PMID- 27826939
OWN - NLM
STAT- MEDLINE
DCOM- 20171010
LR  - 20191210
IS  - 1476-3524 (Electronic)
IS  - 1029-8428 (Linking)
VI  - 31
IP  - 2
DP  - 2017 Feb
TI  - A Novel Iron Chelator-Radical Scavenger Ameliorates Motor Dysfunction and 
      Improves Life Span and Mitochondrial Biogenesis in SOD1(G93A) ALS Mice.
PG  - 230-244
LID - 10.1007/s12640-016-9677-6 [doi]
AB  - The aim of the present study was to evaluate the therapeutic effect of the novel 
      neuroprotective multitarget brain permeable monoamine oxidase inhibitor/iron 
      chelating-radical scavenging drug, VAR10303 (VAR), co-administered with 
      high-calorie/energy-supplemented diet (ced) in SOD1(G93A) transgenic amyotrophic 
      lateral sclerosis (ALS) mice. Administration of VAR-ced was initiated after the 
      appearance of disease symptoms (at day 88), as this regimen is comparable with 
      the earliest time at which drug therapy could start in ALS patients. Using this 
      rescue protocol, we demonstrated in the current study that VAR-ced treatment 
      provided several beneficial effects in SOD1(G93A) mice, including improvement in 
      motor performance, elevation of survival time, and attenuation of iron 
      accumulation and motoneuron loss in the spinal cord. Moreover, VAR-ced treatment 
      attenuated neuromuscular junction denervation and exerted a significant 
      preservation of myofibril regular morphology, associated with a reduction in the 
      expression levels of genes related to denervation and atrophy in the 
      gastrocnemius (GNS) muscle in SOD1(G93A) mice. These effects were accompanied by 
      upregulation of mitochondrial DNA and elevated activities of complexes I and II 
      in the GNS muscle. We have also demonstrated that VAR-ced treatment upregulated 
      the mitochondrial biogenesis master regulator, peroxisome proliferator-activated 
      receptor-gamma co-activator 1alpha (PGC-1alpha) and increased PGC-1alpha-targeted metabolic genes 
      and proteins, such as, PPARgamma, UCP1/3, NRF1/2, Tfam, and ERRalpha in GNS muscle. These 
      results provide evidence of therapeutic potential of VAR-ced in SOD1(G93A) mice 
      with underlying molecular mechanisms, further supporting the importance role of 
      multitarget iron chelators in ALS treatment.
FAU - Golko-Perez, Sagit
AU  - Golko-Perez S
AD  - Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, 
      P.O.B. 9697, 31096, Haifa, Israel.
FAU - Amit, Tamar
AU  - Amit T
AD  - Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, 
      P.O.B. 9697, 31096, Haifa, Israel.
FAU - Bar-Am, Orit
AU  - Bar-Am O
AD  - Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, 
      P.O.B. 9697, 31096, Haifa, Israel.
FAU - Youdim, Moussa B H
AU  - Youdim MB
AD  - Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, 
      P.O.B. 9697, 31096, Haifa, Israel.
FAU - Weinreb, Orly
AU  - Weinreb O
AD  - Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, 
      P.O.B. 9697, 31096, Haifa, Israel. worly@technion.ac.il.
LA  - eng
PT  - Journal Article
DEP - 20161108
PL  - United States
TA  - Neurotox Res
JT  - Neurotoxicity research
JID - 100929017
RN  - 0 (5-(2-(methylprop-2-ynylamino)ethyl)quinolin-8-ol)
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Hydroxyquinolines)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.15.1.1 (Sod1 protein, mouse)
RN  - EC 1.15.1.1 (Superoxide Dismutase-1)
RN  - EC 1.3.5.1 (Electron Transport Complex II)
RN  - EC 7.1.1.2 (Electron Transport Complex I)
SB  - IM
MH  - Amyotrophic Lateral Sclerosis/diet therapy/*drug therapy
MH  - Animals
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Combined Modality Therapy
MH  - DNA, Mitochondrial/*metabolism
MH  - Denervation
MH  - Electron Transport Complex I/metabolism
MH  - Electron Transport Complex II/metabolism
MH  - Female
MH  - Gene Expression/drug effects
MH  - Hydroxyquinolines/*pharmacology/*therapeutic use
MH  - Iron/metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Motor Neurons/drug effects
MH  - Motor Skills/*drug effects
MH  - Muscle, Skeletal/metabolism
MH  - Myofibrils/drug effects
MH  - Neuromuscular Junction/pathology
MH  - Oxidative Stress/drug effects
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
MH  - Spinal Cord/metabolism/physiology
MH  - Superoxide Dismutase-1/genetics
MH  - *Survival Rate
MH  - Up-Regulation/drug effects
OTO - NOTNLM
OT  - Amyotrophic lateral sclerosis
OT  - Mitochondrial biogenesis
OT  - Multifunctional iron chelator
OT  - SOD1G93A mice
EDAT- 2016/11/09 06:00
MHDA- 2017/10/11 06:00
CRDT- 2016/11/10 06:00
PHST- 2016/06/30 00:00 [received]
PHST- 2016/10/13 00:00 [accepted]
PHST- 2016/10/05 00:00 [revised]
PHST- 2016/11/09 06:00 [pubmed]
PHST- 2017/10/11 06:00 [medline]
PHST- 2016/11/10 06:00 [entrez]
AID - 10.1007/s12640-016-9677-6 [pii]
AID - 10.1007/s12640-016-9677-6 [doi]
PST - ppublish
SO  - Neurotox Res. 2017 Feb;31(2):230-244. doi: 10.1007/s12640-016-9677-6. Epub 2016 
      Nov 8.