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

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 1

Sustained treatment with δV1-1 reduces hypertension-induced encephalopathy in the DS rat model.

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Sustained treatment with δV1-1 reduces hypertension-induced encephalopat...
(A) DS rats were fed a high-salt diet (8% NaCl) from 6 to 15 weeks of age and treated with saline, TAT, or PKC peptide regulators beginning at 11 weeks via s.c. implanted osmotic pumps that delivered peptides at a rate of 1.0 mg/kg/d. Any seizures, twitchings, paralysis, or lethargy exhibited by the animals was recorded by an observer blinded to the treatments. DS rats were treated with peptide regulators, including inhibitors selective for βII, δ, or ε PKC from 11 to 15 weeks. Sustained treatment with the δPKC inhibitor δV1-1 significantly increased the survival of DS rats (*P < 0.01, log-rank test). (B) None of the treatments affected cardiac function measured by fractional shortening at the age of 15 weeks. Data are mean ± SEM (n = 12–16 rats per group). (C) δV1-1 treatment significantly improved the neurological status of DS rats. Individual neurological symptoms were recorded and the percentage of each major behavioral symptom of encephalopathy in each group of animals was monitored (n = 24 rats per group). *P < 0.01 versus saline- or TAT-treated group, Fisher’s exact test. (D) None of the treatments affected the elevated blood pressure. Data are mean ± SEM (n = 24 rats per group).