A Novel Zinc Chelator, 1H10, Ameliorates Experimental Autoimmune Encephalomyelitis by Modulating Zinc Toxicity and AMPK Activation.

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.

• Authors: Bo Young Choi, Jeong Hyun Jeong, Jae-Won Eom, Jae-Young Koh, Yang-Hee Kim, Sang Won Suh
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 9 (May 10 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32397660 (Publication Type: Journal Article)

Chemical References

• Cation Transport Proteins
• Chelating Agents
• Slc30a3 protein, mouse
• AMP-Activated Protein Kinases
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse
• Zinc

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• B-Lymphocytes (drug effects, immunology)
• Blood-Brain Barrier (drug effects, metabolism)
• Cation Transport Proteins (metabolism)
• Cells, Cultured
• Chelating Agents (chemistry, pharmacology)
• Demyelinating Diseases (drug therapy)
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, immunology, pathology)
• Female
• Immunohistochemistry
• Macrophages (drug effects)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred C57BL
• Microglia (drug effects, metabolism)
• Neurons (drug effects, metabolism)
• Phosphorylation
• Spinal Cord (drug effects, metabolism, pathology)
• T-Lymphocytes (drug effects, immunology)
• Zinc (toxicity)