Hesperidin reduces adverse symptomatic intracerebral hemorrhage by promoting TGF-β1 for treating ischemic stroke using tissue plasminogen activator

Neurol Sci. 2020 Jan;41(1):139-147. doi: 10.1007/s10072-019-04054-4. Epub 2019 Sep 2.


Treatment with recombinant tissue plasminogen activator (rt-PA) is the most effective therapeutic option against brain ischemic stroke at the present time. However, elevated incidence of symptomatic intracerebral hemorrhage (SIH) greatly hinders ideal treatment outcome of rt-PA. We sought to assess the impacts of hesperidin on SIH following rt-PA therapies. Patients with ischemic stroke were assigned into two groups in a random fashion, to receive either rt-PA + placebo (Pc) or rt-PA + hesperidin. Treatment outcome was evaluated 24 h after the initial reperfusion using the transcranial Doppler ultrasonography (TCD) and the NIH Stroke Scale (NIHSS). Further, serum concentrations of transforming growth factor (TGF)-β1, matrix metalloproteinase (MMP)-2, and MMP-9 were examined. Following the initial administration, stroke patients continued to receive either daily Pc or daily hesperidin, and the treatment outcome after 7 days was examined using the TCD, NIHSS, Glasgow Outcome Scale (GOS), and the Modified Rankin Scale (MRS). Combined treatment of rt-PA with hesperidin yielded significant improvement of outcomes, as revealed by better TCD and NIHSS scores as well as decreased SIH incidences, which could be attributable to elevation of TGF-β1 and reduction in serum levels of both MMP-2 and MMP-9 caused by hesperidin. Follow-up hesperidin treatment for 7 consecutive days also markedly enhanced the recovery of stroke patients, as indicated by TCD, MRS, GOS, and NIHSS. Findings of the present study strongly suggested potential clinical application of hesperidin supplement in rt-PA therapies to reduce SIH and thereby improve the treatment outcomes of rt-PA in patients with ischemic stroke.

Keywords: Brain ischemic stroke; Hesperidin; Recombinant tissue plasminogen activator (rt-PA); Symptomatic intracerebral hemorrhage; Transforming growth factor (TGF)-β1.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Biomarkers / blood
  • Brain Ischemia / blood
  • Brain Ischemia / drug therapy*
  • Cerebral Hemorrhage / blood
  • Cerebral Hemorrhage / chemically induced
  • Cerebral Hemorrhage / drug therapy*
  • Drug Therapy, Combination
  • Female
  • Fibrinolytic Agents / administration & dosage
  • Fibrinolytic Agents / adverse effects
  • Follow-Up Studies
  • Hesperidin / administration & dosage*
  • Humans
  • Male
  • Middle Aged
  • Stroke / blood
  • Stroke / drug therapy*
  • Tissue Plasminogen Activator / administration & dosage*
  • Tissue Plasminogen Activator / adverse effects
  • Transforming Growth Factor beta1* / blood
  • Treatment Outcome


  • Biomarkers
  • Fibrinolytic Agents
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • Hesperidin
  • Tissue Plasminogen Activator