Key Points
- Fisetin increased good recovery rates from 29% to 41.9% within 24 hours
- After 7 days, 45.2% of delayed-treatment patients taking fisetin had favorable outcomes
- Markers of inflammation and blood–brain barrier damage were significantly reduced
- Improvements in these biomarkers strongly matched improvements in neurological recovery
Methods
192 people with ischemic stroke were grouped based on how quickly they received treatment, called onset-to-treatment time (OTT):
All patients received standard rt-PA. Within each timing group, they were randomly assigned to receive either fisetin or a placebo.
This created four groups:
- 0–3 hour OTT + Fisetin: rt-PA + 100 mg fisetin at the start, then 100 mg daily for 7 days.
- 0–3 hour OTT + Placebo: rt-PA + placebo at the start, then placebo daily for 7 days.
- 3–5 hour OTT + Fisetin: rt-PA + 100 mg fisetin at initiation, then 100 mg daily for 7 days.
- 3–5 hour OTT + Placebo: rt-PA + placebo at initiation, then placebo daily for 7 days.
Researchers measured recovery using the National Institutes of Health Stroke Scale (NIHSS), a scoring system used to assess stroke severity.
They also measured blood markers linked to inflammation and blood–brain barrier damage: MMP-2, MMP-9, and C-reactive protein (CRP).
Fisetin Improved Recovery When Treatment Was Delayed
In patients treated within the ideal 0–3 hour window, fisetin did not significantly change outcomes.
However, in patients treated later (3–5 hours after stroke onset), fisetin significantly improved recovery.
"Fisetin dramatically improved the treatment outcomes of the patients with stroke in the delayed OTT strata, as revealed by lower NIHSS scores."
At 24 hours in the delayed group:
- 41.9% of fisetin patients had favorable neurological scores
- 29.0% of placebo patients had favorable scores
Notably, outcomes in delayed patients receiving fisetin approached those of patients treated within the optimal 0–3 hour window.
"NIHSS scores of patients receiving simultaneous fisetin treatment was statistically indistinguishable from that of patients receiving placebo."
After 7 days of continued treatment:
- 45.2% of delayed patients on fisetin had favorable outcomes
- 32.3% on placebo
This suggests fisetin helped patients who missed the ideal 3-hour window recover almost as well as those treated early and may support both acute protection and early-stage neurological recovery.
Fisetin Reduced Brain-Damage Markers
Matrix metalloproteinases (MMP-2 and MMP-9) are enzymes that can weaken the blood–brain barrier during stroke. CRP reflects systemic inflammation.
Fisetin significantly lowered all three markers at both 1 and 7 days.
"1 day after the initial treatment, serum levels of both MMPs and CRP in both 0- to 3-hour and 3- to 5-hour OTT strata were noticeably reduced in fisetin-treated patients."
Importantly, reductions in these markers strongly matched improvements in neurological scores.
"Indeed, strong linear correlations between changes in the NIHSS scores and the serum levels of all 3 factors were observed."
The greater the drop in MMP-2, MMP-9, and CRP, the better the patient's recovery.
By reducing these enzymes and inflammatory markers, fisetin may help stabilize the blood–brain barrier and protect brain tissue during reperfusion (restoration of blood flow).
Conclusion
The improvements observed in delayed-treatment patients provide evidence that fisetin may enhance the effectiveness of clot-dissolving therapy when administered beyond the standard treatment window.
"In the 3- to 5-hour OTT strata, overall NIHSS scores were significantly improved… just 1 day after the initial rt-PA and fisetin treatment."
"The beneficial effect of fisetin was likely attributable to reduced levels of MMP-2, MMP-9, and CRP in the serum."
This clinical trial suggests fisetin may help extend the treatment window for clot-dissolving stroke therapy from 3 hours toward 5 hours.
"Fisetin may possess the potential to supplement traditional rt-PA treatments among patients with stroke… and thereby extend the otherwise narrow therapeutic window and improve the treatment outcomes."
If confirmed in larger trials, this approach could allow more stroke patients to benefit from treatment while reducing inflammatory damage associated with blood–brain barrier breakdown.
