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

Umschweif, Gali; Alexandrovich, Alexander; Trembovler, Victoria; Horowitz, Michal; Shohami, Esther

doi:10.1038/jcbfm.2012.193

Cited by 52 publications

(56 citation statements)

References 43 publications

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“…Both NGF and BDNF are strongly linked to neuroprotection and neuroregeneration (for a review see [63]), partly via the induction of Akt and ERK1/2 signaling [60,63,64]. Furthermore, both NGF and BDNF were shown to promote the elevation of Akt-mediated hypoxia inducible factor 1α [65,66], which was recently described as an indispensable factor for the spontaneous recovery after TBI in our model [67].…”

Section: Cgp42112a Induces Improved Motor Recovery and Cognitive Funcmentioning

confidence: 70%

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

et al. 2014

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Angiotensin II receptor type 2 (AT 2 ) agonists have been shown to limit brain ischemic insult and to improve its outcome. The activation of AT 2 was also linked to induced neuronal proliferation and differentiation in vitro. In this study, we examined the therapeutic potential of AT 2 activation following traumatic brain injury (TBI) in mice, a brain pathology that displays ischemia-like secondary damages. The AT 2 agonist CGP42112A was continuously infused immediately after closed head injury (CHI) for 3 days. We have followed the functional recovery of the injured mice for 35 days post-CHI, and evaluated cognitive function, lesion volume, molecular signaling, and neurogenesis at different time points after the impact. We found dose-dependent improvement in functional recovery and cognitive performance after CGP42112A treatment that was accompanied by reduced lesion volume and induced neurogenesis in the neurogenic niches of the brain and also in the injury region. At the cellular/molecular level, CGP42112A induced early activation of neuroprotective kinases protein kinase B (Akt) and extracellular-regulated kinases ½ (ERK½), and the neurotrophins nerve growth factor and brain-derived neurotrophic factor; all were blocked by treatment with the AT 2 antagonist PD123319. Our results suggest that AT 2 activation after TBI promotes neuroprotection and neurogenesis, and may be a novel approach for the development of new drugs to treat victims of TBI.

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Section: Cgp42112a Induces Improved Motor Recovery and Cognitive Funcmentioning

confidence: 70%

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

et al. 2014

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“…21 Levels of HIF-1a were B50% higher in sham HA mice compared with sham NT mice. Six hours after TBI, HA mice still had higher levels (Po0.05), which showed a decline for up to 72 hours.…”

Section: Pd123319 Abolishes Heat Acclimation-mediated Reduction In Lementioning

confidence: 91%

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

Umschweif

Shabashov²,

Alexandrovich³

et al. 2014

J Cereb Blood Flow Metab

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Long-term exposure of mice to mild heat (341C±11C) 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 (AT 2 ) expression and hypothalamic neurogenesis. Accumulating data suggest that activation of the brain AT 2 receptor confers protection against several types of brain pathologies, including ischemia, a hallmark of the secondary injury occurring following TBI. As AT 2 activates the same pro-survival pathways involved in HA-mediated neuroprotection (e.g., Akt phosphorylation, hypoxia-inducible factor 1a (HIF-1a), and brain-derived neurotrophic factor (BDNF)), we examined the role of AT 2 in HA-mediated neuroprotection after TBI. Using an AT 2 -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 AT 2 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-1a pathways are upregulated by HA and inhibited on PD123319 administration, suggesting that these pathways play a role in AT 2 signaling in HA mice. In conclusion, AT 2 is involved in HA-mediated neuroprotection, and AT 2 activation may be protective and should be considered a novel drug target in the treatment of TBI patients.

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“…Since then the list of "acclimation-associated" activated target genes has grown and includes mitochondrial enzymes involved in glycolysis, the electron transport chain [e.g., PDK1 (pyruvate dehydrogenase kinase) and COX (cytochrome oxidase, respectively (84)] suggesting mitochondrial adaptation. EpoR (erythropoietin receptors), VEGF (vascular endothelial growth factor) the water channel Aquaporine 4 (132,205,232), and the small heat shock protein hemoxygenase (132) have also been identified as targets of acclimation. Orchestrated interactions among the metabotrophic genes (e.g., anaerobic vs. aerobic and enhanced capillarization) are likely to improve the efficiency of the acclimated phenotype.…”

Section: Hypoxia Inducible Factor-is It Essential?mentioning

confidence: 99%

Heat Acclimation, Epigenetics, and Cytoprotection Memory

Horowitz

2014

Comprehensive Physiology

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Heat acclimation is a within-life phenotypic adaptation to heat. Plasticity of the thermoregulatory system is crucial for the induction of heat acclimation. In the last two decades, it has become clear that heat causes adaptive shifts in gene expression which adjust the protein balance. These changes are part of the evolvement of the acclimated phenotype. The molecular-cellular aspects of some acclimatory mechanisms that have only been explained by physiological-effectorial mechanisms have been discovered. This review attempts to bridge the gap between the classic physiological heat acclimation profile and the molecular/cellular mechanisms underlying the evolvement of the acclimated phenotype. Heat acclimation leads to leftward and rightward shifts in temperature thresholds of heat dissipation organs and thermal injury, respectively, thereby expanding the acclimated dynamic thermoregulatory range. Interactions between ambient temperature and afferent drives from effector organs to the hypothalamic thermoregulatory center with modifications in warm/cold sensitive neuron ratio and excitability contribute to the threshold changes. The altered threshold for thermal injury is associated with progressive enhancement of inducible cytoprotective networks, including HSP70, HSF1, and HIF-1ɑ. These molecules are also important in acclimatory kinetics. Aspects of cross-adaption, cross-tolerance and interference with heat acclimation are explained using molecular-cellular physiological interactions, with the heart, skeletal muscles, and water secretory glands as models. Lastly, the roles of epigenetic mechanisms in transcriptional regulation during induction of the acclimated phenotype, its decay, and reinduction are discussed. Posttranslational histone modifications in the promoters of hsp70 and hsp90 form part of our prototype model of heat-acclimation-mediated cytoprotective memory.

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

Cited by 52 publications

References 43 publications

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

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

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

Heat Acclimation, Epigenetics, and Cytoprotection Memory

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