Angiotensin II Receptor Type 2 Activation Does Not Influence Brain Damage, Neurological Impairment and Inflammation After Experimental Traumatic Brain Injury

Abstract Antagonism of the angiotensin II type 1 receptor (AT1) improves neurological function and reduces brain damage after experimental traumatic brain injury (TBI), which may be partly a result of enhanced indirect angiotensin II type 2 receptor (AT2) stimulation. AT2 stimulation was demonstrated to act neuroprotective via anti-inflammatory, vasodilatory, and neuroregenerative mechanisms in experimental cerebral pathology models. We recently demonstrated an upregulation of AT2 after TBI suggesting a protective mechanism. The present study investigated the effect of post-traumatic (5 days after TBI) AT2 activation via high and low doses of a selective AT2 agonist, compound 21 (C21), compared to vehicle-treated controls. No differences in the extent of the TBI-induced lesions were found between both doses of C21 and the controls. We then tested AT2-knockdown animals for secondary brain damage after experimental TBI. Lesion volume and neurological outcomes in AT2-deficient mice were similar to those in wild-type control mice at both 24 hours and 5 days post-trauma. Thus, in contrast to AT1 antagonism, AT2 modulation does not influence the initial pathophysiological mechanisms of TBI in the first 5 days after the insult, indicating that AT2 plays only a minor role in the early phase following trauma-induced brain damage.

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Neuroprotection after Traumatic Brain Injury in Heat-Acclimated Mice Involves Induced Neurogenesis and Activation of Angiotensin Receptor Type 2 Signaling

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.93 ◽

2014 ◽

Vol 34 (8) ◽

pp. 1381-1390 ◽

Cited By ~ 23

Author(s):

Gali Umschweif ◽

Dalia Shabashov ◽

Alexander G Alexandrovich ◽

Victoria Trembovler ◽

Michal Horowitz ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Hypoxia Inducible Factor ◽

Receptor Type ◽

Lesion Volume ◽

Angiotensin Ii Receptor ◽

Akt Phosphorylation ◽

Survival Pathways ◽

Angiotensin Receptor Type 2

Long-term exposure of mice to mild heat (34°C ± 1°C) confers neuroprotection against traumatic brain injury (TBI); however, the underling mechanisms are not fully understood. Heat acclimation (HA) increases hypothalamic angiotensin II receptor type 2 (AT2) expression and hypothalamic neurogenesis. Accumulating data suggest that activation of the brain AT2 receptor confers protection against several types of brain pathologies, including ischemia, a hallmark of the secondary injury occurring following TBI. As AT2 activates the same pro-survival pathways involved in HA-mediated neuroprotection (e.g., Akt phosphorylation, hypoxia-inducible factor 1α (HIF-1α), and brain-derived neurotrophic factor (BDNF)), we examined the role of AT2 in HA-mediated neuroprotection after TBI. Using an AT2-specific antagonist PD123319, we found that the improvements in motor and cognitive recovery as well as reduced lesion volume and neurogenesis seen in HA mice were all diminished by AT2 inhibition, whereas no significant alternations were observed in control mice. We also found that nerve growth factor/tropomyosin-related kinase receptor A (TrkA), BDNF/TrkB, and HIF-1α pathways are upregulated by HA and inhibited on PD123319 administration, suggesting that these pathways play a role in AT2 signaling in HA mice. In conclusion, AT2 is involved in HA-mediated neuroprotection, and AT2 activation may be protective and should be considered a novel drug target in the treatment of TBI patients.

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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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