Idazoxan reduces blood–brain barrier damage during experimental autoimmune encephalomyelitis in mouse

Targeting transporters: Promoting blood–brain barrier repair in response to oxidative stress injury

“…JAM-1 is a 40-kDa member of the IgG superfamily and mediates early attachment of adjacent endothelial cells during BBB development (Dejana et al 2000). Additionally, loss of JAM protein expression is directly correlated with BBB disruption and injury (Yeung et al 2008; Hoffman et al 2009; Wang et al 2014). Additionally, studies in an immortalized human brain endothelial cell line (hCMEC/d3) showed that inflammatory stimulation led to increased paracellular solute diffusion, which correlated with JAM movement away from the tight junction, further suggesting a central role in maintaining BBB integrity (Haarmann et al 2010).…”

“…In cerebral microvascular endothelial cells, various claudin isoforms have been detected including claudin-1, −3, and −5 (Witt et al 2003; Hawkins et al 2004; Forster et al 2008; Ronaldson et al 2009; Wang et al 2011). In experimental stroke models (Gibson et al 2014; Wang et al 2014) and inflammatory pain (Huber et al 2001; Brooks et al 2006; Ronaldson et al 2009), altered expression of claudin-5 that correlated with enhanced paracellular permeability has been reported. In contrast, studies in bovine brain microvascular endothelial cells subjected showed that in vitro hypoxia did not alter cellular expression of claudin-1 (Mark and Davis, 2002).…”

“…For many drugs, it is this discrete balance between influx and efflux that determines if a therapeutic agent will be able to protect the BBB from oxidative stress-associated injury. The complexity of drug transporter biology at the BBB is further underscored by the observation that functional expression of transporters can be dramatically altered by oxidative stress (Hong et al 2006; Ronaldson and Bendayan, 2008; Wang et al 2014). A thorough understanding of the regulation and functional expression of endogenous BBB transporters in both health and disease is essential for the provision of effective pharmacotherapy.…”

“…A thorough understanding of signaling pathways involved in Mrp regulation during oxidative stress will enable development of pharmacological approaches to target Mrp-mediated efflux (i.e., GSH transport) for the purpose of preventing BBB dysfunction in diseases with an oxidative stress component. One intriguing pathway is signaling mediated by nuclear factor E2-related factor-2 (Nrf2), a sensor of oxidative stress (Alfieri et al 2011; Wang et al 2014). In the presence of ROS, the cytosolic Nrf2 repressor Kelch-like ECH-associated protein 1 (Keap1) undergoes structural alterations that cause dissociation from the Nrf2-Keap1 complex.…”

“…This enables Nrf2 to translocate to the nucleus and induce transcription of genes that possess an antioxidant response element at their promoter (Hayashi et al 2003; Ma, 2013). It has been demonstrated that activation of Nrf2 signaling induces expression of Mrp1, Mrp2, and Mrp4 (Hayashi et al 2003; Vollrath et al 2006; Maher et al 2007; Aleksunes et al 2008; Xu et al 2010; Wang et al 2014). An emerging concept is that Nrf2 acts as a double-edged sword (Ma, 2013): on one hand, Nrf2 is required for protecting tissues from oxidative stress; on the other, its activation can lead to deleterious effects.…”