Mechanisms of Nattokinase in Protection of Cerebral Ischemia

Eur J Pharmacol. 2014 Dec 15;745:144-51. doi: 10.1016/j.ejphar.2014.10.024. Epub 2014 Oct 27.


In vivo, the level of cyclic Adenosine Monophosphate (cAMP) and the pathway of the Janus Kinase1/Signal Transducers and Activators of Transcription1 (JAK1/STAT1) were studied. In vitro, the Ca(2+) mobilization in human platelet stimulated by thrombin was observed. In addition, vasomotion of vascular smooth muscle was measured by adding KCl or norepinephrine(NE) under the Ca(2+) contained bath solutions. The effect induced by NE in the presence of N-nitro-L-arginine methyl ester (L-NAME) or indometacin (Indo) was also detected. At last, the levels of tissue plasminogen activator (t-PA) and Plasminogen activator inhibitor-1 (PAI-1) in cultured supernatans in Human umbilical vein endothelial cells (Huvecs) were measured by means of ELISA kit. Results showed that Nattokinase (NK) significantly increased the cAMP level, activated the signal passage of JAK1/STAT1 in injured part and inhibited remarkably the rise of platelet intracellular Ca(2+) ([Ca(2+)]i) in human platelet. Furthermore, NK relaxed rat thoracic aortic artery in the dose-dependent manner and in the endothelium dependent manner and its effect could be attenuated by L-NAME. Also, the secretion of t-PA and PAI-1 were reduced stimulated by Adr on Huvecs. These data indicated that the neuroprotective effect of NK was associated with its antiplatelet activity by elevating cAMP level and attenuating the calcium release from calcium stores; with its anti-apoptotic effect through the activation of JAK1/STAT1 pathway; with its relaxing vascular smooth muscle by promoting synthesis and release of NO, reducing ROC calcium ion influx and with its protection on endothelial cells through increasing fibrinolytic activity and facilitating spontaneous thrombolysis.

Keywords: Cyclic adenosine monophosphate; Human umbilical vein endothelial cells; Janus kinase1/signal transducers and activators of transcription1; Nattokinase; Plasminogen activator inhibitor-1; Tissue plasminogen activator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / physiology
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism
  • Brain Ischemia / genetics
  • Brain Ischemia / metabolism
  • Brain Ischemia / prevention & control*
  • Calcium Signaling / drug effects
  • Cyclic AMP / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Janus Kinase 1 / genetics
  • Male
  • Malondialdehyde / metabolism
  • Neuroprotective Agents / pharmacology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • STAT1 Transcription Factor / genetics
  • Signal Transduction / drug effects
  • Subtilisins / pharmacology*
  • Superoxide Dismutase / metabolism
  • Vasodilation / drug effects


  • Neuroprotective Agents
  • RNA, Messenger
  • STAT1 Transcription Factor
  • Stat1 protein, rat
  • Malondialdehyde
  • Cyclic AMP
  • Superoxide Dismutase
  • Jak1 protein, rat
  • Janus Kinase 1
  • Subtilisins
  • nattokinase