Activation of Akt/GSK-3beta/beta-catenin signaling pathway is involved in survival of neurons after traumatic brain injury in rats

Zhao, Shichao; Fu, Jidi; Liu, Xiangrong; Wang, Tony; Zhang, Jialiang; Zhao, Yuanli

doi:10.1179/1743132812y.0000000025

Cited by 90 publications

(66 citation statements)

References 38 publications

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“…The altered Akt dynamics suggest that AT 2 activation induces early neuroprotection, which, in turn, may explain the reduced tissue damage and the delayed development of improved motor outcome. Akt is a widely studied mediator that has been shown to play a role in neuroprotection after TBI in our model, as well as in other TBI models [50][51][52]. Our findings are in accordance with previous in vitro studies that nominated Akt as a potential downstream target of AT 2 activation [19,29,53,54].…”

Section: Cgp42112a Induces Improved Motor Recovery and Cognitive Funcsupporting

confidence: 82%

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 Funcsupporting

confidence: 82%

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

et al. 2014

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“…Thus, we could speculate that the alteration of p-AKT/AKT induced by BDNF overexpression under the pathological circumstances was linked with the change of NeuN, 5-HT as well as GAP-43. These were supported from other literatures which indicated BDNF-AKT signal as crucial pathway in pulmonary injury, traumatic brain injury and cerebral ischemia [52][53][54][55][56][57].…”

Section: Bdnf Overexpression May Lead To Thermal Hyperalgesiasupporting

confidence: 85%

BDNF Overexpression Exhibited Bilateral Effect on Neural Behavior in SCT Mice Associated with AKT Signal Pathway

et al. 2016

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Spinal cord injury (SCI), a severe health problem in worldwide, was commonly associated with functional disability and reduced quality of life. As the expression of brain-derived neurotrophic factor (BDNF) was substantial event in injured spinal cord, we hypothesized whether BDNF-overexpression could be in favor of the recovery of both sensory function and hindlimb function after SCI. By using BDNF-overexpression transgene mice [CMV-BDNF 26 (CB26) mice] we assessed the role of BDNF on the recovery of neurological behavior in spinal cord transection (SCT) model. BMS score and tail-flick test was performed to evaluate locomotor function and sensory function, respectively. Immunohistochemistry was employed to detect the location and the expression of BDNF, NeuN, 5-HT, GAP-43, GFAP as well as CGRP, and the level of p-AKT and AKT were examined through western blot analysis. BDNF overexpressing resulted in significant locomotor functional recovery from 21 to 28 days after SCT, compared with wild type (WT)+SCT group. Meanwhile, the NeuN, 5-HT and GAP-43 positive cells were markedly increased in ventral horn in BDNF overexpression animals, compared with WT mice with SCT. Moreover, the crucial molecular signal, p-AKT/AKT has been largely up-regulated, which is consistent with the improvement of locomotor function. However, in this study, thermal hyperpathia encountered in sham (CB26) group and WT+SCT mice and further aggravated in CB26 mice after SCT. Also, following SCT, the significant augment of positive-GFAP astrocytes and CGRP fibers were found in WT+SCT mice, and further increase was seen in BDNF over-expression transgene mice. BDNF-overexpression may not only facilitate the recovery of locomotor function via AKT pathway, but also contributed simultaneously to thermal hyperalgesia after SCT.

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“…Disruption of the Wnt signaling pathway also inhibits neural crest development and stimulates neurodegeneration (reviewed in references 35, 59, and 60). Finally, canonical Wnt signaling via ␤-catenin activation inhibits apoptosis in several cell types (71)(72)(73), including neurons (74). Although ORF2 interferes with apoptosis (15,16), the cooperative effect of ORF2, S33Y, and MAML1 on survival of Neuro-2A cells following serum withdrawal was not expected.…”

Section: Discussionmentioning

confidence: 99%

β-Catenin, a Transcription Factor Activated by Canonical Wnt Signaling, Is Expressed in Sensory Neurons of Calves Latently Infected with Bovine Herpesvirus 1

Liu

Hancock

Workman

et al. 2016

J Virol

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Like many Alphaherpesvirinae subfamily members, bovine herpesvirus 1 (BoHV-1) expresses an abundant transcript in latently infected sensory neurons, the latency-related (LR)-RNA. LR-RNA encodes a protein (ORF2) that inhibits apoptosis, interacts with Notch family members, interferes with Notch-mediated transcription, and stimulates neurite formation in cells expressing Notch. An LR mutant virus containing stop codons at the amino terminus of ORF2 does not reactivate from latency or replicate efficiently in certain tissues, indicating that LR gene products are important. In this study, ␤-catenin, a transcription factor activated by the canonical Wnt signaling pathway, was frequently detected in ORF2-positive trigeminal ganglionic neurons of latently infected, but not mock-infected, calves. Conversely, the lytic cycle regulatory protein (BoHV-1 infected cell protein 0, or bICP0) was not frequently detected in ␤-catenin-positive neurons in latently infected calves. During dexamethasone-induced reactivation from latency, mRNA expression levels of two Wnt antagonists, Dickkopf-1 (DKK-1) and secreted Frizzled-related protein 2 (SFRP2), were induced in bovine trigeminal ganglia (TG), which correlated with reduced ␤-catenin protein expression in TG neurons 6 h after dexamethasone treatment. ORF2 and a coactivator of ␤-catenin, mastermind-like protein 1 (MAML1), stabilized ␤-catenin protein levels and stimulated ␤-catenin-dependent transcription in mouse neuroblastoma cells more effectively than MAML1 or ORF2 alone. Neuroblastoma cells expressing ORF2, MAML1, and ␤-catenin were highly resistant to cell death following serum withdrawal, whereas most cells transfected with only one of these genes died. The Wnt signaling pathway interferes with neurodegeneration but promotes neuronal differentiation, suggesting that stabilization of ␤-catenin expression by ORF2 promotes neuronal survival and differentiation. IMPORTANCEBovine herpesvirus 1 (BoHV-1) is an important pathogen of cattle, and like many Alphaherpesvirinae subfamily members establishes latency in sensory neurons. Lifelong latency and the ability to reactivate from latency are crucial for virus transmission. Maintaining the survival and normal functions of terminally differentiated neurons is also crucial for lifelong latency. Our studies revealed that BoHV-1 gene products expressed during latency stabilize expression of the transcription factor ␤-catenin and perhaps its cofactor, mastermind-like protein 1 (MAML1). In contrast to expression during latency, ␤-catenin expression in sensory neurons is not detectable following treatment of latently infected calves with the synthetic corticosteroid dexamethasone to initiate reactivation from latency. A viral protein (ORF2) expressed in a subset of latently infected neurons stabilized ␤-catenin and MAML1 in transfected cells. ORF2, ␤-catenin, and MAML1 also enhanced cell survival when growth factors were withdrawn, suggesting that these genes enhance survival of latently infected neurons. Bovine herpesvirus 1 (BoH...

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Activation of Akt/GSK-3beta/beta-catenin signaling pathway is involved in survival of neurons after traumatic brain injury in rats

Cited by 90 publications

References 38 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

BDNF Overexpression Exhibited Bilateral Effect on Neural Behavior in SCT Mice Associated with AKT Signal Pathway

β-Catenin, a Transcription Factor Activated by Canonical Wnt Signaling, Is Expressed in Sensory Neurons of Calves Latently Infected with Bovine Herpesvirus 1

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