Hyperglycemia aggravates brain damage after
diffuse axonal injury (DAI), but the underlying mechanisms are not fully defined. In this study, we aimed to investigate a possible role for
hyperglycemia in the disruption of blood-brain barrier (BBB) integrity in a rat model of DAI and the underlying mechanisms. Accordingly, 50%
glucose was intraperitoneally injected after DAI to establish the
hyperglycemia model.
Hyperglycemia treatment aggravated neurological impairment and axonal injury, increased cell apoptosis and glial activation, and promoted the release of inflammatory factors, including TNF-α, IL-1β, and
IL-6. It also exacerbated BBB disruption and decreased the expression of tight junction-associated
proteins, including ZO-1,
claudin-5, and occludin-1, whereas the PPARγ agonist
rosiglitazone (RSG) had the opposite effects. An in vitro BBB model was established by a monolayer of human microvascular endothelial cells (HBMECs).
Hyperglycemia induction worsened the loss of BBB integrity induced by
oxygen and
glucose deprivation (OGD) by increasing the release of inflammatory factors and decreasing the expression of tight junction-associated
proteins.
Hyperglycemia further reduced the expression of PPARγ and
caveolin-1, which significantly decreased after DAI and OGD.
Hyperglycemia also further increased the expression of
toll-like receptor 4 (TLR4), which significantly increased after OGD. Subsequently, the PPARγ agonist RSG increased
caveolin-1 expression and decreased TLR4 expression and inflammatory factor levels. In contrast,
caveolin-1 siRNA abrogated the protective effects of RSG in the in vitro BBB model of
hyperglycemia by increasing TLR4 and Myd88 expression and the levels of inflammatory factors, including TNF-α, IL-1β, and
IL-6. Collectively, we demonstrated that
hyperglycemia was involved in mediating secondary injury after DAI by disrupting BBB integrity by inducing
inflammation through the PPARγ/
caveolin-1/TLR4 pathway.