Beneficial Role of Rosuvastatin in Blood–Brain Barrier Damage Following Experimental Ischemic Stroke

Abstract

Hemorrhage transformation is the most challenging preventable complication in thrombolytic therapy and is related to recombinant tissue plasminogen activator (rt-PA)-induced blood–brain barrier (BBB) damage. Intraperitoneal injections of normal or high doses of rosuvastatin were administered to Balb/c mice 20 min prior to middle cerebral artery occlusion (MCAO) surgery for 3 h followed by reperfusion with rt-PA thrombolytic therapy and cerebral blood flow monitoring to investigate whether a high or normal dose of rosuvastatin reduces BBB damage after brain ischemia and rt-PA reperfusion. The integrity of the BBB was ameliorated by normal and high doses of rosuvastatin as determined from Evans blue staining, ultrastructure assessments and immunochemistry at 24 h after reperfusion. The levels of TJ proteins were preserved, potentially by targeting platelet-derived growth factor receptor α (PDGFR-α) and low-density lipoprotein receptor-related protein 1 (LRP1) to inhibit the expression of matrix metalloproteinase proteins (MMPs) by reducing the levels of phosphorylated c-jun-N-terminal kinase (pJNK), phosphorylated mitogen-activated protein kinase (MAPK) p38 (pP38) and increasing the levels of phosphorylated extracellular regulated protein kinases (pERK), and tissue inhibitor of metalloproteinases (TIMPs), as inferred from Western blotting and molecular docking analyses. In summary, rosuvastatin reduced rt-PA therapy-associated BBB permeability by PDGFR-α- and LRP1-associated MAPK pathways to reduce the mortality of mice, and a normal dose of rosuvastatin exerted greater preventative effects on reducing BBB damage than did a high dose in the time window of thrombolytic therapy.

Dysfunction of 67-kDa Laminin Receptor Disrupts BBB Integrity via Impaired Dystrophin/AQP4 Complex and p38 MAPK/VEGF Activation Following Status Epilepticus

“…Similar to 67-kDa LR neutralization, recombinant tissue plasminogen activator (r-tPA) induces BBB disruption, and subsequently results in vasogenic edema (Copin et al, 2011), which is mitigated by p38 MAPK inhibitor (Garraud et al, 2016). Rosuvastatin (a lipid-lowering agent) also ameliorates r-tPA-induced BBB damage by reducing the activities of JNK and p38 MAPK (Lu et al, 2018). Indeed, tPA activates ERK1/2, JNK, AKT and p38 MAPK signaling pathways (Pineda et al, 2012).…”

Epidermal growth factor treatment has protective effects on the integrity of the blood‑brain barrier against cerebral ischemia injury in bEnd3 cells

“…Therefore, further investigation on whether EGF preserves BBB integrity against ischemic stroke by modulating the MAPK and Akt signaling pathways is required. Additionally, electron microscopy is an effective approach for observing BBB disruption at the ultrastructure level (32) and this method maybe explored in future BBB studies.…”

Cryptotanshinone Attenuates Oxygen-Glucose Deprivation/ Recovery-Induced Injury in an in vitro Model of Neurovascular Unit

“…In addition, the activation of MAPK signaling pathways is associated with BBB damage (Figure 6) and aggravates CIRI by promoting the production of inflammatory cytokines (43, 44). BBB disruption is a hallmark of stroke and a mediator of CIRI and stroke progression (45).…”