The LPA-CDK5-Tau Pathway Mediates Neuronal Injury in an In Vitro Model of Ischemia-Reperfusion Insult

Abstract Lysophosphatidic acid (LPA) is a common glycerol phospholipid and an important extracellular signaling molecule. LPA binds to its receptors and mediates a variety of biological effects, including the pathophysiological process underlying ischemic brain damage and traumatic brain injury. However, the molecular mechanisms mediating the pathological role of LPA are not clear. Here, we found that LPA activates cyclin-dependent kinase 5 (CDK5). CDK5 phosphorylates tau, which leads to neuronal cell death. Inhibition of LPA production or blocking its receptors reduced the abnormal activation of CDK5 and phosphorylation of tau, thus reversing the death of neurons. Our data indicate that the LPA-CDK5-Tau pathway plays an important role in the pathophysiological process after ischemic stroke. Inhibiting the LPA pathway may be a potential therapeutic target for treating ischemic brain injury.

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Crocetin Mitigates Irradiation Injury in an In Vitro Model of the Pubertal Testis: Focus on Biological Effects and Molecular Mechanisms

Molecules ◽

10.3390/molecules26061676 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1676

Author(s):

Giulia Rossi ◽

Martina Placidi ◽

Chiara Castellini ◽

Francesco Rea ◽

Settimio D'Andrea ◽

...

Keyword(s):

In Vitro Model ◽

Molecular Mechanisms ◽

Biological Effects ◽

Cellular Damage ◽

X Rays ◽

Adolescent Cancer ◽

Radiation Induced ◽

Vitro Model ◽

Underlying Mechanisms

Infertility is a potential side effect of radiotherapy and significantly affects the quality of life for adolescent cancer survivors. Very few studies have addressed in pubertal models the mechanistic events that could be targeted to provide protection from gonadotoxicity and data on potential radioprotective treatments in this peculiar period of life are elusive. In this study, we utilized an in vitro model of the mouse pubertal testis to investigate the efficacy of crocetin to counteract ionizing radiation (IR)-induced injury and potential underlying mechanisms. Present experiments provide evidence that exposure of testis fragments from pubertal mice to 2 Gy X-rays induced extensive structural and cellular damage associated with overexpression of PARP1, PCNA, SOD2 and HuR and decreased levels of SIRT1 and catalase. A twenty-four hr exposure to 50 μM crocetin pre- and post-IR significantly reduced testis injury and modulated the response to DNA damage and oxidative stress. Nevertheless, crocetin treatment did not counteract the radiation-induced changes in the expression of SIRT1, p62 and LC3II. These results increase the knowledge of mechanisms underlying radiation damage in pubertal testis and establish the use of crocetin as a fertoprotective agent against IR deleterious effects in pubertal period.

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p53-mediated neuronal cell death in ischemic brain injury

Neuroscience Bulletin ◽

10.1007/s12264-010-1111-0 ◽

2010 ◽

Vol 26 (3) ◽

pp. 232-240 ◽

Cited By ~ 54

Author(s):

Li-Zhi Hong ◽

Xiao-Yuan Zhao ◽

Hui-Ling Zhang

Keyword(s):

Cell Death ◽

Brain Injury ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ischemic Brain Injury ◽

Ischemic Brain

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Oxidative stress and endoplasmic reticulum (ER) stress in the development of neonatal hypoxic–ischaemic brain injury

Biochemical Society Transactions ◽

10.1042/bst20170017 ◽

2017 ◽

Vol 45 (5) ◽

pp. 1067-1076 ◽

Cited By ~ 30

Author(s):

Claire Thornton ◽

Ana A. Baburamani ◽

Anton Kichev ◽

Henrik Hagberg

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Brain Injury ◽

Molecular Mechanisms ◽

Treatment Options ◽

Neuronal Cell Death ◽

Birth Asphyxia ◽

Neuronal Cell ◽

Term Neonates ◽

Ischaemic Brain

Birth asphyxia in term neonates affects 1–2/1000 live births and results in the development of hypoxic–ischaemic encephalopathy with devastating life-long consequences. The majority of neuronal cell death occurs with a delay, providing the potential of a treatment window within which to act. Currently, treatment options are limited to therapeutic hypothermia which is not universally successful. To identify new interventions, we need to understand the molecular mechanisms underlying the injury. Here, we provide an overview of the contribution of both oxidative stress and endoplasmic reticulum stress in the development of neonatal brain injury and identify current preclinical therapeutic strategies.

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Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury

Nature Communications ◽

10.1038/s41467-021-24469-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Zhongyuan Bao ◽

Yinlong Liu ◽

Binglin Chen ◽

Zong Miao ◽

Yiming Tu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Lipid Peroxidation ◽

Cell Death ◽

Brain Injury ◽

Neuronal Degeneration ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Prokineticin 2

AbstractProkineticin-2 (Prok2) is an important secreted protein likely involved in the pathogenesis of several acute and chronic neurological diseases through currently unidentified regulatory mechanisms. The initial mechanical injury of neurons by traumatic brain injury triggers multiple secondary responses including various cell death programs. One of these is ferroptosis, which is associated with dysregulation of iron and thiols and culminates in fatal lipid peroxidation. Here, we explore the regulatory role of Prok2 in neuronal ferroptosis in vitro and in vivo. We show that Prok2 prevents neuronal cell death by suppressing the biosynthesis of lipid peroxidation substrates, arachidonic acid-phospholipids, via accelerated F-box only protein 10 (Fbxo10)-driven ubiquitination, degradation of long-chain-fatty-acid-CoA ligase 4 (Acsl4), and inhibition of lipid peroxidation. Mice injected with adeno-associated virus-Prok2 before controlled cortical impact injury show reduced neuronal degeneration and improved motor and cognitive functions, which could be inhibited by Fbxo10 knockdown. Our study shows that Prok2 mediates neuronal cell deaths in traumatic brain injury via ferroptosis.

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Xenon Neurotoxicity in Rat Hippocampal Slice Cultures Is Similar to Isoflurane and Sevoflurane

Anesthesiology ◽

10.1097/aln.0b013e31829417f0 ◽

2013 ◽

Vol 119 (2) ◽

pp. 335-344 ◽

Cited By ~ 31

Author(s):

Heather Brosnan ◽

Philip E. Bickler

Keyword(s):

Cell Death ◽

Hippocampal Neurons ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Neuron Death ◽

Neuroprotective Effects ◽

Low Concentrations ◽

Vitro Model ◽

Developing Neurons

Abstract Background: Anesthetic neurotoxicity in the developing brain of rodents and primates has raised concern. Xenon may be a nonneurotoxic alternative to halogenated anesthetics, but its toxicity has only been studied at low concentrations, where neuroprotective effects predominate in animal models. An equipotent comparison of xenon and halogenated anesthetics with respect to neurotoxicity in developing neurons has not been made. Methods: Organotypic hippocampal cultures from 7-day-old rats were exposed to 0.75, 1, and 2 minimum alveolar concentrations (MAC) partial pressures (60% xenon at 1.2, 2.67, and 3.67 atm; isoflurane at 1.4, 1.9, and 3.8%; and sevoflurane at 3.4 and 6.8%) for 6 h, at atmospheric pressure or in a pressure chamber. Cell death was assessed 24 h later with fluorojade and fluorescent dye exclusion techniques. Results: Xenon caused death of hippocampal neurons in CA1, CA3, and dentate regions after 1 and 2 MAC exposures, but not at 0.75 MAC. At 1 MAC, xenon increased cell death 40% above baseline (P < 0.01; ANOVA with Dunnett test). Both isoflurane and sevoflurane increased neuron death at 1 but not 2 MAC. At 1 MAC, the increase in cell death compared with controls was 63% with isoflurane and 90% with sevoflurane (both P < 0.001). Pretreatment of cultures with isoflurane (0.75 MAC) reduced neuron death after 1 MAC xenon, isoflurane, and sevoflurane. Conclusion: Xenon causes neuronal cell death in an in vitro model of the developing rodent brain at 1 MAC, as does isoflurane and sevoflurane at similarly potent concentrations. Preconditioning with a subtoxic dose of isoflurane eliminates this toxicity.

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MLN4924 Exerts a Neuroprotective Effect against Oxidative Stress via Sirt1 in Spinal Cord Ischemia-Reperfusion Injury

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/7283639 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 4

Author(s):

Sifei Yu ◽

Lei Xie ◽

Zhuochao Liu ◽

Changwei Li ◽

Yu Liang

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Ischemia Reperfusion Injury ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Spinal Cord Ischemia ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Sirtuin 1

Oxidative stress is a leading contributor to spinal cord ischemia-reperfusion (SCIR) injury. Recently, MLN4924, a potent and selective inhibitor of the NEDD8-activating enzyme, was shown to exert a neuroprotective effect against oxidative stress in vitro. However, it is unknown whether MLN4924 plays a protective role against SCIR injury. In the present study, we found that MLN4924 treatment significantly attenuated oxidative stress and neuronal cell death induced by H2O2 in SH-SY-5Y neural cells and during rat SCIR injury. Furthermore, MLN4924 administration restored neurological and motor functions in rats with SCIR injury. Mechanistically, we found that MLN4924 protects against H2O2- and SCIR injury-induced neurodegeneration by regulating sirtuin 1 (Sirt1) expression. Collectively, these findings demonstrate the neuroprotective role of MLN4924 against oxidative stress in SCIR injury via Sirt1.

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Comparing effects of CDK inhibition and E2F1/2 ablation on neuronal cell death pathways in vitro and after traumatic brain injury

Cell Death and Disease ◽

10.1038/s41419-018-1156-y ◽

2018 ◽

Vol 9 (11) ◽

Cited By ~ 7

Author(s):

Taryn G. Aubrecht ◽

Alan I. Faden ◽

Boris Sabirzhanov ◽

Ethan P. Glaser ◽

Brian A. Roelofs ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Brain Injury ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Cell Death Pathways

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Familiar amyotrophic lateral sclerosis (FALS)-linked SOD1 mutation accelerates neuronal cell death by activating cleavage of caspase-4 under ER stress in an in vitro model of FALS

Neurochemistry International ◽

10.1016/j.neuint.2010.08.023 ◽

2010 ◽

Vol 57 (7) ◽

pp. 838-843 ◽

Cited By ~ 2

Author(s):

Yoshihisa Koyama ◽

Toru Hiratsuka ◽

Shinsuke Matsuzaki ◽

Satoru Yamagishi ◽

Shinsuke Kato ◽

...

Keyword(s):

Cell Death ◽

Amyotrophic Lateral Sclerosis ◽

Er Stress ◽

In Vitro Model ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Sod1 Mutation ◽

Vitro Model ◽

Lateral Sclerosis

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RIPK1 or RIPK3 deletion prevents progressive neuronal cell death and improves memory function after traumatic brain injury

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01236-0 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Antonia Clarissa Wehn ◽

Igor Khalin ◽

Marco Duering ◽

Farida Hellal ◽

Carsten Culmsee ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Brain Injury ◽

Brain Damage ◽

Molecular Mechanisms ◽

Memory Function ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Interacting Protein ◽

Deficient Mice

AbstractTraumatic brain injury (TBI) causes acute and subacute tissue damage, but is also associated with chronic inflammation and progressive loss of brain tissue months and years after the initial event. The trigger and the subsequent molecular mechanisms causing chronic brain injury after TBI are not well understood. The aim of the current study was therefore to investigate the hypothesis that necroptosis, a form a programmed cell death mediated by the interaction of Receptor Interacting Protein Kinases (RIPK) 1 and 3, is involved in this process. Neuron-specific RIPK1- or RIPK3-deficient mice and their wild-type littermates were subjected to experimental TBI by controlled cortical impact. Posttraumatic brain damage and functional outcome were assessed longitudinally by repetitive magnetic resonance imaging (MRI) and behavioral tests (beam walk, Barnes maze, and tail suspension), respectively, for up to three months after injury. Thereafter, brains were investigated by immunohistochemistry for the necroptotic marker phosphorylated mixed lineage kinase like protein(pMLKL) and activation of astrocytes and microglia. WT mice showed progressive chronic brain damage in cortex and hippocampus and increased levels of pMLKL after TBI. Chronic brain damage occurred almost exclusively in areas with iron deposits and was significantly reduced in RIPK1- or RIPK3-deficient mice by up to 80%. Neuroprotection was accompanied by a reduction of astrocyte and microglia activation and improved memory function. The data of the current study suggest that progressive chronic brain damage and cognitive decline after TBI depend on the expression of RIPK1/3 in neurons. Hence, inhibition of necroptosis signaling may represent a novel therapeutic target for the prevention of chronic post-traumatic brain damage.

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