Abstract TP445: Angiotensin Receptor Type 1 Deficiency Attenuates Brain Damage and Improves Outcome After Experimental Traumatic Brain Injury

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Jong Youl Kim ◽  
Nuri Kim ◽  
Meshell Johnson ◽  
Midoir A. Yenari
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Lesion Size ◽  
Receptor Type ◽  
Neurological Deficits ◽  
Brain Hemorrhage ◽  
Angiotensin Ii Receptor ◽  
Improved Outcomes ◽  
Adhesive Removal

Inflammation which accompanies traumatic brain injury (TBI) can exacerbate neurological deficits. Thus, anti-inflammatory treatments have the potential to improve outcome. Angiotensin II receptor type 1 (ART1) mediates vasoconstriction, and its inhibition has been widely used to treat hypertension. However, recent work has suggested that it may also modulate apoptosis, and neuroinflammation. Thus, treatment with already available ART1 blockers may have additional neuroprotective value. We explore the contribution of ART1 to neuroprotection and brain hemorrhage in a model of TBI. Male, wildtype (Wt) and ART1 knockout (Ko) mice were subjected to TBI using controlled cortical impact (CCI). This model leads to reproducible traumatic brain injury with disruption of motor function and hemorrhage into the area of injury. Sensorimotor function (adhesive removal & elevated body swing tests), brain hemorrhage and lesion size were assessed at 3, 7 and 14 days. To explore the clinical relevance of ART1 in brain injury, we also gave Wt mice an ATR1 inhibitor (candesartan, 0.1mg/kg IP). We found that ATR1 deficient mice were protected from CCI as evidenced by decreased lesion and hemorrhage volumes (decreases of ∼40% in lesion size amongst Ko mice, n=6/group, p<0.05), improved neurobehavioral outcomes (n=6/group, p<0.05) and fewer activated microglia in Ko mice (p<0.05). This was also associated with decreased cytokine expression relative to Wt. Candesartan similarly protected against brain injury and improved neurological outcome out to 14 days post CCI (n=6/group, p<0.05). These data are consistent with the notion that ART1 contributes negatively to traumatic brain injury, and its inhibition or deficiency leads to improved outcomes and decreased immune responses. Considering the clinical availability of ART1 inhibitors, this approach may be a promising novel therapeutic target against TBI and related conditions including stroke.

scholarly journals Angiotensin Receptor Type 1 Inhibition in Lymphopenia and in Neutropenia After Traumatic Brain Injury In Mice: a Randomized Controlled Study (ATLANTIS)

2021 ◽  
Author(s):  
Ralph Timaru-Kast ◽  
Shila P. Coronel-Castello ◽  
Tobias Krämer ◽  
André V. Hugonnet ◽  
Michael K.E. Schäfer ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Damage ◽  
Receptor Type ◽  
Wild Type ◽  
Secondary Brain Damage ◽  
Neutrophil Depletion ◽  
Cerebral Inflammation

Abstract Background: Cerebral inflammation with invasion of neutrophils and lymphocytes is an important factor in the process of secondary brain damage expansion after traumatic brain injury (TBI). Depletion of neutrophils in mice has been shown to reduce neurologic impairment after TBI. The intrinsic cerebral renin-angiotensin system is an important mediator of cerebral inflammation, as inhibition of the angiotensin II receptor type 1 (AT1) with candesartan improves neurologic recovery, and reduces secondary brain damage and cerebral neutrophil invasion after TBI. The present study was therefore designed to determine the role of immune cells in AT1 inhibition-mediated neuroprotection after TBI. Methods: In study A we assessed the effect of neutrophil depletion in mice after TBI. In study B we investigated the impact of RAG1 deficiency (RAG1-/-; mice without mature B- and T-lymphocytes) after TBI. In study C we investigated the role of neutrophils in candesartan mediated protection after TBI in wild-type mice with and without neutrophil depletion. In study D we examined the role of lymphocytes in AT1 inhibition mediated neuroprotection after TBI in RAG1-/-.Results: Neutropenic and RAG1-/- mice showed reduced brain damage compared to control groups. In control antibody treated wild type mice AT1 inhibition reduced lesion volumes and inflammation compared to vehicle, while in neutropenic mice, candesartan had no effect. In RAG1-/- mice AT1 inhibition resulted in reduction of brain damage and neuroinflammation compared to vehicle group. Conclusion: The present results demonstrate, that reduction of neutrophils and of lymphocytes as well as AT1 inhibition in wild type and RAG1-/- mice reduce brain damage and inflammation after TBI. However, AT1 inhibition was neuroprotective in RAG1-/- mice, but not in neutropenic mice. Therefore, the results indicate that AT1 inhibition mediated neuroprotection may be exerted by anti-inflammatory effects on neutrophils, with a subsequent reduction of neutrophil invasion.

scholarly journals Modeling traumatic brain injury combined with hemorrhagic shock in rats: Neurological assessment and PET imaging with 18F-fluorodeoxyglucaric acid

2021 ◽  
Author(s):  
Hibah O Awwad ◽  
Andria Hedrick ◽  
Alex Mdzinarishvili ◽  
Hailey Houson ◽  
Kelly Standifer ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Hemorrhagic Shock ◽  
Tissue Injury ◽  
Brain Lesion ◽  
Lesion Size ◽  
Neurological Deficits ◽  
Lesion Volume ◽  
Sprague Dawley ◽  
The Impact

Traumatic brain injury (TBI)is a major cause of death and disability worldwide. Hemorrhagic shock (HS) aggravates tissue injury and complicates TBI recovery. We studied the combined insult of mild TBI and HS and investigated the impact of varying loss of blood volume on neurologic deficit and brain lesion volume. A novel positron emission tomography (PET) technique was employed to monitor tissue injury. Male Sprague Dawley rats received mTBI by controlled cortical impact (CCI) followed by withdrawal of 0%, 30-40%, 45%, or 50% of blood (mTBI, mTBI+HS≤40%, mTBI+HS45%, and mTBI+HS50%, respectively). Neurological deficit (mNSS= 5.6, 7.6, and 12.3) and mortality (2/12, 2/6, and 7/12) were higher in mTBI+HS≤40%, mTBI+HS45%, and mTBI+HS50%, than in mTBI alone rats (no death; mNSS=3.3). Histologic lesion size increased 3.5-fold in mTBI+HS50% compared to mTBI alone and the infarct-avid PET agent 18F-fluorodeoxyglucaric acid (FGA) proportionately detected tissue necrosis in mTBI+HS50% rats. Based on these results, we conclude that HS aggravates mTBI-induced neurological deficits, tissue injury and mortality. PET using 18F-FGA as an imaging marker can detect the extent of injury in a non-invasive manner.

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

2014 ◽  
Vol 34 (8) ◽  
pp. 1381-1390 ◽  
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.

scholarly journals Nitroxides affect neurological deficits and lesion size induced by a rat model of traumatic brain injury

Nitric Oxide ◽  
2020 ◽  
Vol 97 ◽  
pp. 57-65
Author(s):  
Razia Zakarya ◽  
Arjun Sapkota ◽  
Yik Lung Chan ◽  
Jadvi Shah ◽  
Sonia Saad ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Rat Model ◽  
Lesion Size ◽  
Neurological Deficits

scholarly journals Rhein Protects Against Neurological Deficits After Traumatic Brain Injury in Mice via Inhibiting Neuronal Pyroptosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Fangfang Bi ◽  
Huaifen Ma ◽  
Chen Ji ◽  
Cuicui Chang ◽  
Wenbo Liu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neurological Deficits

scholarly journals Intraoperative hypothermia during vascular neurosurgical procedures

2009 ◽  
Vol 26 (5) ◽  
pp. E24 ◽  
Author(s):  
Raymond Choi ◽  
Robert H. Andres ◽  
Gary K. Steinberg ◽  
Raphael Guzman
Keyword(s):  
Traumatic Brain Injury ◽  
Clinical Trials ◽  
Brain Injury ◽  
Animal Models ◽  
Mild Hypothermia ◽  
Scientific Evidence ◽  
Neurosurgical Procedures ◽  
Ischemic Damage ◽  
Intraoperative Hypothermia ◽  
Improved Outcomes

Increasing evidence in animal models and clinical trials for stroke, hypoxic encephalopathy for children, and traumatic brain injury have shown that mild hypothermia may attenuate ischemic damage and improve neurological outcome. However, it is less clear if mild intraoperative hypothermia during vascular neurosurgical procedures results in improved outcomes for patients. This review examines the scientific evidence behind hypothermia as a treatment and discusses factors that may be important for the use of this adjuvant technique, including cooling temperature, duration of hypothermia, and rate of rewarming.

Angiotensin II Receptor Type 1 mRNA is Upregulated in Atria of Patients with End-stage Heart Failure

1997 ◽  
Vol 29 (8) ◽  
pp. 2299-2304 ◽  
Author(s):  
Raffi R Kaprielian ◽  
Emmanuel Dupont ◽  
Sassan Hafizi ◽  
Philip A Poole-Wilson ◽  
Asghar Khaghani ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Receptor Type ◽  
Angiotensin Ii Receptor ◽  
End Stage Heart Failure ◽  
End Stage

Abstract 230: Differential Effects of Prehospital Hypotension and Injury Severity in Isolated vs. Multisystem Major Traumatic Brain Injury

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Daniel W Spaite ◽  
Chengcheng Hu ◽  
Bentley J Bobrow ◽  
Bruce J Barnhart ◽  
Vatsal Chikani ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Injury Severity ◽  
Treatment Effectiveness ◽  
Guideline Implementation ◽  
Body Region ◽  
Head Region ◽  
Differential Effects ◽  
Severe Tbi

Background: In hospital-based studies, hypotension (HT, SBP <90) is more likely to occur in multisystem traumatic brain injury (MTBI) than isolated (ITBI). However, there are few EMS studies on this issue. Hypothesis: Prehospital HT is associated with differential effects in MTBI and ITBI and these effects are influenced by the severity of primary brain injury. Methods: Inclusion: TBI cases in the EPIC Study (NIH 1R01NS071049) before TBI guideline implementation (1/07-3/14). ITBI: Major TBI cases (CDC Barell Matrix Type 1) that had no injury with ICD9-based Regional Severity Score [RSS (AIS equivalent)] ≥3 in any other body region. MTBI: Type 1 TBI plus at least one non-head region injury with RSS ≥3. Results: Included were 13,435 cases [Excl: age <10 (5.9%), missing data (6.2%)]. 10,374 (77.2%) were ITBI, 3061 (22.8%) MTBI. Mortality: ITBI: 7.7% (797/10,374), MTBI: 19.2% (587/3061, p<0.0001). Prehospital HT occurred 3.5 times more often in MTBI (14.8%, 453/3061 vs 4.2%, 437/10,374; p<0.0001). Among HT cases, 40.8% (185/453) with MTBI died vs 30.9% with ITBI (135/437; p<0.0001). In the hypotensive moderate/severe TBI cohort (RSS-Head 3/4), MTBI mortality was 2.4 times higher (17.2%, 40/232) than ITBI (7.1%, 17/240, p = 0.001). However, in the hypotensive very/extremely severe TBI group (RSS-Head 5/6), mortality was almost identical in MTBI (73.4%, 141/192) and ITBI (72.1%, 116/161, p = 0.864). Conclusion: Among major TBI patients with prehospital HT, those with MTBI were much more likely to die than those with ITBI. However, this association varied dramatically with TBI severity. In mod/severe TBI cases with HT, MTBI mortality was 2.4 times higher than in ITBI. In contrast, in very/extremely severe TBI with HT, there was no identifiable mortality difference. Thus, in cases with substantial potential to survive the primary brain injury (mod/severe), outcome is markedly worse in patients with multisystem injuries. However, in very/extremely severe TBI, non-head region injuries have no apparent association with mortality. This may be because the TBI is the primary factor leading to death in these cases. The main EPIC study is evaluating whether this severity-based difference in “effect” has implications for TBI guideline treatment effectiveness.

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