Stroke has imposed a heavy burden on human society due to its high incidence, disability and mortality rates [1]. Diabetes mellitus (DM), as an independent risk factor for stroke, not only increases the incidence of ischemic stroke, but also significantly aggravates ischemic brain tissue damage [2]. However, the specific mechanism by which DM aggravates cerebral ischemia-reperfusion injury (CI/RI) is not well understood, and there is a lack of effective prevention and treatment methods.

The blood brain barrier (BBB) mainly refers to a semi-permeable membrane formed by the connection and interaction of the non-cellular matrix and cellular matrix in neurovascular unit, which can participate in the regulation and maintenance of brain functioning [3,4]. The normal functioning of the BBB effectively avoided the penetration of harmful substances into the brain tissue, so as to ensure that the cerebral circulation was always stabilized [5]. Studies have shown that BBB disruption is a main event in CI/RI [6,7]. Therefore, strengthening the protection of the BBB has become the key to improve the prognosis of patients with ischemic stroke. Animal experiments [8] and clinical studies [9] have shown that hyperglycemia can aggravate CI/R-induced BBB destruction and brain injury. Therefore, targeting BBB permeability and integrity may be a promising therapeutic approach for the treatment of diabetic CI/RI.

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway is involved in the changes of BBB permeability under various pathological conditions by up-regulating the expressions of tight junction proteins [10,11] and down-regulating the expressions of endothelial cell adhesion molecules [12]. PI3K inhibitor increased the permeability of brain microvascular endothelial cells (BMVECs) after CI/R by down-regulating tight junction proteins [13]. In addition, under hyperglycemia conditions, PI3K inhibitor significantly prevented the protective effect of selenium on the BBB after CI/RI [8]. Therefore, the PI3K/Akt signaling pathway may be a therapeutic target for diabetic CI/RI. Studies have reported that tribbles homolog 3 (TRIB3) can inhibit PI3K/AKT signaling pathway [14,15] and participate in the development of diabetes-related diseases [16]. Global cerebral ischemia-reperfusion injury (GCI/RI) increases TRB3 expression, and knockdown of TRB3 alleviates neuronal apoptosis after GCI/R [17]. However, the role of TRIB3 in regulating the BBB after CI/RI has not been explored.

In conclusion, we speculate that TRIB3 down-regulates tight junction proteins expressions and increases BBB permeability by inhibiting PI3K/AKT signaling pathway, thereby disrupting BBB integrity and promoting brain injury in diabetic CI/R.