Figure 2

Theoretical integration of the human and animal data linking oxidative stress, eNOS uncoupling, low endothelial NO levels, and neuroinflammation to indirect evidence of functional and structural abnormalities of neurovascular unit in major depressive disorder. Adapted with permission from Abbott et al., [185]. This figure describes several putative mechanisms involving neuroinflammation, oxidative stress, endothelial nitric oxide synthase uncoupling, and hyperglutamatergia, as well as their relationships to indirect evidence of neurovascular dysfunction in MDD. Neurovascular endothelial lipofuscin granule accumulation is a marker of endothelial oxidative stress, which we recently documented by ultrastructural analysis of cerebral microvasculature in brain biopsy from a patient with chronic refractory MDD [90]. Abbreviations: AQP4, aquaporin 4; BH₂: dihydrobiopterin; BH₄, tetrahydrobiopterin; CRH, corticotropin-releasing hormone; eNOS, endothelial nitric oxide synthase; mGluR, metabotropic glutamate receptor; MDD, major depressive disorder; MMP, matrix metalloproteinase; NAD(P)H, nicotinamide adenosine dinucleotide phosphate; Na⁺/K⁺ ATPase, sodium-potassium adenosine triphosphatase; NFκB, nuclear factor κB; NMDAR, N-methyl-d-aspartate receptor; NO, nitric oxide, ONOO^-, peroxynitrite; O₂ ^-, superoxide; ROS, reactive oxygen species.