吉村 文

Several lines of evidence suggest that stress induces the neurovascular dysfunction associated with increased blood-brain barrier (BBB) permeability, which could be an important pathology linking stress and psychiatric disorders, including major depressive disorder (MDD). However, the detailed mechanism resulting in BBB dysfunction associated in the pathophysiology of MDD still remains unclear. Herein, we demonstrate the role of vascular endothelial growth factor (VEGF), a key mediator of vascular angiogenesis and BBB permeability, in stress-induced BBB dysfunction and depressive-like behavior development. We implemented an animal model of depression, chronic restraint stress (RS) in BALB/c mice, and found that the BBB permeability was significantly increased in chronically stressed mice. Immunohistochemical and electron microscopic observations revealed that increased BBB permeability was associated with both paracellular and transcellular barrier alterations in the brain endothelial cells. Pharmacological inhibition of VEGF receptor 2 (VEGFR2) using a specific monoclonal antibody (DC101) prevented chronic RS-induced BBB permeability and anhedonic behavior. Considered together, these results indicate that VEGF/VEGFR2 plays a crucial role in the pathogenesis of depression by increasing the BBB permeability, and suggest that VEGFR2 inhibition could be a potential therapeutic strategy for the MDD subtype associated with BBB dysfunction.

<p>Objectives: Proximal stoma creation in neonates results in growth failure and distal intestinal atrophy. "Recycling stool" consists of stool injection from the proximal limb to the distal limb of a stoma. Because this method may prevent distal bowel atrophy and increase body weight, we investigated the effects of recycling stool upon distal intestinal mucosa by generating an ileostomy model in rats.</p><p>Methods: An ileostomy was created 5 cm proximal to the cecum in male Wistar/ST rats. Discharged stool or saline was injected into the distal limb, twice per day for 7 days. The intestinal adaptation was assessed by measuring the villus height and counting goblet cell number. Proliferation and apoptosis were analyzed by Ki67 and TUNEL immunostaining.</p><p>Results: The ratios of the height of the distal villi (D) to the that of proximal villi (P) were 0.97 (median [range] of D and P length: 421 [240–729] μm and 436 [294–638] μm, P<0.05) in the stool-injected group and 0.81 in the saline-injected group (442 [315–641] μm and 548 [236–776] μm, P<0.05). Compared with the saline-injected group, the stool-injected group showed elevated numbers of goblet cells (3.6 [2.0–7.6] vs. 4.9 [2.4–7.5] cells/100-μm villus length) and Ki67-positive cells (26.8% [13.8%–35.4%] vs. 40.1% [31.2%–45.7%]), along with a reduced number of apoptotic cells (5.0 [2.0–14.0] vs. 4.0 [1.0–9.0] cells/100-μm villus length).</p><p>Conclusions: Recycling stool prevented distal intestinal atrophy; this experimental design may facilitate further studies concerning alternative methods to prevent intestinal atrophy and growth failure.</p>