Transferrin Receptor Mediated Brain Uptake During Ischemia and Reperfusion

Authors

  • Jiukuan Hao Department of Pharmaceutical Sciences, University of Cincinnati
  • Ulrich Bickel Department of Pharmaceutical Sciences and Center for Blood-Brain Barrier Research, Texas Tech University Health Sciences Center

DOI:

https://doi.org/10.18433/J3B303

Abstract

Purpose. Drug delivery by transferrin receptor-mediated transport at the blood-brain barrier has shown beneficial effects in animal models of stroke, but it is unclear whether receptor mediated uptake remains functional in the ischemic tissue. The present study addressed that question in a mouse model of brain focal ischemia, permanent or transient middle cerebral artery occlusion (MCAO). Methods. Brain accumulation of 125I-labeled 8D3, a mouse-specific transferrin receptor antibody, or of the isotype control UPC-10 used as vascular marker, was measured autoradiographically by phosphorimaging in the core ischemic region on cryostat brain sections up to 24h after ischemia or reperfusion. Cerebral blood flow was quantitatively determined in the same animals after administration of 99mTc-ECD (Neurolite). Results. Apparent volume of distribution obtained with UPC-10 indicated no significant nonspecific leakage of the blood-brain barrier at any time point. Although brain uptake of 8D3 gradually declined compared to healthy tissue under MCAO, VD remained significantly higher than VD of UPC-10 up to 5h. In transient MCAO the brain uptake recovered to levels as in healthy tissue immediately after reperfusion. Conclusion. Transferrin receptor-mediated brain uptake, which is an energy dependent vesicular transport process, is sensitive to reduction in blood supply but remains partially functional for several hours after onset of ischemia. The uptake shows complete recovery after reperfusion. These results support the use of transferrin receptor-mediated brain drug delivery in the early phase of ischemia and in the phase when blood flow is restored.

 

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Author Biography

Ulrich Bickel, Department of Pharmaceutical Sciences and Center for Blood-Brain Barrier Research, Texas Tech University Health Sciences Center

Ulrich Bickel, M.D., graduated from the Medical School at the University of Ulm (Germany) in 1984 and completed a specialization in Clinical Pharmacology in 1991 (Benjamin-Franklin Hospital of the Free University of Berlin, Germany). After a period as postdoc in the Department of Medicine and Brain Research Institute at the University of California, Los Angeles (1991-1994), he pursued his academic career at Philipps-University of Marburg, Germany (1994-1999). Dr. Bickel joined the faculty in the Department of Pharmaceutical Sciences in 1999. His research focuses on novel strategies for drug delivery to the brain using physiological transport mechanisms at the blood-brain barrier. He has recently obtained funding from the National Multiple Sclerosis Soci

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Published

2013-09-16

How to Cite

Hao, J., & Bickel, U. (2013). Transferrin Receptor Mediated Brain Uptake During Ischemia and Reperfusion. Journal of Pharmacy & Pharmaceutical Sciences, 16(4), 541–550. https://doi.org/10.18433/J3B303

Issue

Section

Pharmaceutical Sciences; Review Articles