Protein Nanoparticle-Related Osmotic Pressure Modifies Nonselective Permeability of the Blood–Brain Barrier by Increasing Membrane Fluidity
Received 13 November 2020
Accepted for publication 19 January 2021
Published 1 March 2021 Volume 2021:16 Pages 1663—1680
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Mian Wang
Chen Li,1,2,* LinLin Chen,1,2,* YuanYuan Wang,1,2 TingTing Wang,1,2 Dong Di,1,2 Hao Zhang,1,3 HuanHuan Zhao,1,2 Xu Shen,1,2 Jun Guo1– 3
1School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 2Key Laboratory of Drug Target and Drug for Degenerative Disease, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 3Science and Technology Experimental Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Jun Guo
School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Qixia District, Nanjing, Jiangsu, 210023, People’s Republic of China
Email [email protected]
Background: Intracellular tension plays a crucial role in the destruction of the blood–brain barrier (BBB) in response to lesion stimuli. Tight junction structure could be primarily affected by tension activity. In this study, we aimed to determine the effects of extracellular BBB damage on intracellular tension activity, and elucidate the mechanism underlying the effects of intracellular protein nanoparticle-related osmotic pressure on BBB permeability.
Methods: The intracellular tension for tight junction proteins occludin and ZO1 was evaluated using the fluorescence resonance energy transfer (FRET)-based tension probes and cpstFRET analysis. The changes in mobility ratios of occludin were evaluated via the fluorescence recovery after photobleaching (FRAP) test. The cytoplasmic osmotic pressure (OP) was measured using Osmometer. The count rate of cytoplasmic nanoparticles was detected by Nanosight NS300. The activation of cofilin and stathmin was examined by Western blot analysis. The BBB permeability in vivo was determined via the changes of Evans Blue (EB) injected into SD rats. The tight junction formation was assessed by the measurement of transendothelial electrical resistance (TEER). Intracellular calcium or chloride ions were measured using Fluo-4 AM or MQAE dyes.
Results: BBB lesions were accompanied by changes in occludin/ZO1 tension. Increases in intracellular osmotic pressure were involved in alteration of BBB permeability, possibly through the depolymerization of microfilaments or microtubules and mass production of protein nanoparticles according to the Donnan effect. Recovery of protein nanoparticle-related osmotic pressure could effectively reverse the effects of changes in occludin/ZO1 tension under BBB lesions. Outward tension of intracellular osmotic potential also caused upregulation of membrane fluidity, which promoted nonselective drug influx.
Conclusion: Our results suggest a crucial mechanical mechanism underlying BBB lesions, and protein nanoparticle-related osmotic pressure could be a novel therapeutic target for BBB lesion-related brain diseases.
Keywords: blood–brain barrier, protein nanoparticle-related osmotic pressure, occludin/ZO1 tension, permeability, membrane fluidity
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