A Novel Iron Chelator-Radical Scavenger Ameliorates Motor Dysfunction and Improves Life Span and Mitochondrial Biogenesis in SOD1(G93A) ALS Mice

作者：Golko Perez Sagit; Amit Tamar; Bar Am Orit; Youdim Moussa B H; Weinreb Orly

来源：Neurotoxicity Research, 2017, 31(2): 230-244.

DOI：10.1007/s12640-016-9677-6

• Amyotrophic lateral sclerosis
• Multifunctional iron chelator
• Mitochondrial biogenesis
• SOD1(G93A) 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 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 1 alpha (PGC-1 alpha) and increased PGC-1 alpha-targeted metabolic genes and proteins, such as, PPAR gamma, UCP1/3, NRF1/2, Tfam, and ERR alpha 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.

• 出版日期2017-2