Effect of Small Molecule Vasopressin V1a and V2 Receptor Antagonists on Brain Edema Formation and Secondary Brain Damage following Traumatic Brain Injury in Mice

Inflammatory mechanisms are known to contribute to the pathophysiology of traumatic brain injury (TBI). Since bradykinin is one of the first mediators activated during inflammation, we investigated the role of bradykinin and its receptors in posttraumatic secondary brain damage. We subjected wild-type (WT), B1-, and B2-receptor-knockout mice to controlled cortical impact (CCI) and analyzed tissue bradykinin as well as kinin receptor mRNA and protein expression up to 48 h thereafter. Brain edema, contusion volume, and functional outcome were assessed 24 h and 7 days after CCI. Tissue bradykinin was maximally increased 2 h after trauma ( P<0.01 versus sham). Kinin B1 receptor mRNA was upregulated up to four-fold 24 h after CCI. Immunohistochemistry showed that B1 and B2 receptors were expressed in the brain and were significantly upregulated in the traumatic penumbra 1 to 24 h after CCI. B2R−/− mice had significantly less brain edema (−51% versus WT, 24 h; P<0.001), smaller contusion volumes (∼50% versus WT 24 h and 7 d after CCI; P<0.05), and better functional outcome 7 days after TBI as compared with WT mice ( P<0.05). The present results show that bradykinin and its B2 receptors play a causal role for brain edema formation and cell death after TBI.

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Inhaled Nitric Oxide Reduces Secondary Brain Damage after Traumatic Brain Injury in Mice

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.176 ◽

2012 ◽

Vol 33 (2) ◽

pp. 311-318 ◽

Cited By ~ 49

Author(s):

Nicole A Terpolilli ◽

Seong-Woong Kim ◽

Serge C Thal ◽

Wolfgang M Kuebler ◽

Nikolaus Plesnila

Keyword(s):

Nitric Oxide ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Damage ◽

Brain Regions ◽

Lesion Volume ◽

Effective Treatment Option ◽

Secondary Brain Damage ◽

Edema Formation ◽

Regional Ischemia

Ischemia, especially pericontusional ischemia, is one of the leading causes of secondary brain damage after traumatic brain injury (TBI). So far efforts to improve cerebral blood flow (CBF) after TBI were not successful because of various reasons. We previously showed that nitric oxide (NO) applied by inhalation after experimental ischemic stroke is transported to the brain and induces vasodilatation in hypoxic brain regions, thus improving regional ischemia, thereby improving brain damage and neurological outcome. As regional ischemia in the traumatic penumbra is a key mechanism determining secondary posttraumatic brain damage, the aim of the current study was to evaluate the effect of NO inhalation after experimental TBI. NO inhalation significantly improved CBF and reduced intracranial pressure after TBI in male C57 Bl/6 mice. Long-term application (24 hours NO inhalation) resulted in reduced lesion volume, reduced brain edema formation and less blood–brain barrier disruption, as well as improved neurological function. No adverse effects, e.g., on cerebral auto-regulation, systemic blood pressure, or oxidative damage were observed. NO inhalation might therefore be a safe and effective treatment option for TBI patients.

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Arginine Vasopressin V1a Receptor-Deficient Mice Have Reduced Brain Edema and Secondary Brain Damage following Traumatic Brain Injury

Journal of Neurotrauma ◽

10.1089/neu.2012.2807 ◽

2013 ◽

Vol 30 (16) ◽

pp. 1442-1448 ◽

Cited By ~ 19

Author(s):

Katrin Rauen ◽

Raimund Trabold ◽

Christian Brem ◽

Nicole A. Terpolilli ◽

Nikolaus Plesnila

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Edema ◽

Brain Damage ◽

Arginine Vasopressin ◽

Secondary Brain Damage ◽

V1a Receptor ◽

Vasopressin V1a Receptor ◽

Deficient Mice

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Neuropeptide release influences brain edema formation after diffuse traumatic brain injury

Brain Edema XII ◽

10.1007/978-3-7091-0651-8_55 ◽

2003 ◽

pp. 257-260 ◽

Cited By ~ 17

Author(s):

Robert Vink ◽

A. Young ◽

C. J. Bennett ◽

X. Hu ◽

C. O. Connor ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Edema ◽

Edema Formation ◽

Neuropeptide Release ◽

Brain Edema Formation

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Lost Polarization of Aquaporin4 and Dystroglycan in the Core Lesion after Traumatic Brain Injury Suggests Functional Divergence in Evolution

BioMed Research International ◽

10.1155/2015/471631 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Hui Liu ◽

Gou ping Qiu ◽

Fei Zhuo ◽

Wei hua Yu ◽

Shan quan Sun ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Edema ◽

Early Stage ◽

Functional Divergence ◽

Edema Formation ◽

Aqp4 Expression ◽

The Core ◽

Perivascular Area ◽

Brain Edema Formation

Objective. To understand how aquaporin4 (AQP4) and dystroglycan (DG) polarized distribution change and their roles in brain edema formation after traumatic brain injury (TBI).Methods. Brain water content, Evans blue detection, real-time PCR, western blot, and immunofluorescence were used.Results. At an early stage of TBI, AQP4 and DG maintained vessel-like pattern in perivascular endfeet; M1, M23, and M1/M23 were increased in the core lesion. At a later stage of TBI, DG expression was lost in perivascular area, accompanied with similar but delayed change of AQP4 expression; expression of M1, M23, and DG and the ratio of M1/M2 were increased.Conclusion. At an early stage, AQP4 and DG maintained the polarized distribution. Upregulated M1 and M23 could retard the cytotoxic edema formation. At a later stage AQP4 and DG polarized expression were lost from perivascular endfeet and induced the worst cytotoxic brain edema. The alteration of DG expression could regulate that of AQP4 expression after TBI.

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