Tissue plasminogen activator disrupts the blood-brain barrier through increasing the inflammatory response mediated by pericytes after cerebral ischemia

Abstract

Pericytes, important elements of the blood-brain barrier (BBB), play critical roles in maintaining BBB integrity and modulating hemostasis, angiogenesis, inflammation and phagocytic function. We investigated whether pericytes are involved in the recombinant tissue plasminogen activator (rt-PA)-induced inflammatory response, which disrupts the BBB, and investigated the potential mechanisms. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD) were employed to mimic hypoxic-ischemic conditions. Rt-PA was intravenously injected into mice 1 h after 1 h MCAO, and Rt-PA was added to the culture medium after 4 h OGD. Rt-PA treatment aggravated the disruption of the BBB compared with hypoxia treatment, and etanercept (TNF-α inhibitor) combined with rt-PA alleviated the rt-PA-induced BBB disruption in vivo and in vitro. Rt-PA treatment increased the TNF-α and MCP-1 levels and decreased the TGF-β, p-Smad2/3 and PDGFR-β levels compared with hypoxia treatment in vivo and vitro. TGF-β combined with rt-PA decreased TNF-α and MCP-1 secretion and alleviated BBB disruption compared with rt-PA; these changes were abrogated by TPO427736 HCL (a TGF-β/p-Smad2/3 pathway inhibitor) cotreatment in vitro. Rt-PA did not decrease TGF-β and p-Smad2/3 expression in PDGFR-β-overexpressing pericytes after OGD. These findings identify PDGFR-β/TGF-β/p-Smad2/3 signaling in pericytes as a new therapeutic target for the treatment of rt-PA-induced BBB damage.

Curcumin ameliorates ischemic stroke injury in rats by protecting the integrity of the blood‑brain barrier

“…There is increasing evidence that inflammation contributed to the progression of ischemia-induced secondary brain damage, leading to aggravated dysregulation of the BBB, as well as cerebral edema (3,4). Thus, identification of novel drugs to protect against ischemic stroke and to understand the underlying mechanisms involved is important to combat this pathology (5).…”

Neuroprotective effects of four different fluids on cerebral ischaemia/reperfusion injury in rats through stabilization of the blood–brain barrier

“…Changes in the expression of RGS5 and PDGFR‐β, as the characteristic proteins of pericytes, cellular components of the BBB, can indirectly reflect the condition of these cells and reveal the degree of damage to the BBB after CI/R injury (Özen et al, 2018; Yang et al, 2019). PDGF and the PDGF receptor (PDGFR) are widely expressed in the CNS and function as mitotic agents and growth factors by acting on a series of cells, promoting mitosis and chemotaxis of glial cells and mesenchymal cells.…”

Systemic Inflammation Indices in Patients With Acute Ischemic Stroke Treated With Intravenous Tissue Plasminogen Activator: Clinical Yield and Utility

“…29 This early inflammation may contribute to the development of cerebral hemorrhage after systemic thrombolysis because tPA increases inflammation in infarct tissue, increases matrix metalloproteinase level, and disrupts the blood–brain barrier; these changes induce bleeding. 30,31 Matrix metalloproteinases worsen tissue injury and resulting in poor prognosis in post-tPA hemorrhage, just like in primary intracerebral hemorrhage. 32 At this point, the NLR, which correlates with hemorrhagic transformation and hemorrhagic tissue damage, 33 may be useful in predicting prognosis in patients treated with IV tPA for acute stroke.…”