The blood–brain barrier (BBB) is an anatomical and biochemical barrier that protects the brain from potentially harmful substances (Wrobel and Toborek 2016). The BBB is a highly selective membrane barrier in the brain microvasculature that facilitates transport between the systemic circulation and the central nervous system (Wiranowska 1992). The BBB regulates homeostasis of the central nervous system (CNS) by forming a tightly regulated neurovascular unit (NVU) that includes endothelial cells (ECs), pericytes and astrocytic endfeet, which jointly maintain normal brain function (Charles et al. 1996; Go 1997; Lai and Kuo 2005). The presence of the BBB is capable of preventing some substances, mostly harmful, from entering the brain tissue from blood. The BBB acts as a physical and metabolic barrier between the CNS and the peripheral circulation, exerting regulatory and protective effects on the microenvironment of the brain (Rivest et al. 2000). Under normal circumstances, the primary function of the BBB is to establish and maintain homeostasis in the CNS. Once the BBB is destroyed, the brain is particularly vulnerable to infection and damage (Petito and Cash 1992; Eralinna et al. 1996; Woodman et al. 1999).
Reperfusion remains a leading cause of disability and death globally, and its therapeutic management is an extremely challenging problem in clinical practice. The recovery of blood supply, referred to as reperfusion, has been considered a standard therapeutic option for ischemia (Cuevas et al. 1998). In addition to preventing the growth of infarction volume, reperfusion has been reported to aggravate ischemic damage, including early disruption of the blood–brain barrier (BBB) (Aoki et al. 2002; Pluta 2003; Pillai et al. 2009). One of the pathophysiological characteristics of cerebral ischemic reperfusion injury (CIRI) is the destruction of the BBB (Pluta 2003). During CIRI, BBB damage leads to the infiltration of inflammatory cells into the brain, which further aggravates cerebral inflammation and edema (Warach and Latour 2004; Dimitrijevic et al. 2006; McColl et al. 2008). Thus, increasing attention is turning towards the identification of potential targeted drugs to protect the BBB against ischemia–reperfusion injury.
Cerebral ischemia–reperfusion injury can result in brain microvasculature and blood–brain barrier (BBB) breakdown, leading to increased BBB permeability (Bederson et al. 1986; Abdullahi et al. 2018). Disruption of the BBB following CIRI results in brain edema, a primary event that affects both morbidity and mortality (Cheslow and Alvarez 2016). Subsequently, various mediators are released that enhance vasogenic and/or cytotoxic brain edema (Eltzschig and Eckle 2011). These include glutamate, lactate, H+, K+, Ca2+, nitric oxide, arachidonic acid and its metabolites, free oxygen radicals, histamine, and kinins (Eltzschig and Eckle 2011). The permeability of the BBB to endogenous proteins, such as immunoglobulin G (IgG), is increased following experimental CIRI (Akiguchi et al. 1998; Michalski et al. 2010). An additional consequence of BBB disruption is the infiltration of leukocytes into brain tissue, accompanied by microglial activation and inflammation (Michalski et al. 2010).
Brain microvascular ECs are a key component in the pathophysiological mechanism of BBB dysfunction after ischemic reperfusion. However, the regulatory mechanism governing endothelial cell death is still unclear. Recently, it was implied that Receptor Interacting Protein Kinase 1 (RIPK1), which is a crucial necroptotic and apoptotic mediator in CIRI, might play an essential role in regulating endothelial cell death during the progression of CIRI (Chen J et al. 2019; Rehorova et al. 2019). RIPK1 is a serine/threonine protein kinase. The kinase activity of RIPK1 is stimulated by the tumor necrosis factor (TNF) death signal, and subsequent downstream necroptosis is activated (Chen AQ et al. 2019). Activated RIPK1 self-phosphorylates at serine 166, then recruits RIPK3 (Receptor Interacting serine/threonine Protein Kinase 3) and MLKL (Mixed Lineage Kinase domain Like protein) (Newton et al. 2016; Qu et al. 2017). The polymer RIPK1/RIPK3/MLKL leads to cell necroptosis during the progression of ischemia and reperfusion (Chen et al. 2018; Zhu and Sun 2018; Hribljan et al. 2019).
In this study, the physiological function of RIPK1 was investigated to elucidate the mechanism of blood–brain barrier destruction during the process of CIRI, which might contribute to the development or optimization of a clinical intervention approach.