Inhibition of c-Jun N-terminal kinase prevents blood-brain barrier disruption and normalizes the expression of tight junction proteins clautin-5 and ZO-1 in a rat model of subarachnoid hemorrhage.

Abstract

BACKGROUND:

The c-Jun N-terminal kinase (JNK) proteins are encoded by three genes (JNK1, JNK2, and JNK3), giving rise to multiple isoforms via alternative splicing. JNK inhibition using a chemical inhibitor SP600125 confers neuroprotection in an animal model of subarachnoid hemorrhage (SAH). The aim of this study is to investigate whether the protective effects of SP600125 were associated with modulation of tight junction proteins including claudin-5 and ZO-1 and to define which JNK isoforms were involved in the early brain injury after SAH.

METHODS:

Seventy-five male Sprague Dawley rats (weighing 300-350 g) were randomly assigned to five groups (n = 15): (1) sham, (2) SAH, (3) SAH + DMSO (dimethyl sulfoxide), (4) SAH + 10 mg/kg SP600125, and (5) SAH + 30 mg/kg SP600125. SP600125 or DMSO was injected intraperitoneally 1 h before and 6 h after the induction of SAH. Animals from all the groups were killed 24 h after SAH, and brain tissues were dissected and subjected to electron microscopic examination, Western blot analysis, and histological evaluation.

RESULTS:

SP600125 pretreatment restored tight junctions and attenuated blood-brain barrier (BBB) disruption and cerebral edema after SAH, coupled with reduced apoptosis in the cerebral cortex. SP600125 exposure restored the reduced expression of both claudin-5 and ZO-1 following SAH and normalized the levels of JNK1 and JNK3.

CONCLUSION:

Our data demonstrate that the JNK signaling plays an important role in the regulation of tight junction proteins and BBB integrity, and thus represents a promising target against brain injuries after SAH.

• Authors: Duo Chen, Xiang-tai Wei, Jun-hong Guan, Jiang-wei Yuan, Yu-tao Peng, Lei Song, Yun-hui Liu
• Journal: Acta neurochirurgica (Acta Neurochir (Wien)) Vol. 154 Issue 8 Pg. 1469-76; discussion 1476 (Aug 2012) ISSN: 0942-0940 [Electronic] Austria
• PMID: 22661329 (Publication Type: Journal Article)

Chemical References

• Anthracenes
• Claudin-5
• Cldn5 protein, rat
• Tjp1 protein, rat
• Zonula Occludens-1 Protein
• pyrazolanthrone
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Anthracenes (therapeutic use)
• Apoptosis (drug effects)
• Blood-Brain Barrier (drug effects, metabolism, pathology)
• Brain (metabolism, pathology)
• Claudin-5 (metabolism)
• Disease Models, Animal
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Male
• Microscopy, Electron, Transmission
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Subarachnoid Hemorrhage (complications, drug therapy, metabolism, pathology)
• Tight Junctions (drug effects, pathology, ultrastructure)
• Zonula Occludens-1 Protein (metabolism)