro-survival pathways (BDNF, AKT and ERK) and with reduction of mutant huntingtin aggregation. A-971432 also protected blood-brain barrier (BBB) homeostasis in the same mice. Interestingly, when administered early in the disease, before any overt symptoms, A-971432 completely protected HDmice fromthe classic progressivemotor deficit and preserved BBB integrity. Beside representing a promising strategy to take into consideration for the development of alternative therapeutic options for HD, selective stimulation of S1P receptor 5may be also seen as an effective approach to target brain vasculature defects in the disease.
| Original language | English |
|---|---|
| Pages (from-to) | 2490-2501 |
| Number of pages | 12 |
| Journal | Human Molecular Genetics |
| Volume | 27 |
| Issue number | 14 |
| DOIs | |
| Publication status | Published - Jul 15 2018 |
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ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)
Cite this
Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington's disease. / Di Pardo, Alba; Castaldo, Salvatore; Amico, Enrico; Pepe, Giuseppe; Marracino, Federico; Capocci, Luca; Giovannelli, Alfredo; Madonna, Michele; van Bergeijk, Jeroen; Buttari, Fabio; van der Kam, Elizabeth; Maglione, Vittorio.
In: Human Molecular Genetics, Vol. 27, No. 14, 15.07.2018, p. 2490-2501.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington's disease
AU - Di Pardo, Alba
AU - Castaldo, Salvatore
AU - Amico, Enrico
AU - Pepe, Giuseppe
AU - Marracino, Federico
AU - Capocci, Luca
AU - Giovannelli, Alfredo
AU - Madonna, Michele
AU - van Bergeijk, Jeroen
AU - Buttari, Fabio
AU - van der Kam, Elizabeth
AU - Maglione, Vittorio
PY - 2018/7/15
Y1 - 2018/7/15
N2 - Huntington's disease (HD) is themost common neurodegenerative disorder for which no effective cure is yet available. Although several agents have been identified to provide benefits so far, the number of therapeutic options remains limited with only symptomatic treatment available. Over the past few years, we have demonstrated that sphingolipid-based approachesmay open the door to newandmore targeted treatments for the disease. In this study, we investigated the therapeutic potential of stimulating sphingosine-1-phosphate (S1P) receptor 5 by the new selective agonist A-971432 (provided by AbbVie) in R6/2mice, a widely used HD animalmodel. Chronic administration of low-dose (0.1mg/kg) A-971432 slowed down the progression of the disease and significantly prolonged lifespan in symptomatic R6/2mice. Such beneficial effects were associated with activation of pro-survival pathways (BDNF, AKT and ERK) and with reduction of mutant huntingtin aggregation. A-971432 also protected blood-brain barrier (BBB) homeostasis in the same mice. Interestingly, when administered early in the disease, before any overt symptoms, A-971432 completely protected HDmice fromthe classic progressivemotor deficit and preserved BBB integrity. Beside representing a promising strategy to take into consideration for the development of alternative therapeutic options for HD, selective stimulation of S1P receptor 5may be also seen as an effective approach to target brain vasculature defects in the disease.
AB - Huntington's disease (HD) is themost common neurodegenerative disorder for which no effective cure is yet available. Although several agents have been identified to provide benefits so far, the number of therapeutic options remains limited with only symptomatic treatment available. Over the past few years, we have demonstrated that sphingolipid-based approachesmay open the door to newandmore targeted treatments for the disease. In this study, we investigated the therapeutic potential of stimulating sphingosine-1-phosphate (S1P) receptor 5 by the new selective agonist A-971432 (provided by AbbVie) in R6/2mice, a widely used HD animalmodel. Chronic administration of low-dose (0.1mg/kg) A-971432 slowed down the progression of the disease and significantly prolonged lifespan in symptomatic R6/2mice. Such beneficial effects were associated with activation of pro-survival pathways (BDNF, AKT and ERK) and with reduction of mutant huntingtin aggregation. A-971432 also protected blood-brain barrier (BBB) homeostasis in the same mice. Interestingly, when administered early in the disease, before any overt symptoms, A-971432 completely protected HDmice fromthe classic progressivemotor deficit and preserved BBB integrity. Beside representing a promising strategy to take into consideration for the development of alternative therapeutic options for HD, selective stimulation of S1P receptor 5may be also seen as an effective approach to target brain vasculature defects in the disease.
UR - http://www.scopus.com/inward/record.url?scp=85050819926&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050819926&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddy153
DO - 10.1093/hmg/ddy153
M3 - Article
C2 - 29688337
AN - SCOPUS:85050819926
VL - 27
SP - 2490
EP - 2501
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 14
ER -