Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence

Table 1 Putative mechanisms of neurovascular dysfunction and blood–brain barrier hyperpermeability in major depressive disorder in the context of established mechanisms in various neurological disorders

Mechanisms	Major depressive disorder				Neurological disorders
	Human	Sources	Animal	Sources	Human	Sources
Oxidative stress
eNOS uncoupling, decreased NO	■	[53–59]	■	[60]	●	[61–63]
Increased ROS synthesis	●	[10, 14–16, 64–84]	●	[64, 85]	●	[42, 63, 86]
Cerebral hypoperfusion	●	[87–91]	N/A	…	●	[92–96]
MMP activation	■	[97]	?	…	●	[39, 42, 98–101]
Decreased E-cadherin activity	?	…	?	…	?^a	[38, 102]
Tight junction alteration	?	…	?	…	●	[31, 38, 41, 103–106]
Endothelial cytoskeletal alteration	?	…	?	…	●	[31]
Increased NMDAR expression^b		[107–111]	●	[40]	●	[112]
Mitochondrial alterations	●	[65, 113–121]	●	[65, 122]	●	[11, 123–125]
Neuroinflammation
Astroglial loss	●	[20, 21, 126–133]	●	[134–138]	●	[139–141]
Decreased AQP4	●	[142]	●	[143]	●	[144–146]
Microglial activation	●	[18, 147, 148]	●	[149–152]	●	[42, 98, 153, 154]
Proinflammatory cytokines	●	[23, 155]	●	[156, 157]	●	[42, 98]
Bradykinin alteration	●^c	[158]	●	[159]	●	[159, 160]
Hyperglutamatergia	●	[4, 161–163]	●	[164]	●	[165–167]
Mast cell activation	●^c	[168, 169]	?	…	●	[170, 171]
Increased ICAM-1 and VCAM-1		[172–174]	?	…	●	[175–178]
Other mechanisms
Increased P-glycoprotein activity	●	[179, 180]	●	[181]	●	[179]

Symbol key: ●, documented in the central nervous system in major depressive disorder; ■, not documented in the central nervous system, but associated with major depressive disorder; ?, insufficient data; , mixed evidence.
Abbreviations: AQP4, aquaporin 4; eNOS, endothelial nitric oxide synthase; ICAM-1, intercellular adhesion molecule 1; NMDAR, N-methyl-D-aspartate receptor; MMP, matrix metalloproteinases; ROS, reactive oxygen species; VCAM-1, vascular cell adhesion molecule 1.
a. Refers to data that has only been shown in animal models.
b. Refers to human data in major depressive disorder refers to increased NMDAR expression that was not specific to the endothelium. Human data of NMDAR subunit composition alteration in neurological disorders was shown in cultured human blood–brain barrier endothelial cells. Animal data refer to increased cerebrovascular endothelial NMDAR subunit 1 (NR1) expression upon exposure to oxidative stress (this was not a depressive-like behavior or chronic stress animal model, though this evidence may be relevant to MDD where oxidative stress is documented).
c. Refers to abnormalities for which only limited data exists.

ISSN: 1742-2094