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The Journal of Neuroscience, September 10, 2003, 23(23):8351-8359

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Dead-Space Microdomains Hinder Extracellular Diffusion in Rat Neocortex during Ischemia

Sabina Hrabtová,¹ Jan Hrabe,² and Charles Nicholson¹

¹Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016, and ²Center for Advanced Brain Imaging, Nathan S. Kline Institute, Orangeburg, New York 10962

During ischemia, the transport of molecules in the extracellular space (ECS) is obstructed in comparison with healthy brain tissue, but the cause is unknown. Extracellular tortuosity (), normally 1.6, increases to 1.9 in ischemic thick brain slices (1000 µm), but drops to 1.5 when 70,000 M_r dextran (dex70) is added to the tissue as a background macromolecule. We hypothesized that the ischemic increase in arises from diffusion delays in newly formed dead-space microdomains of the ECS. Accordingly, decreases when dead-space diffusion is eliminated by trapping dex70 in these microdomains. We tested our hypothesis by analyzing the diffusion of several molecules in neocortical slices. First we showed that diffusion of fluorescent dex70 in thick slices declined over time, indicating the entrapment of background macromolecules. Next, we measured diffusion of tetramethylammonium (TMA⁺) (74 M_r) to show that the reduction of depended on the size of the background macromolecule. The synthetic polymer, 40,000 M_r polyvinylpyrrolidone, reduced in thick slices, whereas 10,000 M_r dextran did not. The dex70 was also effective in normoxic slices (400 µm) after hypoosmotic stress altered the ECS to mimic ischemia. Finally, the dex70 effect was confirmed independently of TMA⁺ using fluorescent 3000 M_r dextran as a diffusion marker in thick slices: decreased from 3.29 to 2.44. Taken together, these data support our hypothesis and offer a novel explanation for the origin of the large observed in ischemic brain. A semiquantitative model of dead-space diffusion corroborates this new interpretation of

Key words: extracellular space; diffusion; tortuosity; volume fraction; background macromolecules; ischemia; dwell-time diffusion model

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Received April 22, 2003; revised July 15, 2003; accepted July 16, 2003.

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