Dead-space microdomains hinder extracellular diffusion in rat neocortex during ischemia.

Area of Science:

• Neuroscience
• Biophysics
• Physiology

Background:

• Molecule transport in the brain's extracellular space (ECS) is impaired during ischemia.
• The underlying cause of this obstruction, particularly the increase in extracellular tortuosity (lambda), remains unknown.

Purpose of the Study:

• To investigate the hypothesis that increased ECS tortuosity during ischemia is caused by diffusion delays in newly formed dead-space microdomains.
• To determine if eliminating these dead-space microdomains can restore normal molecule transport.

Main Methods:

• Analysis of molecule diffusion in neocortical brain slices under varying conditions.
• Measurement of extracellular tortuosity (lambda) using fluorescent dextran and tetramethylammonium (TMA+).
• Application of different sized macromolecules (dextran, polyvinylpyrrolidone) to block dead-space microdomains.

Main Results:

• Diffusion of fluorescent dextran in thick slices decreased over time, indicating macromolecule entrapment.
• The reduction in tortuosity (lambda) by background macromolecules was dependent on their size.
• Dextran effectively reduced lambda in both ischemic and osmotically stressed normoxic slices, supporting the dead-space hypothesis.

Conclusions:

• The study supports the hypothesis that increased extracellular tortuosity during ischemia arises from diffusion delays in dead-space microdomains.
• Trapping macromolecules in these microdomains effectively reduces tortuosity and improves molecule transport.
• This provides a novel explanation for transport obstruction in ischemic brain tissue.