Iron Overload Exacerbates the Risk of Hemorrhagic Transformation After tPA (Tissue-Type Plasminogen Activator) Administration in Thromboembolic Stroke Mice

Abstract

Background and Purpose— Recanalization with tPA (tissue-type plasminogen activator) is the only pharmacological therapy available for patients with ischemic stroke. However, the percentage of patients who may receive this therapy is limited by the risk of hemorrhagic transformation (HT)—the main complication of ischemic stroke. Our aim is to establish whether iron overload affects HT risk, to identify mechanisms that could help to select patients and to prevent this devastating complication. Methods— Mice fed with control or high-iron diet were subjected to thromboembolic stroke, with or without tPA therapy at different times after occlusion. Blood samples were collected for determination of malondialdehyde, matrix metalloproteinases, and fibronectin. Brain samples were collected 24 hours after occlusion to determine brain infarct and edema size, hemorrhage extension, IgG extravasation, and inflammatory and oxidative markers (neutrophil infiltration, 4-hydroxynonenal, and matrix metalloproteinase-9 staining). Results— Despite an increased rate of recanalization, iron-overload mice showed less neuroprotection after tPA administration. Importantly, iron overload exacerbated the risk of HT after early tPA administration, accelerated ischemia-induced serum matrix metalloproteinase-9 increase, and enhanced basal serum lipid peroxidation. High iron increased brain lipid peroxidation at most times and neutrophil infiltration at the latest time studied. Conclusions— Our data showing that iron overload increases the death of the compromised tissues, accelerates the time of tPA-induced reperfusion, and exacerbates the risk of HT may have relevant clinical implications for a safer thrombolysis. Patients with stroke with iron overload might be at high risk of HT after fibrinolysis, and, therefore, clinical studies must be performed to confirm our results.

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

“…Accumulating evidence has demonstrated that ferroptosis is dependent on iron or iron-dependent ROS [ 99 , 100 ]. Iron overload causes prolonged upregulation of transport receptors, increases peripheral iron uptake via the BBB, and exacerbates the risk of hemorrhagic transformation [ 101 ]. Besides, iron overload also enhances basal serum lipid peroxidation after early t-PA administration [ 101 ].…”

Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis

“…Iron overload is a major source of oxidative stress in ischemic brains (Carbonell and Rama, 2007). In addition, iron overload exacerbated the risk of hemorrhagic transformation in animal models of transient ischemia plus early reperfusion (García-Yébenes et al, 2012; García-Yébenes et al, 2018); therefore, in iron-overloaded animals, an initial ischemic event has higher probability to become an ICH. The contribution of iron overload to widespread the damage in the ICH is supported by the fact that systemic iron overload (estimated using high serum FT levels) was associated with higher perihematoma edema and poor outcomes in patients with ICH (Mehdiratta et al, 2008; Perez de la Ossa et al, 2010; Bakhshayesh et al, 2014; Garton et al, 2017).…”

Serum Iron for Prognosis of Acute Ischemic Stroke by Endovascular Treatment

“…In humans, iron, as a necessary microelement, is associated with many diseases, and the exact function of iron in acute ischemic stroke is still debatable. However, a point worth confirming is that iron plays a role in the unfavorable prognosis of acute ischemic stroke and hemorrhage transmission [15,16]. Nevertheless, those studies mainly adopted intravenous medicine treatment, and the actual recanalization was unclear, besides, the research on iron focused mainly on neurological protection and medical treatment after acute ischemic stroke.…”