Elsevier

Neuroscience

Volume 180, 28 April 2011, Pages 272-279
Neuroscience

Neurodegeneration, Neuroprotection, and Disease-Oriented Neuroscience
Research Paper
Fluid-percussion brain injury induces changes in aquaporin channel expression

https://doi.org/10.1016/j.neuroscience.2011.02.020Get rights and content

Abstract

Edema, the accumulation of excess fluid, is a major pathological change in the brain that contributes significantly to pathology and mortality after moderate to severe brain injury. Edema is regulated by aquaporin (AQP) channels which transport water across cellular membranes. Six AQPs are found in the brain (1, 3, 4, 5, 8, and 9), and previous studies have found that AQP4 is regulated after traumatic brain injury (TBI). To further understand how AQPs contribute to brain edema, we investigated whether expression of AQP1, 3, and 9 are also regulated after TBI. Adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury (FPI) or sham surgery. After induction of FPI, the injured, ipsilateral parietal cortex and hippocampus were dissected and analyzed by Western blotting. We observed a small decrease in AQP3 and 4 levels at 7 days after FPI in the ipsilateral, parietal cortex. Both AQP1 and 9 significantly increased within 30 min post-injury and remained elevated for up to 6 h in the ipsilateral, parietal cortex. Aqp1 and 9 mRNA levels were also significantly increased at 30 min post-FPI. Administration of an AQP1 and 4 antagonist, AqB013, non-significantly increased brain water content in sham, non-injured animals, and did not prevent edema formation 24 h after trauma in either the parietal cortex or hippocampus. These results indicate that Aqp1 and 9 mRNA and protein levels increase after moderate parasagittal FPI and that an inhibitor of AQP1 and 4 does not decrease edema after moderate parasagittal FPI.

Highlights

▶Fluid-percussion brain injury induces increases in aquaporin 1 and 9. ▶Levels of aquaporins 3 and 4 are decreased after fluid-percussion brain injury. ▶An inhibitor of aquaporin 1 and 4 increases water content in the non-injured brain. ▶Aquaporin 1 and 4 inhibition does not reduce edema after fluid-percussion brain injury.

Section snippets

Fluid-percussion brain injury model

The experiments were carried out using 99 adult male Sprague Dawley rats (300–400 g, Charles Rivers Laboratories, Wilmington, MA, USA). All experimental procedures were in compliance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and approved by the University of Miami Institutional Animal Care and Use Committee. Animals were anesthetized with 3% isoflurane, 70% N2O, and 30% O2. The animals received a 4.8 mm craniotomy (3.8 mm posterior to bregma, 2.5 mm

Results

AQP4 has been shown to be highly regulated in several experimental brain injury models (Ke et al., 2001, Kiening et al., 2002, Sun et al., 2003, Zhao et al., 2005, Guo et al., 2006, Taya et al., 2008, Ding et al., 2009, Higashida et al., 2011). However, whether other AQPs are regulated after moderate parasagittal FPI is still unknown. In the uninjured brain, AQP1 expression is restricted to the choroid plexus (Speake et al., 2003). To determine if this expression pattern changes after injury,

Discussion

Understanding the changes that occur after brain injury in molecules that subserve water transport may yield novel therapeutic targets for the treatment of edema. To this end, we analyzed the brain for changes in the water channels AQP1, 3, 4, and 9 after moderate parasagittal FPI. We observed that AQP1 and 9 significantly increased in the ipsilateral parietal cortex after injury, whereas AQP3 and 4 were unchanged except for a slight decrease at 7 days post-injury. These changes in protein were

Conclusion

In summary, our data demonstrate that after moderate parasagittal FPI, levels of AQP1 and 9, but not AQP3 or 4, significantly increase from 30 min to 24 h post-injury. Pharmacological inhibition of AQP1 and 4 with a novel drug increased water content in the non-injured brain, and did not reduce edema induced by TBI. These studies suggest that AQP9 is a potential therapeutic target to reduce edema and prevent the devastating consequences of edema after TBI, and that antagonists of AQP water

Acknowledgments

This work was supported by The Miami Project to Cure Paralysis, The Buoniconti Fund to Cure Paralysis, and the Channel 7 Children's Research Foundation, Australia. We thank Dr. C. Falo for scientific input, Dr. G. Flynn for providing AqB013, and Drs. Helen Bramlett and Michael Norenberg for critical reading of the manuscript.

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