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.

Zinc and Central Nervous System Disorders

“…Clioquinol (CQ) and ZnT3 gene deletion were shown to significantly suppress EAE (an animal model of MS)-associated clinical features and neuropathological changes, as well as inhibit MMP-9 activation, BBB disruption and immune cell infiltration, implying the involvement of synaptic Zn 2+ in myelin damage of spinal cord white matter [227,228]. Likewise, similar results were also found in a recent study using 1H10, a novel Zn 2+ chelator [229].…”

The Inhibition of Zinc Excitotoxicity and AMPK Phosphorylation by a Novel Zinc Chelator, 2G11, Ameliorates Neuronal Death Induced by Global Cerebral Ischemia

“…Our lab reported that excessive vesicular zinc released from presynaptic terminals and subsequent zinc accumulation into post-synaptic neurons induced multiple neuron death cascades, such as reactive oxygen species (ROS) production and poly(ADP-ribose) polymerase-1 (PARP-1) activation [ 45 , 46 ]. We also demonstrated that microglia activation and MMP-9 activation induced BBB disruption, which is also involved in zinc toxicity in the brain [ 41 , 47 , 48 ]. Cytoplasmic zinc increases were prevented by the intracerebroventricular (i.c.v) injection of the zinc chelator, CaEDTA [ 7 , 10 ].…”

Zinc Homeostasis: An Emerging Therapeutic Target for Neuroinflammation Related Diseases

“…1H10 is an inhibitor of AMP-activated protein kinase (AMPK) phosphorylation, and it was experimentally demonstrated that 1H10 also has the ability to chelate Zn 2+ . Intraperitoneal injection of 1H10 in mice inhibited EAE-induced demyelination and microglia/macrophage activation, inhibited EAE-induced MMP-9 activation and zinc plaque formation and alleviated multiple sclerosis (MS) [ 85 ]. Therefore, inhibition of AMPK phosphorylation or chelation of Zn 2+ may be an effective target for MS treatment.…”