Targeting Caveolin-1 and Claudin-5 with AY9944, Improve Blood-Brain Barrier Permeability; Computational Simulation and Experimental Study

Cell Mol Neurobiol. 2022 May;42(4):1125-1139. doi: 10.1007/s10571-020-01004-z. Epub 2020 Nov 21.

Abstract

The current study aimed to determine the protective effect of AY9944 related to Caveolin-1 and Claudin-5 role in lipid raft, which can rescue the blood-brain barrier from enhanced permeability. Therefore, in vivo analyses were performed following ischemia in normal, ischemic, and AY9944-treated animal groups. The results revealed that AY9944 reduced the infarct size, edema, and brain water content. The extravasation of Alb-Alexa 594 and biocytin-TMR was minimum in the AY9944-treated animals. The results showed a significant decrease in the expression level of Caveolin-1 over 8 h and 48 h and a remarkable increase in the level of Claudin-5 over 48 h following ischemia in AY9944-treated animals. Molecular docking simulation demonstrated that AY9944 exerts a possible protective role via attenuating the interaction of the Caveolin-1 and cholesterol in lipid raft. These findings point out that AY9944 plays a protective role in stroke by means of blood-brain barrier preservation. Proper neural function essentially needs a constant homeostatic brain environment which is provided by the blood-brain barrier. Rescuing blood-brain barrier from enhanced permeability via inducing the protective effect of AY9944 related to caveolin-1 and claudin-5 role in lipid raft was the aim of the current study.

Keywords: Blood–brain barrier; Brain ischemia; Caveolin 1; Claudin-5; Middle cerebral artery; Molecular docking simulation; Stroke; Tight junction proteins.

MeSH terms

  • Animals
  • Blood-Brain Barrier*
  • Caveolin 1* / metabolism
  • Claudin-5 / metabolism
  • Molecular Docking Simulation
  • Permeability
  • trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / metabolism
  • trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / pharmacology

Substances

  • Caveolin 1
  • Claudin-5
  • trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride