Polyoxometalate nanoclusters act as broad-spectrum antioxidants to alleviate ischemic stroke by intrathecal injection

Objectives: Stroke is the fifth leading cause of death in the United States, responsible for approximately 1 in 20 deaths. More than 87% of all strokes are an ischemic stroke, which is caused in part by the generation of reactive oxygen species (ROS) in the penumbra following ischemia/reperfusion injury (IRI). We aim to alleviate cerebral IRI by intrathecal injection of molybdenum-based nanoclusters (POM) for neuronal protection by acting as nanoantioxidants.

Methods: The antioxidant properties of POM were evaluated for hydrogen peroxide, superoxide anion, and hydroxyl radicals. POM was chelator-free radiolabeled with Zr-89 for PET imaging. The middle cerebral artery occlusion (MCAO) surgery model was Irats with the MCAO model, the biodistribution was studied by PET imaging. The efficacy of POM treatment was compared to sham, sham+POM, and PBS treated rats three days after MCAO was performed. Magnetic resonance imaging (MRI) and 2,3,5-triphenyltetrazolium chloride (TTC) staining were used to assess cerebral IRI. Oxidative stress in the brain tissue homogenate of each treatment group was evaluated by measuring levels of superoxide dismutase (SOD) and malondialdhyde (MDA). Additionally, since oxidative stress initiates inflammatory damage, levels of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured for each treatment group.

Results: PET imaging studies found that the accumulation of ⁸⁹Zr-POM in the brain following intrathecal injection was 6.6 ± 1.6%ID/g, which was significantly higher than that in the heart, lung, liver, spleen, and kidney. MRI determined that the infarct area was greater for PBS treated rats compared to POM treated rats or sham groups, suggesting POM ameliorated cerebral damage. Compared with the sham groups, the PBS-treated group was found to have lower SOD and higher MDA levels due to oxidative stress from ischemic brain damage. However, treatment with POM nanoclusters recovered SOD and MDA levels similar to sham groups. Levels of IL-6 and TNF-α in the PBS-treated group were much higher than those in the sham groups. Importantly, the anti-oxidative effects of POM substantially decreased TNF-α and IL-6 levels. Conclusion: Intrathecal injection significantly improved the delivery and efficacy of POM nanoclusters to the brain, resulting in the rapid accumulation of POM nanoclusters in the ischemic penumbra. Due to this, we confirmed that the POM nanoclusters could be used as nano-antioxidants to inhibit oxidative stress as well as inflammatory damage effectively.

• Download figure
• Open in new tab
• Download powerpoint