[Frontiers in Bioscience 11, 1323-1327, May 1, 2006]

Experimental therapy with tissue kallikrein against cerebral ischemia

Julie Chao, and Lee Chao

Department Of Biochemistry And Molecular Biology, Medical University Of South Carolina, Charleston, South Carolina 29425, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. The Tissue Kallikrein-Kinin System
4. Brain Kallikrein-Kinin System in Blood Pressure Regulation
5. Tissue Kallikrein-Kinin System in Hemorrhagic Stroke
6. Neuroprotection by Local Delivery of the Kallikrein Gene
7. Systemic Kallikrein Gene Delivery Protects Against Ischemic Brain Injury
8. Direct Neuroprotective Effect of Kallikrein via Protein Infusion
9. Role of Kinin B2 Receptor in Neuroprotection Against Ischemic Stroke
10. Neuroprotective Effect of Delayed Kallikrein Gene Delivery or Protein Infusion
11. Novel Roles of Kallikrein and kinin As Anti-inflammatory and Anti-Oxidative Agents
12. Future Aspect of Tissue Kallikrein in Stroke Therapy
13. Acknowledgments
14. References

1. ABSTRACT

Tissue kallikrein is a serine proteinase capable of cleaving kininogen substrate to produce the potent vasodilator kinin peptide. Kinin mediates a complex set of physiological actions through its receptor signaling. Systemic delivery of the kallikrein gene in an adenoviral vector significantly reduced stroke-induced mortality rate, blood pressure elevation, and aortic hypertrophy in hypertensive Dahl-salt sensitive rats fed a high salt diet. Using a focal cerebral ischemic rat model induced by middle cerebral artery occlusion, intravenous or intracerebroventricular kallikrein gene delivery significantly reduced ischemia/repefusion (I/R)-induced neurological deficits, cerebral infarction, neuronal and glial cell apoptosis, and inflammatory cell infiltration, while promoting angiogenesis and neurogenesis in the ischemic brain. A continuous infusion of a sub-depressor dose of tissue kallikrein protein through implanted minipump decreased I/R-induced neurological dysfunction and cerebral infarction, inflammation and oxidative stress independent of kallikrein's blood pressure-lowering effect. Moreover, kallikrein offered neuroprotection even when delivered at one day after the onset of stroke. Kallikrein's protective effects were blocked by the kinin B2 receptor antagonist icatibant. The role of the kinin B2 receptor in mediating the protective effect against ischemic brain injury was further confirmed by increases in mortality rate and post-ischemic brain injury in kinin B2 receptor-deficient mice. Taken together, these results suggest a novel function of kallikrein as an anti-inflammatory and anti-oxidative agent in protecting the brain against ischemic stroke-induced injuries. These findings also raise the possibility that tissue kallikrein may have value in the treatment of acute ischemic stroke.