Brain endothelial permeability, transport, and flow assessed over 10 orders of magnitude using the in situ brain perfusion technique.

Autor: Smith, Quentin R., Mandula, Haritha, Parepally, Jagan Mohan R., Oki, Jun, Thomas, Fancy, Thorsheim, Helen R., Al-Ahmad, Abraham J., Abbruscato, Thomas J., Ask, Per, Hage, David S., Robinson, Peter J.
Zdroj: Fluids & Barriers of the CNS; 12/17/2024, Vol. 21 Issue 1, p1-41, 41p
Abstrakt: Background: Cerebral blood flow normally places a limit on the magnitude of brain vascular permeability (P) that can be measured in vivo. At normal cerebral blood flow, this limit falls at the lower end of lipophilicity for most FDA-approved CNS drugs. In this study, we report on two methods that can be used to overcome this limitation and measure brain vascular permeability values that are up to ~1000 times higher using the in situ brain perfusion technique. Methods: Rat brain was perfused with physiological saline at increased flow rate and in the presence of various concentrations of plasma protein, serum albumin or alpha-acid glycoprotein. Plasma protein was added to the saline perfusion fluid to lower extraction into the measurable range using the Crone Renkin "diffusion-flow" equation to calculate brain PoS. Results: Cerebrovascular Po was determined for 125 solutes, of which 78 showed little or no evidence of active efflux transport. Fifty of the solutes were in the lipophilicity zone (Log Poct 1–5) of most FDA-approved CNS drugs. Care was taken to ensure the integrity of the brain vasculature during perfusion and to measure flow accurately using markers that had been verified for the flow rates. The results showed a linear relationship between Log Po and Log Poct over ~10 orders of magnitude with values for diazepam, estradiol, testosterone, and other agents that exceed prior published values by fivefold to 200-fold. Conclusions: The results show that brain vascular permeability can be measured directly in vivo for highly lipophilic solutes and the PS values obtained match reasonably with that predicted by the Crone-Renkin flow diffusion equation with care taken to validate the accuracy for the component measurements and with no need to invoke "enhanced" or "induced" dissociation. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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