Conformationally altered hyaluronan mitigates the symptoms of Parkinson disease in mice

Native hyaluronan (HAn) is poor in exerting anti‐inflammatory responses. However, interchain‐dissociated or conformationally altered HA significantly inhibits complement activation. To induce interchain dissociation, HA was heat treated, quickly frozen, and quickly thawed prior to interacting with serum complement. Here, HAn is subjected to sonication for indicated times. Heat was generated up to 70 o C during sonication. Time‐related sonication HA preparations (HAson) exhibit various extent of degradation. These samples are conformationally altered due to heat treatment for 1 to 24 hr and the resulting degradation. We examined whether HAn and HAson block rotenone‐induced Parkinson’s disease (PD) in mice. Rotenone, an environmental pesticide, inhibits mitochondrial complex I and causes aggregation of α‐synuclein for leading to neuronal death. Immune competent BALB/c and C57BL/6 mice received PBS, HAn, or HAson preparations (200 μg in 100 µl PBS) via tail vein injections for two consecutive weeks, and were allowed to rest for 14 days. The mice were then challenged with rotenone (5 mg/kg) via subcutaneous injections and subjected to indicated tests two weeks later. Mice receiving HAson8 (sonication for 8 hours) significantly resisted the development of rotenone‐induced acute PD symptoms (~80% of improved mouse mobility by footprint analysis), as compared to mice receiving PBS, HAn, and other HAson preparations (4, 12, 16 and 24 hr sonication), respectively. HAson8 also blocked pentylenetetrazol‐mediated seizure in mice. All the HA preparations were not toxic to the animals, and did not alter the normal behavior of mice during experiments involving rotarod test and Barnes water maze analysis. As a potent inhibitor of Alzheimer’s disease, Zfra4‐10 peptide significantly restores memory loss, reduces PTZ‐mediated seizure and retards PD progression. Mechanistically, Zfra4‐10 binds membrane hyaluronidase Hyal‐2 to signal with WWOX and Smad4 to activate Hyal‐2+ spleen Z cells for blocking neurodegeneration. It is suggested that compared to HAn, HAson8 strongly binds membrane Hyal‐2 for Z cell activation and mitigating PD symptoms.