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Neuronal damage and functional deficits are ameliorated by inhibition of aquaporin and HIF1α after traumatic brain injury (TBI).
- Source :
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Journal of the neurological sciences [J Neurol Sci] 2012 Dec 15; Vol. 323 (1-2), pp. 134-40. Date of Electronic Publication: 2012 Oct 03. - Publication Year :
- 2012
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Abstract
- The present study, using a rodent model of closed-head diffuse traumatic brain injury (TBI), investigated the role of dysregulated aquaporins (AQP) 4 and 9, as well as hypoxia inducible factor -1α(HIF-1α) on brain edema formation, neuronal injury, and functional deficits. TBI was induced in adult (400-425 g), male Sprague-Dawley rats using a modified Marmarou's head impact-acceleration device (450 g weight dropped from 2m height). Animals in each treatment group were administered intravenous anti-AQP4 or -AQP9 antibodies or 2-Methoxyestradiol (2ME2, an inhibitor of HIF-1α) 30 min after injury. At 24h post-TBI, animals (n=6 each group) were sacrificed to examine the extent of brain edema by water content, as well as protein expression of AQP and HIF-1α by Western immune-blotting. At 48-hours post-TBI, neuronal injury (n=8 each group) was assessed by FluoroJade (FJ) histochemistry. Spatial learning and memory deficits were evaluated by radial arm maze (n=8 each group) up to 21 days post-TBI. Compared to non-injured controls, significant (p<0.05) increases in the expression of AQP4 and -9 were detected in the brains of injured animals. In addition, significant (p<0.05) brain edema after TBI was associated with increases (p <0.05) both in neuronal injury (FJ labeling) and neurobehavioral deficits. Selective inhibition of either AQP4 or -9, or HIF-1α significantly (p<0.05) decreased the expression of the proteins. In addition, inhibition of the AQPs and HIF-1α significantly (p<0.05) ameliorated brain edema, as well as the number of injured neurons in cortical layers II/III and V/VI, striatum and hippocampal regions CA1/CA3. Finally, compared to the non-treated TBI animals, AQP or HIF-1α inhibition significantly (p<0.01) improved neurobehavioral outcomes after TBI. Taken together, the present data supports a causal relation between HIF-AQP mediated cerebral edema, secondary neuronal injury, and tertiary behavioral deficits post-TBI. The data further suggests that upstream modulation of the molecular patho-trajectory effectively ameliorates both neuronal injury and behavioral deficits post-TBI.<br /> (Copyright © 2012. Published by Elsevier B.V.)
- Subjects :
- 2-Methoxyestradiol
Animals
Aquaporin 4 antagonists & inhibitors
Aquaporin 4 biosynthesis
Aquaporin 4 genetics
Aquaporin 4 immunology
Aquaporins antagonists & inhibitors
Aquaporins biosynthesis
Aquaporins genetics
Aquaporins immunology
Brain Damage, Chronic etiology
Brain Damage, Chronic prevention & control
Brain Damage, Chronic psychology
Brain Edema etiology
Brain Edema prevention & control
Brain Injuries complications
Brain Injuries pathology
Brain Injuries physiopathology
Brain Injuries psychology
CA1 Region, Hippocampal pathology
CA3 Region, Hippocampal pathology
Cell Membrane Permeability drug effects
Corpus Striatum pathology
Estradiol pharmacology
Estradiol therapeutic use
Fluoresceins
Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit biosynthesis
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Immunoglobulin G immunology
Immunoglobulin G pharmacology
Male
Maze Learning drug effects
Memory Disorders etiology
Memory Disorders prevention & control
Nerve Tissue Proteins antagonists & inhibitors
Nerve Tissue Proteins biosynthesis
Nerve Tissue Proteins genetics
Neurons pathology
Organic Chemicals pharmacokinetics
Rats
Rats, Sprague-Dawley
Aquaporin 4 physiology
Aquaporins physiology
Brain Injuries drug therapy
Estradiol analogs & derivatives
Hypoxia-Inducible Factor 1, alpha Subunit physiology
Immunoglobulin G therapeutic use
Nerve Tissue Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1878-5883
- Volume :
- 323
- Issue :
- 1-2
- Database :
- MEDLINE
- Journal :
- Journal of the neurological sciences
- Publication Type :
- Academic Journal
- Accession number :
- 23040263
- Full Text :
- https://doi.org/10.1016/j.jns.2012.08.036