Brain penetrating IgG-erythropoietin fusion protein is neuroprotective following intravenous treatment in Parkinson's disease in the mouse

作者：Zhou Qing Hui; Hui Eric Ka Wai; Lu Jeff Zhiqiang; Boado Ruben J; Pardridge William M^*

来源：Brain Research, 2011, 1382: 315-320.

DOI：10.1016/j.brainres.2011.01.061

• Blood-brain barrier
• Parkinson's disease
• Erythropoietin
• Monoclonal antibody

Parkinson's disease (PD) is caused by oxidative stress, and erythropoietin (EPO) reduces oxidative stress in the brain. However, EPO cannot be developed as a treatment for PD, because EPO does not cross the blood-brain barrier (BBB). A brain penetrating form of human EPO has been developed wherein EPO is fused to a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), which is designated as the cTfFtMAb-EPO fusion protein. The TfRMAb acts as a molecular Trojan horse to transport the fused EPO into brain via transport on the BBB TfR. Experimental PD was induced in adult mice by the intra-striatal injection of 6-hydroxydopamine, and PD mice were treated with 1 mg/kg of the cTfRMAb-EPO fusion protein intravenously (IV) every other day starting 1 h after toxin injection. Following 3 weeks of treatment mice were euthanized for measurement of striatal tyrosine hydroxylase (TH) enzyme activity. Mice treated with the cTfRMAb-EPO fusion protein showed a 306% increase in striatal TH enzyme activity, which correlated with improvement in three assays of neurobehavior. The blood hematocrit increased 10% at 2 weeks, with no further changes at 3 weeks of treatment. A sandwich ELISA showed the immune reaction against the cTfRMAb-EPO fusion protein was variable and low titer. In conclusion, the present study demonstrates that a brain penetrating form of EPO is neuroprotective in PD following IV administration with minimal effects on erythropoiesis.

• 出版日期2011-3-25