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 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 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 Proneurotrophins Induce Apoptotic Neuronal Death After Controlled Cortical Impact Injury in Adult Mice

ASN NEURO ◽  
2020 ◽  
Vol 12 ◽  
pp. 175909142093086
Author(s):  
Laura E. Montroull ◽  
Deborah E. Rothbard ◽  
Hur D. Kanal ◽  
Veera D’Mello ◽  
Vincent Dodson ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Neuronal Death ◽  
Apoptotic Cell ◽  
Neuronal Cell ◽  
Adult Brain ◽  
Neurotrophin Receptor ◽  
Cortical Impact ◽  
Impact Injury

The p75 neurotrophin receptor (p75NTR) can regulate multiple cellular functions including proliferation, survival, and apoptotic cell death. The p75NTR is widely expressed in the developing brain and is downregulated as the nervous system matures, with only a few neuronal subpopulations retaining expression into adulthood. However, p75NTR expression is induced following damage to the adult brain, including after traumatic brain injury, which is a leading cause of mortality and disability worldwide. A major consequence of traumatic brain injury is the progressive neuronal loss that continues secondary to the initial trauma, which ultimately contributes to cognitive decline. Understanding mechanisms governing this progressive neuronal death is key to developing targeted therapeutic strategies to provide neuroprotection and salvage cognitive function. In this study, we demonstrate that a cortical impact injury to the sensorimotor cortex elicits p75NTR expression in apoptotic neurons in the injury penumbra, confirming previous studies. To establish whether preventing p75NTR induction or blocking the ligands would reduce the extent of secondary neuronal cell death, we used a noninvasive intranasal strategy to deliver either siRNA to block the induction of p75NTR, or function-blocking antibodies to the ligands pro-nerve growth factor and pro-brain-derived neurotrophic factor. We demonstrate that either preventing the induction of p75NTR or blocking the proneurotrophin ligands provides neuroprotection and preserves sensorimotor function.

Identification of apoptotic genes mediating TGF-β/Smad3-induced cell death in intestinal epithelial cells using a genomic approach

2007 ◽  
Vol 292 (1) ◽  
pp. G28-G38 ◽  
Author(s):  
Yanna Cao ◽  
Lu Chen ◽  
Weili Zhang ◽  
Yan Liu ◽  
Harry T. Papaconstantinou ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Intestinal Epithelial ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
Genomic Approach ◽  
Apoptotic Genes ◽  
Induced Apoptosis

Transforming growth factor (TGF)-β-dependent apoptosis is important in the elimination of damaged or abnormal cells from normal tissues in vivo. Previously, we have shown that TGF-β inhibits the growth of rat intestinal epithelial (RIE)-1 cells. However, RIE-1 cells are relatively resistant to TGF-β-induced apoptosis due to a low endogenous Smad3-to-Akt ratio. Overexpression of Smad3 sensitizes RIE-1 cells (RIE-1/Smad3) to TGF-β-induced apoptosis by altering the Smad3-to-Akt ratio in favor of apoptosis. In this study, we utilized a genomic approach to identify potential downstream target genes that are regulated by TGF-β/Smad3. Total RNA samples were analyzed using Affymetrix oligonucleotide microarrays. We found that TGF-β regulated 518 probe sets corresponding to its target genes. Interestingly, among the known apoptotic genes included in the microarray analyses, only caspase-3 was induced, which was confirmed by real-time RT-PCR. Furthermore, TGF-β activated caspase-3 through protein cleavage. Upstream of caspase-3, TGF-β induced mitochondrial depolarization, cytochrome c release, and cleavage of caspase-9, which suggests that the intrinsic apoptotic pathway mediates TGF-β-induced apoptosis in RIE-1/Smad3 cells.

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.

scholarly journals Treatment of traumatic brain injury with thymosin β4 in rats

2011 ◽  
Vol 114 (1) ◽  
pp. 102-115 ◽  
Author(s):  
Ye Xiong ◽  
Asim Mahmood ◽  
Yuling Meng ◽  
Yanlu Zhang ◽  
Zheng Gang Zhang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Sham Group ◽  
Therapeutic Potential ◽  
Cell Loss ◽  
Saline Group ◽  
Lesion Volume ◽  
Male Wistar Rats ◽  
Left Parietal Cortex ◽  
First Time

Object This study was designed to investigate the efficacy of delayed thymosin β4 (Tβ4) treatment of traumatic brain injury (TBI) in rats. Methods Young adult male Wistar rats were divided into the following groups: 1) sham group (6 rats); 2) TBI + saline group (9 rats); 3) and TBI + Tβ4 group (10 rats). Traumatic brain injury was induced by controlled cortical impact over the left parietal cortex. Thymosin β4 (6 mg/kg) or saline was administered intraperitoneally starting at Day 1 and then every 3 days for an additional 4 doses. Neurological function was assessed using a modified neurological severity score (mNSS), foot fault, and Morris water maze tests. Animals were killed 35 days after injury, and brain sections were stained for immunohistochemistry to assess angiogenesis, neurogenesis, and oligodendrogenesis after Tβ4 treatment. Results Compared with the saline treatment, delayed Tβ4 treatment did not affect lesion volume but significantly reduced hippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, increased oligodendrogenesis in the CA3 region, and significantly improved sensorimotor functional recovery and spatial learning. Conclusions These data for the first time demonstrate that delayed administration of Tβ4 significantly improves histological and functional outcomes in rats with TBI, indicating that Tβ4 has considerable therapeutic potential for patients with TBI.

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