Neutrophil protein kinase Cδ as a mediator of stroke-reperfusion injury
Wen-Hai Chou, … , Donna M. Ferriero, Robert O. Messing
Wen-Hai Chou, … , Donna M. Ferriero, Robert O. Messing
Published July 1, 2004
Citation Information: J Clin Invest. 2004;114(1):49-56. https://doi.org/10.1172/JCI21655.
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Article Neuroscience

Neutrophil protein kinase Cδ as a mediator of stroke-reperfusion injury

Abstract

Thrombolysis is widely used to intervene in acute ischemic stroke, but reestablishment of circulation may paradoxically initiate a reperfusion injury. Here we describe studies with mice lacking protein kinase Cδ (PKCδ) showing that absence of this enzyme markedly reduces reperfusion injury following transient ischemia. This was associated with reduced infiltration of peripheral blood neutrophils into infarcted tissue and with impaired neutrophil adhesion, migration, respiratory burst, and degranulation in vitro. Total body irradiation followed by transplantation with bone marrow from PKCδ-null mice donors reduced infarct size and improved neurological outcome in WT mice, whereas marrow transplantation from WT donors increased infarction and worsened neurological scores in PKCδ-null mice. These results indicate an important role for neutrophil PKCδ in reperfusion injury and strongly suggest that PKCδ inhibitors could prove useful in the treatment of stroke.

Authors

Wen-Hai Chou, Doo-Sup Choi, Hong Zhang, Dezhi Mu, Tom McMahon, Viktor N. Kharazia, Clifford A. Lowell, Donna M. Ferriero, Robert O. Messing

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Figure 3

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Cerebrovascular anatomy and cerebral blood flow. (A and B) Shown are rep...
Cerebrovascular anatomy and cerebral blood flow. (A and B) Shown are representative images of the ventral (A) and dorsal (B) surfaces of brains from PKCδ+/+ and PKCδ –/ – mice perfused with black ink. The points of anastomoses between the MCA and the ACA are circled and connected by the line of anastomoses to define the respective vascular territories. (C) Distances from the line of anastomoses to the midline in PKCδ+/+ (n = 3) and PKCδ –/ – (n = 3) mice were measured at coronal planes 2, 4, and 6 mm from the frontal pole. (D) Regional cerebral blood flow before and during 1 hour of MCAO and during the first hour of reperfusion in PKCδ+/+ (n = 3) and PKCδ –/ – (n = 3) mice. Relative cerebral blood flow was expressed as the percentage of the Doppler signal intensity of the ischemic compared with the contralateral hemisphere. (E) The microvasculature in the cortex of PKCδ+/+ and PKCδ –/ – mice revealed by NADPH diaphorase histochemistry. The scale bar corresponds to 250 & μ;m.