Claudin-5: A Pharmacological Target to Modify the Permeability of the Blood-Brain Barrier

Biol Pharm Bull. 2021;44(10):1380-1390. doi: 10.1248/bpb.b21-00408.


Claudin-5 is the dominant tight junction protein in brain endothelial cells and exclusively limits the paracellular permeability of molecules larger than 400 Da across the blood-brain barrier (BBB). Its pathological impairment or sustained down-regulation has been shown to lead to the progression of psychiatric and neurological disorders, whereas its expression under physiological conditions prevents the passage of drugs across the BBB. While claudin-5 enhancers could potentially act as vascular stabilizers to treat neurological diseases, claudin-5 inhibitors could function as delivery systems to enhance the brain uptake of hydrophilic small-molecular-weight drugs. Therefore, the effects of claudin-5 manipulation on modulating the BBB in different neurological diseases requires further examination. To manipulate claudin-5 expression levels and function, several claudin-5 modulating molecules have been developed. In this review, we first describe the molecular, cellular and pathological aspects of claudin-5 to highlight the mechanisms of claudin-5 enhancers/inhibitors. We then discuss recently developed claudin-5 enhancers/inhibitors and new methods to discover these molecules.

Keywords: blood–brain barrier; claudin-5; drug delivery system; tight junction; vascular stabilization.

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Capillary Permeability / drug effects*
  • Claudin-5 / agonists*
  • Claudin-5 / antagonists & inhibitors*
  • Claudin-5 / metabolism
  • Drug Discovery / methods
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Humans
  • Models, Animal
  • Tight Junctions / drug effects


  • Claudin-5