Neuroprotective Agents Target Molecular Mechanisms of Programmed Cell Death After Traumatic Brain Injury

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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Increases in bcl-2 protein in cerebrospinal fluid and evidence for programmed cell death in infants and children after severe traumatic brain injury

The Journal of Pediatrics ◽

10.1067/mpd.2000.106903 ◽

2000 ◽

Vol 137 (2) ◽

pp. 197-204 ◽

Cited By ~ 64

Author(s):

Robert S.B. Clark ◽

Patrick M. Kochanek ◽

P.David Adelson ◽

Michael J. Bell ◽

Joseph A. Carcillo ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Cerebrospinal Fluid ◽

Brain Injury ◽

Programmed Cell Death ◽

Severe Traumatic Brain Injury ◽

Infants And Children ◽

In Infants And Children

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Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions

Biomedicines ◽

10.3390/biomedicines8100389 ◽

2020 ◽

Vol 8 (10) ◽

pp. 389

Author(s):

Abbas Jarrahi ◽

Molly Braun ◽

Meenakshi Ahluwalia ◽

Rohan V. Gupta ◽

Michael Wilson ◽

...

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Cell Death ◽

Brain Injury ◽

Molecular Mechanisms ◽

Mechanical Damage ◽

Therapeutic Interventions ◽

Secondary Injury ◽

Edema Formation ◽

Molecular Events

Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.

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Proteolytic Mechanisms of Cell Death Following Traumatic Brain Injury

10.21236/ada421034 ◽

2003 ◽

Author(s):

Ronald L. Hayes

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Brain Injury

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Progress in understanding the role of lncRNA in programmed cell death

Cell Death Discovery ◽

10.1038/s41420-021-00407-1 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Na Jiang ◽

Xiaoyu Zhang ◽

Xuejun Gu ◽

Xiaozhuang Li ◽

Lei Shang

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Molecular Mechanisms ◽

Membrane Receptors ◽

Gene Expressions ◽

Apoptosis Pathway ◽

Stem Cell Pluripotency ◽

Extrinsic Apoptosis ◽

Related Proteins ◽

Cycle Regulation

AbstractLong non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides but not translated into proteins. LncRNAs regulate gene expressions at multiple levels, such as chromatin, transcription, and post-transcription. Further, lncRNAs participate in various biological processes such as cell differentiation, cell cycle regulation, and maintenance of stem cell pluripotency. We have previously reported that lncRNAs are closely related to programmed cell death (PCD), which includes apoptosis, autophagy, necroptosis, and ferroptosis. Overexpression of lncRNA can suppress the extrinsic apoptosis pathway by downregulating of membrane receptors and protect tumor cells by inhibiting the expression of necroptosis-related proteins. Some lncRNAs can also act as competitive endogenous RNA to prevent oxidation, thereby inhibiting ferroptosis, while some are known to activate autophagy. The relationship between lncRNA and PCD has promising implications in clinical research, and reports have highlighted this relationship in various cancers such as non-small cell lung cancer and gastric cancer. This review systematically summarizes the advances in the understanding of the molecular mechanisms through which lncRNAs impact PCD.

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Novel Synthetic and Natural Therapies for Traumatic Brain Injury

Current Neuropharmacology ◽

10.2174/1570159x19666210225145957 ◽

2021 ◽

Vol 19 ◽

Author(s):

Denise Battaglini ◽

Dorota Siwicka-Gieroba ◽

Patricia RM Rocco ◽

Fernanda Ferreira Cruz ◽

Pedro Leme Silva ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Damage ◽

Molecular Mechanisms ◽

Antioxidant Properties ◽

Secondary Brain Injury ◽

Specific Recommendation ◽

Novel Therapies ◽

Secondary Brain Damage ◽

Late Treatment

: Traumatic brain injury (TBI) is a major cause of disability and death worldwide. The initial mechanical insult results in tissue and vascular disruption with hemorrhages and cellular necrosis that is followed by a dynamic secondary brain damage that presumably results in additional destruction of the brain. In order to minimize deleterious consequences of the secondary brain damage-such as inflammation, bleeding or reduced oxygen supply. The old concept of the -staircase approach- has been updated in recent years by most guidelines and should be followed as it is considered the only validated approach for the treatment of TBI. Besides, a variety of novel therapies have been proposed as neuroprotectants. The molecular mechanisms of each drug involved in inhibition of secondary brain injury can result as potential target for the early and late treatment of TBI. However, no specific recommendation is available on their use in clinical setting. The administration of both synthetic and natural compounds, which act on specific pathways involved in the destructive processes after TBI, even if usually employed for the treatment of other diseases, can show potential benefits. This review represents a massive effort towards current and novel therapies for TBI that have been investigated in both pre-clinical and clinical settings. This review aims to summarize the advancement in therapeutic strategies basing on specific and distinct -target of therapies-: brain edema, ICP control, neuronal activity and plasticity, anti-inflammatory and immunomodulatory effects, cerebral autoregulation, antioxidant properties, and future perspectives with the adoption of mesenchymal stromal cells.

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