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 Angiotensin Receptor Type 2 Activation Induces Neuroprotection and Neurogenesis After Traumatic Brain Injury

2014 ◽  
Vol 11 (3) ◽  
pp. 665-678 ◽  
Author(s):  
Gali Umschweif ◽  
Sigal Liraz-Zaltsman ◽  
Dalia Shabashov ◽  
Alexander Alexandrovich ◽  
Victoria Trembovler ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Receptor Type ◽  
Angiotensin Receptor ◽  
Angiotensin Receptor Type 2

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

2021 ◽  
Author(s):  
Ralph Timaru-Kast ◽  
Andreas Garcia Bardon ◽  
Clara Luh ◽  
Shila P. Coronel-Castello ◽  
Phuriphong Songarj ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Angiotensin Ii ◽  
Brain Damage ◽  
Minor Role ◽  
Protective Mechanism ◽  
Lesion Volume ◽  
Angiotensin Ii Receptor ◽  
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.

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 Heat Acclimation Provides Sustained Improvement in Functional Recovery and Attenuates Apoptosis after Traumatic Brain Injury

2009 ◽  
Vol 30 (3) ◽  
pp. 616-627 ◽  
Author(s):  
Gali Umschwief ◽  
Na'ama A Shein ◽  
Alexander G Alexandrovich ◽  
Victoria Trembovler ◽  
Michal Horowitz ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Apoptotic Cell ◽  
Heat Acclimation ◽  
Lesion Volume ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
Akt Phosphorylation ◽  
Activity Measurements ◽  
Induced Apoptosis

Heat acclimation (HA) offers functional neuroprotection in mice after traumatic brain injury (TBI). This study further characterizes endogenous neuroprotection acquired by HA (34±1°C, 30 d) after TBI. We establish here the ability of HA to induce sustained functional benefits and to reduce activation of apoptotic pathways. Neurobehavioral recovery, assessed by the Neurological Severity Score, was greater in HA mice up to 8 days after injury as compared with normothermic controls ( P<0.05) and lesion volume was also smaller in the HA group ( P<0.05). Reduced apoptotic cell death in HA mice was confirmed using caspase-3 activity measurements and immunohistochemistry. To investigate the underlying molecular pathways, expression levels of intrinsic apoptotic pathway-related proteins were examined. HA mice displayed higher mitochondrial levels of antiapoptotic Bcl-xL, accompanied by lower proapoptotic Bad levels and decreased cytochrome c release, suggesting a higher apoptotic threshold. Taken together with our previous reports, indicating increased Akt phosphorylation and antioxidative capacity, alongside with reduced tumor necrosis α levels after TBI in HA animals, the current results support the involvement of an antiapoptotic effect in HA-induced neuroprotection. Current results warrant further study as TBI-induced apoptosis may persist over weeks after injury, possibly providing a target for belated therapeutic intervention.

scholarly journals Hypoxia-Inducible Factor 1 is Essential for Spontaneous Recovery from Traumatic Brain Injury and is a Key Mediator of Heat Acclimation Induced Neuroprotection

2013 ◽  
Vol 33 (4) ◽  
pp. 524-531 ◽  
Author(s):  
Gali Umschweif ◽  
Alexander G Alexandrovich ◽  
Victoria Trembovler ◽  
Michal Horowitz ◽  
Esther Shohami
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Motor Function ◽  
Spontaneous Recovery ◽  
Hypoxia Inducible Factor ◽  
Heat Acclimation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Lesion Volume ◽  
Edema Formation ◽  
Glucose Transporter 1

Heat acclimation (HA), a well-established preconditioning model, confers neuroprotection in rodent models of traumatic brain injury (TBI). It increases neuroprotective factors, among them is hypoxia-inducible factor 1α (HIF-1α), which is important in the response to postinjury ischemia. However, little is known about the role of HIF-1α in TBI and its contribution to the establishment of the HA protecting phenotype. Therefore, we aimed to explore HIF-1α role in TBI defense mechanisms as well as in HA-induced neuroprotection. Acriflavine was used to inhibit HIF-1 in injured normothermic (NT) or HA mice. After TBI, we evaluated motor function recovery, lesion volume, edema formation, and body temperature as well as HIF-1 downstream transcription targets, such as glucose transporter 1 (GLUT1), vascular endothelial growth factor, and aquaporin 4. We found that HIF-1 inhibition resulted in deterioration of motor function, increased lesion volume, hypothermia, and reduced edema formation. All these parameters were significantly different in the HA mice. Western blot analysis and enzyme-linked immunosorbent assay showed reduced levels of all HIF-1 downstream targets in HA mice, however, only GLUT1 was downregulated in NT mice. We conclude that HIF-1 is a key mediator in both spontaneous recovery and HA-induced neuroprotection after TBI.

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

2012 ◽  
Vol 33 (2) ◽  
pp. 311-318 ◽  
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.

scholarly journals A combination antioxidant therapy to inhibit NOX2 and activate Nrf2 decreases secondary brain damage and improves functional recovery after traumatic brain injury

2017 ◽  
Vol 38 (10) ◽  
pp. 1818-1827 ◽  
Author(s):  
Raghavendar Chandran ◽  
TaeHee Kim ◽  
Suresh L Mehta ◽  
Eshwar Udho ◽  
Vishal Chanana ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Motor Function ◽  
Neurological Dysfunction ◽  
Vehicle Group ◽  
Lesion Volume ◽  
Post Injury ◽  
Cortical Contusion ◽  
Nrf2 Activator

Uncontrolled oxidative stress contributes to the secondary neuronal death that promotes long-term neurological dysfunction following traumatic brain injury (TBI). Surprisingly, both NADPH oxidase 2 (NOX2) that increases and transcription factor Nrf2 that decreases reactive oxygen species (ROS) are induced after TBI. As the post-injury functional outcome depends on the balance of these opposing molecular pathways, we evaluated the effect of TBI on the motor and cognitive deficits and cortical contusion volume in NOX2 and Nrf2 knockout mice. Genetic deletion of NOX2 improved, while Nrf2 worsened the post-TBI motor function recovery and lesion volume indicating that decreasing ROS levels might be beneficial after TBI. Treatment with either apocynin (NOX2 inhibitor) or TBHQ (Nrf2 activator) alone significantly improved the motor function after TBI, but had no effect on the lesion volume, compared to vehicle control. Whereas, the combo therapy (apocynin + TBHQ) given at either 5 min/24 h or 2 h/24 h improved motor and cognitive function and decreased cortical contusion volume compared to vehicle group. Thus, both the generation and disposal of ROS are important modulators of oxidative stress, and a combo therapy that prevents ROS formation and potentiates ROS disposal concurrently is efficacious after TBI.

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