ecallantide and Infarction--Middle-Cerebral-Artery

Thrombolytic therapy using tissue plasminogen activator (tPA) in acute stroke is associated with increased risks of cerebral hemorrhagic transformation and angioedema. Although plasma kallikrein (PKal) has been implicated in contributing to both hematoma expansion and thrombosis in stroke, its role in the complications associated with the therapeutic use of tPA in stroke is not yet available. We investigated the effects of tPA on plasma prekallikrein (PPK) activation and the role of PKal on cerebral outcomes in a murine thrombotic stroke model treated with tPA. We show that tPA increases PKal activity in vitro in both murine and human plasma, via a factor XII (FXII)-dependent mechanism. Intravenous administration of tPA increased circulating PKal activity in mice. In mice with thrombotic occlusion of the middle cerebral artery, tPA administration increased brain hemorrhage transformation, infarct volume, and edema. These adverse effects of tPA were ameliorated in PPK (Klkb1)-deficient and FXII-deficient mice and in wild-type (WT) mice pretreated with a PKal inhibitor prior to tPA. tPA-induced brain hemisphere reperfusion after photothrombolic middle cerebral artery occlusion was increased in Klkb1

Topics: Administration, Intravenous; Angioedema; Animals; Cerebral Hemorrhage; Disease Models, Animal; Factor XII; Fibrinolytic Agents; Gene Expression; Humans; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Plasma Kallikrein; Stroke; Thrombolytic Therapy; Thrombosis; Tissue Plasminogen Activator

We have studied the effect of DX-88, a selective recombinant inhibitor of human plasma kallikrein, in transient or permanent focal brain ischemia (with or without reperfusion, respectively) induced in C57BL/6 mice. Twenty-four hours after transient ischemia, DX-88 administered at the beginning of ischemia (pre) induced a dose-dependent reduction of ischemic volume that, at the dose of 30 microg/mouse, reached 49% of the volume of saline-treated mice. At the same dose, DX-88 was also able to reduce brain swelling to 32%. Mice treated with DX-88 pre had significantly lower general and focal deficit score. Fluoro-Jade staining, a marker for neuronal degeneration, showed that DX-88-treated mice had a reduction in the number of degenerating cells, compared with saline-treated mice. Seven days after transient ischemia, the DX-88 protective effect was still present. When the inhibitor was injected at the end of ischemia (post), it was still able to reduce ischemic volume, brain swelling, and neurological deficits. DX-88 efficacy was lost when the inhibitor was given 30 min after the beginning of reperfusion (1 h post) or when reperfusion was not present (permanent occlusion model). This study shows that DX-88 has a strong neuroprotective effect in the early phases of brain ischemia preventing reperfusion injury and indicates that inhibition of plasma kallikrein may be a useful tool in the strategy aimed at reducing the detrimental effects linked to reperfusion.

Topics: Animals; Behavior, Animal; Brain; Brain Edema; Cell Count; Cerebrovascular Disorders; Fluoresceins; Fluorescent Dyes; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Mice; Mice, Inbred C57BL; Nerve Degeneration; Neurons; Organic Chemicals; Plasma Kallikrein; Reperfusion Injury

Edema formation is a major problem in large ischemic infarcts, and the underlying breakdown of the blood-brain barrier is only incompletely understood. Here, we report that the tissue kallikrein-kinin system, which influences the permeability of the blood-brain barrier, is activated in stroke. In 22 patients with large infarcts in the territory of the middle cerebral artery, we found elevated plasma concentrations of the tissue kinin kallidin. The data suggest that further studies on a possible role of kinin receptor antagonists on edema after stroke are warranted.

Topics: Female; Humans; Infarction, Middle Cerebral Artery; Kallidin; Kallikrein-Kinin System; Male; Middle Aged; Plasma Kallikrein; Tissue Kallikreins