PMID- 31751571
OWN - NLM
STAT- MEDLINE
DCOM- 20201023
LR  - 20210422
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Print)
IS  - 0014-4886 (Linking)
VI  - 325
DP  - 2020 Mar
TI  - FTY720-Mitoxy reduces synucleinopathy and neuroinflammation, restores behavior 
      and mitochondria function, and increases GDNF expression in Multiple System 
      Atrophy mouse models.
PG  - 113120
LID - S0014-4886(19)30267-5 [pii]
LID - 10.1016/j.expneurol.2019.113120 [doi]
AB  - Multiple system atrophy (MSA) is a fatal disorder with no effective treatment. 
      MSA pathology is characterized by alpha-synuclein (aSyn) accumulation in 
      oligodendrocytes, the myelinating glial cells of the central nervous system 
      (CNS). aSyn accumulation in oligodendrocytes forms the pathognomonic glial 
      cytoplasmic inclusions (GCIs) of MSA. MSA aSyn pathology is also associated with 
      motor and autonomic dysfunction, including an impaired ability to sweat. MSA 
      patients have abnormal CNS expression of glial-cell-line-derived neurotrophic 
      factor (GDNF) and brain-derived neurotrophic factor (BDNF). Our prior studies 
      using the parent compound FTY720, a food and drug administration (FDA) approved 
      immunosuppressive for multiple sclerosis, reveal that FTY720 protects 
      parkinsonian mice by increasing BDNF. Our FTY720-derivative, FTY720-Mitoxy, is 
      known to increase expression of oligodendrocyte BDNF, GDNF, and nerve growth 
      factor (NGF) but does not reduce levels of circulating lymphocytes as it is not 
      phosphorylated so cannot modulate sphingosine 1 phosphate receptors (S1PRs). To 
      preclinically assess FTY720-Mitoxy for MSA, we used mice expressing human aSyn in 
      oligodendrocytes under a 2,' 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) 
      promoter. CNP-aSyn transgenic (Tg) mice develop motor dysfunction between 7 and 9 
      mo, and progressive GCI pathology. Using liquid chromatography-mass spectrometry 
      (LC-MS/MS) and enzymatic assays, we confirmed that FTY720-Mitoxy was stable and 
      active. Vehicle or FTY720-Mitoxy (1.1 mg/kg/day) was delivered to wild type (WT) 
      or Tg littermates from 8.5-11.5 mo by osmotic pump. We behaviorally assessed 
      their movement by rotarod and sweat production by starch‑iodine test. Postmortem 
      tissues were evaluated by qPCR for BDNF, GDNF, NGF and GDNF-receptor RET mRNA and 
      for aSyn, BDNF, GDNF, and Iba1 protein by immunoblot. MicroRNAs (miRNAs) were 
      also assessed by qPCR. FTY720-Mitoxy normalized movement, sweat function and 
      soleus muscle mass in 11.5 mo Tg MSA mice. FTY720-Mitoxy also increased levels of 
      brain GDNF and reduced brain miR-96-5p, a miRNA that acts to decrease GDNF 
      expression. Moreover, FTY720-Mitoxy blocked aSyn pathology measured by sequential 
      protein extraction and immunoblot, and microglial activation assessed by 
      immunohistochemistry and immunoblot. In the 3-nitropropionic acid (3NP) toxin 
      model of MSA, FTY720-Mitoxy protected movement and mitochondria in WT and 
      CNP-aSyn Tg littermates. Our data confirm potent in vivo protection by 
      FTY720-Mitoxy, supporting its further evaluation as a potential therapy for MSA 
      and related synucleinopathies.
CI  - Copyright (c) 2019 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Vidal-Martinez, Guadalupe
AU  - Vidal-Martinez G
AD  - Texas Tech University Health Sciences Center El Paso, Department of Molecular and 
      Translational Medicine, Center of Emphasis in Neurosciences, Graduate School of 
      Biomedical Sciences, Paul L Foster School of Medicine, 5001 El Paso Dr, El Paso, 
      TX 79905, United States of America.
FAU - Segura-Ulate, Ismael
AU  - Segura-Ulate I
AD  - Texas Tech University Health Sciences Center El Paso, Department of Molecular and 
      Translational Medicine, Center of Emphasis in Neurosciences, Graduate School of 
      Biomedical Sciences, Paul L Foster School of Medicine, 5001 El Paso Dr, El Paso, 
      TX 79905, United States of America.
FAU - Yang, Barbara
AU  - Yang B
AD  - Texas Tech University Health Sciences Center El Paso, Department of Molecular and 
      Translational Medicine, Center of Emphasis in Neurosciences, Graduate School of 
      Biomedical Sciences, Paul L Foster School of Medicine, 5001 El Paso Dr, El Paso, 
      TX 79905, United States of America.
FAU - Diaz-Pacheco, Valeria
AU  - Diaz-Pacheco V
AD  - Texas Tech University Health Sciences Center El Paso, Department of Molecular and 
      Translational Medicine, Center of Emphasis in Neurosciences, Graduate School of 
      Biomedical Sciences, Paul L Foster School of Medicine, 5001 El Paso Dr, El Paso, 
      TX 79905, United States of America.
FAU - Barragan, Jose A
AU  - Barragan JA
AD  - Texas Tech University Health Sciences Center El Paso, Department of Molecular and 
      Translational Medicine, Center of Emphasis in Neurosciences, Graduate School of 
      Biomedical Sciences, Paul L Foster School of Medicine, 5001 El Paso Dr, El Paso, 
      TX 79905, United States of America.
FAU - De-Leon Esquivel, Jocelyn
AU  - De-Leon Esquivel J
AD  - Texas Tech University Health Sciences Center El Paso, Department of Molecular and 
      Translational Medicine, Center of Emphasis in Neurosciences, Graduate School of 
      Biomedical Sciences, Paul L Foster School of Medicine, 5001 El Paso Dr, El Paso, 
      TX 79905, United States of America.
FAU - Chaparro, Stephanie A
AU  - Chaparro SA
AD  - Texas Tech University Health Sciences Center El Paso, Department of Molecular and 
      Translational Medicine, Center of Emphasis in Neurosciences, Graduate School of 
      Biomedical Sciences, Paul L Foster School of Medicine, 5001 El Paso Dr, El Paso, 
      TX 79905, United States of America.
FAU - Vargas-Medrano, Javier
AU  - Vargas-Medrano J
AD  - Texas Tech University Health Sciences Center El Paso, Department of Molecular and 
      Translational Medicine, Center of Emphasis in Neurosciences, Graduate School of 
      Biomedical Sciences, Paul L Foster School of Medicine, 5001 El Paso Dr, El Paso, 
      TX 79905, United States of America.
FAU - Perez, Ruth G
AU  - Perez RG
AD  - Texas Tech University Health Sciences Center El Paso, Department of Molecular and 
      Translational Medicine, Center of Emphasis in Neurosciences, Graduate School of 
      Biomedical Sciences, Paul L Foster School of Medicine, 5001 El Paso Dr, El Paso, 
      TX 79905, United States of America. Electronic address: rperezllc@gmail.com.
LA  - eng
GR  - D43 TW008333/TW/FIC NIH HHS/United States
GR  - RL5 GM118969/GM/NIGMS NIH HHS/United States
GR  - R01 NS042094/NS/NINDS NIH HHS/United States
GR  - TL4 GM118971/GM/NIGMS NIH HHS/United States
GR  - D43 TW006152/TW/FIC NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20191118
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Gdnf protein, mouse)
RN  - 0 (Glial Cell Line-Derived Neurotrophic Factor)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn96 microRNA, mouse)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (SNCA protein, human)
RN  - 0 (alpha-Synuclein)
RN  - 0 (fty720-mitoxy)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-ret)
RN  - EC 2.7.10.1 (Ret protein, mouse)
RN  - G926EC510T (Fingolimod Hydrochloride)
SB  - IM
MH  - Animals
MH  - Behavior, Animal/drug effects
MH  - Disease Models, Animal
MH  - Female
MH  - Fingolimod Hydrochloride/*analogs & derivatives/pharmacology
MH  - Gene Expression Regulation/drug effects
MH  - Glial Cell Line-Derived Neurotrophic Factor/*biosynthesis/drug effects
MH  - Humans
MH  - Inflammation/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - MicroRNAs/drug effects/metabolism
MH  - Multiple System Atrophy/metabolism/*pathology
MH  - Neuroprotective Agents/*pharmacology
MH  - Proto-Oncogene Proteins c-ret/biosynthesis/drug effects
MH  - alpha-Synuclein/genetics
PMC - PMC8021391
MID - NIHMS1546512
OTO - NOTNLM
OT  - Anti-inflammatory
OT  - Glioprotection
OT  - Neuroprotection
OT  - Novel therapeutic
OT  - Parkinsonian disorder
OT  - Synucleinopathy
COIS- Declaration of Competing Interest Corresponding author holds US patent # 
      10391066, "Compositions and Methods for the Treatment of Parkinson's Disease", 
      also filed in Canada (CA 2888634) and Mexico (MX 004806), which does not alter 
      adherence to Experimental Neurology policies.
EDAT- 2019/11/22 06:00
MHDA- 2020/10/24 06:00
PMCR- 2021/04/05
CRDT- 2019/11/22 06:00
PHST- 2019/06/16 00:00 [received]
PHST- 2019/11/15 00:00 [revised]
PHST- 2019/11/16 00:00 [accepted]
PHST- 2019/11/22 06:00 [pubmed]
PHST- 2020/10/24 06:00 [medline]
PHST- 2019/11/22 06:00 [entrez]
PHST- 2021/04/05 00:00 [pmc-release]
AID - S0014-4886(19)30267-5 [pii]
AID - 10.1016/j.expneurol.2019.113120 [doi]
PST - ppublish
SO  - Exp Neurol. 2020 Mar;325:113120. doi: 10.1016/j.expneurol.2019.113120. Epub 2019 
      Nov 18.