A Novel Zinc Chelator, 1H10, Ameliorates Experimental Autoimmune Encephalomyelitis by Modulating Zinc Toxicity and AMPK Activation
Open Access
- 10 May 2020
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 21 (9), 3375
- https://doi.org/10.3390/ijms21093375
Abstract
Previous studies in our lab revealed that chemical zinc chelation or zinc transporter 3 (ZnT3) gene deletion suppresses the clinical features and neuropathological changes associated with experimental autoimmune encephalomyelitis (EAE). In addition, although protective functions are well documented for AMP-activated protein kinase (AMPK), paradoxically, disease-promoting effects have also been demonstrated for this enzyme. Recent studies have demonstrated that AMPK contributes to zinc-induced neurotoxicity and that 1H10, an inhibitor of AMPK, reduces zinc-induced neuronal death and protects against oxidative stress, excitotoxicity, and apoptosis. Here, we sought to evaluate the therapeutic efficacy of 1H10 against myelin oligodendrocyte glycoprotein 35-55-induced EAE. 1H10 (5 μg/kg) was intraperitoneally injected once per day for the entire experimental course. Histological evaluation was performed three weeks after the initial immunization. We found that 1H10 profoundly reduced the severity of the induced EAE and that there was a remarkable suppression of demyelination, microglial activation, and immune cell infiltration. 1H10 also remarkably inhibited EAE-associated blood-brain barrier (BBB) disruption, MMP-9 activation, and aberrant synaptic zinc patch formation. Furthermore, the present study showed that long-term treatment with 1H10 also reduced the clinical course of EAE. Therefore, the present study suggests that zinc chelation and AMPK inhibition with 1H10 may have great therapeutic potential for the treatment of multiple sclerosis.Funding Information
- National Research Foundation of Korea (NRF-2017M3C7A1028937, NRF-2019R1A2C4004912)
This publication has 55 references indexed in Scilit:
- AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling networkAgeing Research Reviews, 2012
- Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)British Journal of Pharmacology, 2011
- AMP-activated protein kinase—an energy sensor that regulates all aspects of cell functionGenes & Development, 2011
- Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington’s diseaseThe Journal of cell biology, 2011
- Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal ResearchPLoS Biology, 2010
- AMPK in the brain: its roles in energy balance and neuroprotectionJournal of Neurochemistry, 2009
- Multiple sclerosisThe Lancet, 2008
- Zinc Triggers Microglial ActivationJournal of Neuroscience, 2008
- Neuroprotective Effects of Adenosine Monophosphate- Activated Protein Kinase Inhibition and Gene Deletion in StrokeStroke, 2007
- Clioquinol, a Drug for Alzheimer's Disease Specifically Interfering with Brain Metal Metabolism: Structural Characterization of Its Zinc(II) and Copper(II) ComplexesInorganic Chemistry, 2004