A Novel Iron Chelator-Radical Scavenger Ameliorates Motor Dysfunction and Improves Life Span and Mitochondrial Biogenesis in SOD1G93AALS Mice.
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 SOD1G93Atransgenic 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 SOD1G93Amice, 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 SOD1G93Amice. 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-γ co-activator 1α (PGC-1α) and increased PGC-1α-targeted metabolic genes and proteins, such as, PPARγ, UCP1/3, NRF1/2, Tfam, and ERRα in GNS muscle. These results provide evidence of therapeutic potential of VAR-ced in SOD1G93Amice with underlying molecular mechanisms, further supporting the importance role of multitarget iron chelators in ALS treatment.
Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, P.O.B. 9697, 31096, Haifa, Israel.
Sagit
S
Golko-Perez
Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, P.O.B. 9697, 31096, Haifa, Israel.
Tamar
T
Amit
Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, P.O.B. 9697, 31096, Haifa, Israel.
Orit
O
Bar-Am
Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, P.O.B. 9697, 31096, Haifa, Israel.
Moussa B H
MB
Youdim
Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, P.O.B. 9697, 31096, Haifa, Israel. worly@technion.ac.il.
Orly
O
Weinreb
D000690:Amyotrophic Lateral Sclerosis / Q000178:diet therapy / Q000188:drug therapy*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003714:Denervation; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006912:Hydroxyquinolines / Q000494:pharmacology* / Q000627:therapeutic use*; D007501:Iron / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects; D009048:Motor Skills / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000378:metabolism; D009210:Myofibrils / Q000187:drug effects; D009469:Neuromuscular Junction / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000502:physiology; D000072105:Superoxide Dismutase-1 / Q000235:genetics; D015996:Survival Rate; D015854:Up-Regulation / Q000187:drug effects
C000602792:5-(2-(methylprop-2-ynylamino)ethyl)quinolin-8-ol; D004272:DNA, Mitochondrial; D006912:Hydroxyquinolines; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D007501:Iron; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I
Amyotrophic lateral sclerosis; Mitochondrial biogenesis; Multifunctional iron chelator; SOD1G93A mice