Abstract
When given beyond 4.5 h of stroke onset, tissue plasminogen activator (tPA) induces deleterious side effects in the ischemic brain, notably, hemorrhagic transformation (HT). We examined the efficacy of granulocyte-colony stimulating factor (G-CSF) in reducing delayed tPA-induced HT, cerebral infarction, and neurological deficits in a thromboembolic (TE) stroke model, and whether the effects of G-CSF were sustained for longer periods of recovery. After stroke induction, rats were given intravenous saline (control), tPA (10 mg/kg), or G-CSF (300 μg/kg) + tPA 6 h after stroke. We found that G-CSF reduced delayed tPA-associated HT by 47%, decreased infarct volumes by 33%, and improved motor and neurological deficits by 15% and 25%, respectively. It also prevented delayed tPA treatment-induced mortality by 46%. Immunohistochemistry showed 1.5- and 1.8-fold enrichment of the endothelial progenitor cell (EPC) markers CD34+ and VEGFR2 in the ischemic cortex and striatum, respectively, and 1.7- and 2.8-fold increases in the expression of the vasculogenesis marker von Willebrand factor (vWF) in the ischemic cortex and striatum, respectively, in G-CSF-treated rats compared with tPA-treated animals. Flow cytometry revealed increased mobilization of CD34+ cells in the peripheral blood of rats given G-CSF. These results corroborate the efficacy of G-CSF in enhancing the therapeutic time window of tPA for stroke treatment via EPC mobilization and enhancement of vasculogenesis.
Highlights
On average, one American has a stroke every 40 s, and one dies every 4 min [1]
These promising findings provide impetus for further exploration of the effects of granulocyte-colony stimulating factor (G-CSF) in attenuating delayed tissue plasminogen activator (tPA)-induced outcomes in other experimental stroke models, in line with the Stroke Therapy Academic Industry Roundtable (STAIR) guidelines for clinical development of drug candidates [13], and for studies to determine the mechanisms of action and long-term effects of the drug, in order to enhance its future clinical application
To examine whether G-CSF reduced delayed (i.e., 6 h after stroke) tPA-induced hemorrhagic transformation (HT) and cerebral infarction in a TE model, we evaluated hemorrhage volume and extent of cerebral infarction 3 days after stroke using spectrophotometric hemoglobin assay and 2,3,5-triphenyltetrazolium chloride (TTC) staining, respectively
Summary
One American has a stroke every 40 s, and one dies every 4 min [1]. Of the different types of stroke, acute ischemic stroke is the most common, and successful treatment of this medical condition remains very challenging. We previously reported the efficacy of G-CSF in attenuating delayed tPA-induced HT and in improving post-stroke motor and neurological deficits in an intraluminal filament model of stroke [12]. These promising findings provide impetus for further exploration of the effects of G-CSF in attenuating delayed tPA-induced outcomes in other experimental stroke models, in line with the Stroke Therapy Academic Industry Roundtable (STAIR) guidelines for clinical development of drug candidates [13], and for studies to determine the mechanisms of action and long-term effects of the drug, in order to enhance its future clinical application
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