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Sustained pharmacological inhibition of δPKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats
Xin Qi, … , Raymond A. Sobel, Daria Mochly-Rosen
Xin Qi, … , Raymond A. Sobel, Daria Mochly-Rosen
Published December 20, 2007
Citation Information: J Clin Invest. 2008;118(1):173-182. https://doi.org/10.1172/JCI32636.
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Research Article

Sustained pharmacological inhibition of δPKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats

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Abstract

Hypertensive encephalopathy is a potentially fatal condition associated with cerebral edema and the breakdown of the blood-brain barrier (BBB). The molecular pathways leading to this condition, however, are unknown. We determined the role of δPKC, which is thought to regulate microvascular permeability, in the development of hypertensive encephalopathy using δV1-1 — a selective peptide inhibitor of δPKC. As a model of hypertensive encephalopathy, Dahl salt-sensitive rats were fed an 8% high-salt diet from 6 weeks of age and then were infused s.c. with saline, control TAT peptide, or δV1-1 using osmotic minipumps. The mortality rate and the behavioral symptoms of hypertensive encephalopathy decreased significantly in the δV1-1–treated group relative to the control-treated group, and BBB permeability was reduced by more than 60%. Treatment with δV1-1 was also associated with decreased δPKC accumulation in capillary endothelial cells and in the endfeet of capillary astrocytes, which suggests decreased microvasculature disruption. Treatment with δV1-1 prevented hypertension-induced tight junction disruption associated with BBB breakdown, which suggests that δPKC may specifically act to dysregulate tight junction components. Together, these results suggest that δPKC plays a role in the development of hypertension-induced encephalopathy and may be a therapeutic target for the prevention of BBB disruption.

Authors

Xin Qi, Koichi Inagaki, Raymond A. Sobel, Daria Mochly-Rosen

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Figure 3

Sustained δV1-1 treatment decreases hypertension-induced increases in the permeability of the BBB.

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Sustained δV1-1 treatment decreases hypertension-induced increases in th...
Evans blue dye (30 mg/kg) was injected i.v. at 13 weeks of age in rats fed the high-salt diet. The brains were isolated 30 min after injection. (A) Evans blue dye extravasation in DS rats treated with TAT or δV1-1. (B) Quantification of Evans blue dye extravasation in the parenchyma of DS rat brain. Open circles represent the amount of Evans blue dye in individual brains, and the filled circles represent the mean. Data are mean ± SEM (n = 6 rats per group). F = 17.71, df = 2. **P < 0.01 versus TAT treatment groups, #P < 0.05 versus rats fed the low-salt diet.

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