Vascular Physiology and Protein Disposition in a Preclinical Model of Neurodegeneration

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• 作者：C. Andrew Boswell ; Eduardo E. Mundo ; Bernadette Johnstone ; Sheila Ulufatu ; Michelle G. Schweiger ; Daniela Bumbaca ; Paul J. Fielder ; Saileta Prabhu ; Leslie A. Khawli
• 刊名：Molecular Pharmaceutics
• 出版年：2013
• 出版时间：May 6, 2013
• 年：2013
• 卷：10
• 期：5
• 页码：1514-1521
• 全文大小：361K
• 年卷期：v.10,no.5(May 6, 2013)
• ISSN：1543-8392

文摘

The development of clinically relevant preclinical models that mimic the hallmarks of neurodegenerative disease is an ongoing pursuit in early drug development. In particular, robust physiological characterization of central nervous system (CNS) disease models is necessary to predict drug delivery to target tissues and to correctly interpret pharmacodynamic responses to disease-modifying therapeutic candidates. Efficient drug delivery across the blood鈥揅NS barrier is a particularly daunting task, prompting our strategy to evaluate the biodistribution of five distinct molecular probes in a well-characterized mouse model of neurodegeneration. A transgenic mouse model of amyotrophic lateral sclerosis was selected based on a phenotype resembling clinical symptoms, including loss of motor neurons from the spinal cord and paralysis in one or more limbs, due to expression of a G93A mutant form of human superoxide dismutase (SOD1). The tissue distributions of two proteins, albumin and a representative immunoglobulin G antibody, as well as two blood flow markers, the lipophilic blood flow marker Ceretec (i.e., ^99mTc-HMPAO) and the polar ionic tracer, rubidium-86 chloride (⁸⁶RbCl), were measured following intravenous injection in SOD1^G93A and age-matched control mice. The radiopharmaceutical TechneScan PYP was also used to measure the distribution of ^99mTc-labeled red blood cells as a blood pool marker. Both the antibody and ⁸⁶Rb were able to cross the blood鈥搒pinal cord barrier in SOD1^G93A mice to a greater extent than in control mice. Although the biodistribution patterns of antibody, albumin, and RBCs were largely similar, notable differences were detected in muscle and skin. Moreover, vastly different biodistribution patterns were observed for a lipophilic and polar perfusion agent, with SOD1^G93A mutation resulting in reduced renal filtration rates for the former but not the latter. Overall, the multiprobe strategy provided an opportunity to efficiently collect an abundance of physiological information, including the degree and regional extent of blood鈥揅NS barrier permeability, in a preclinical model of neurodegeneration.

Keywords:

amyotrophic lateral sclerosis; SOD1; vascular volume; blood flow; physiology; blood鈭抌rain barrier; blood鈭抯pinal cord barrier; HMPAO