Fisetin Prolongs Therapy Window of Brain Ischemic Stroke Using Tissue Plasminogen Activator: A Double-Blind Randomized Placebo-Controlled Clinical Trial

Abstract

Recombinant tissue plasminogen activator (rt-PA) can be utilized to treat ischemic stroke with safety and effectiveness but limited by a narrow therapeutic window. In the present clinical trial among patients with stroke, we sought to evaluate the potential of fisetin to extend the therapeutic window of rt-PA treatment. Patients with stroke were divided based on their onset-to-treatment time (OTT) and then randomly assigned to receive the rt-PA treatment combined with fisetin or placebo. Primary outcome was evaluated using the National Institutes of Health Stroke scale (NIHSS), and secondary outcome was assessed by serum levels of matrix metalloproteinase (MMP) 2, MMP 9, and C-reactive protein (CRP). Fisetin dramatically improved the treatment outcomes of the patients with stroke in the delayed OTT strata, as revealed by lower NIHSS scores. The beneficial effect of fisetin was likely attributable to reduced levels of MMP-2, MMP-9, and CRP in the serum, as evidenced by strong linear correlations between serum levels of such markers with the NIHSS scores in all enrolled patients. Fisetin may possess the potential to supplement traditional rt-PA treatments among patients with stroke, particularly for those with delayed OTT, and thereby extend the otherwise narrow therapeutic window and improve the treatment outcomes.

Keywords: C-reactive protein (CRP); fisetin; ischemic stroke; recombinant tissue plasminogen activator (rt-PA).

Figure 1.

Flow chart of study design.

Figure 2.

NIHSS score of all eligible patients 1 day after initial treatment. Scores of 0 to 10 was considered to indicate a favorable outcome. NIHSS indicates National Institutes of Health Stroke scale; OTT, onset-to-treatment time.

Figure 3.

NIHSS score of all eligible patients 7 days after initial treatment. Scores of 0 to 10 was considered to indicate a favorable outcome. NIHSS indicates National Institutes of Health Stroke scale; OTT, onset-to-treatment time.

Figure 4.

Serum levels of MMP-2, MMP-9, and CRP at (A) 1 day and (B) 7 days after initial treatment. Values were normalized as percentage to baseline values in respective treatment groups and expressed as mean (SD). ∗P < .05 fisetin versus placebo treatment at respective OTT groups. CRP indicates C-reactive protein; MMP, matrix metalloproteinase; NIHSS, National Institutes of Health Stroke scale; OTT, onset-to-treatment time; SD, standard deviation.