Inhibition of the PDGFRβ/MMP-9 pathway attenuates CUMS-induced blood-brain barrier disruption, neuroinflammation, and depressive-like behaviors

Background: The underlying mechanisms of major depressive disorder (MDD) remain unclear; however, increasing evidence has linked MDD to blood-brain barrier (BBB) dysfunction. This study aimed to determine whether BBB impairment represents an early pathological change during chronic stress and whether preservation of BBB integrity is associated with attenuation of neuroinflammatory and behavioral abnormalities.

Methods: We employed a time-course (1, 2, and 4 weeks) chronic unpredictable mild stress (CUMS) model in C57BL/6 J mice. Depressive-like behaviors (SPT, FST, TST, OFT), BBB permeability (Evans blue), tight junction (TJ) protein expression (qPCR, Western Blot), ultrastructure (TEM, IF), peripheral and central inflammatory responses (ELISA, qPCR, IF), and transcytosis-related changes (Western Blot, TEM) were systematically assessed at each time point. In separate intervention experiments, the PDGFRβ Inhibitor Imatinib (50 mg/kg/d) or an MMP-9 Inhibitor (20 mg/kg/d) was administered throughout the 4-week CUMS procedure.

Results: Depressive-like behaviors became robustly established by week 4. In contrast, BBB disruption occurred earlier: molecular changes (e.g., Claudin-5 protein loss) were significant at week 1, followed by functional permeability, TJ structural disruption, increased endothelial vesicle density, and inflammatory alterations at week 2. This pathology worsened by week 4. The 4-week Imatinib co-treatment attenuated the development of depressive-like behaviors, alleviated BBB disruption, and reduced neuroinflammatory abnormalities. At the molecular level, CUMS induced a time-dependent upregulation of MMP-9. Imatinib treatment attenuated activation of the PDGFRβ/MMP-9 pathway, whereas MMP-9 inhibition preserved BBB integrity and attenuated central inflammatory abnormalities despite persistently elevated peripheral cytokine levels.

Conclusion: BBB dysfunction is an early pathological event during chronic stress and is associated with both tight junction disruption and transcytosis-related alterations. Pharmacological preservation of BBB integrity was accompanied by reduced neuroinflammation, consistent with BBB integrity being an important modulator of chronic stress-associated central inflammatory abnormalities. The PDGFRβ/MMP-9 pathway may represent a promising mechanism associated with stress-related BBB injury and a potential therapeutic target.