Autophagy in Traumatic Brain Injury: A New Target for Therapeutic Intervention

Zhang, Li; Wang, Handong

doi:10.3389/fnmol.2018.00190

Cited by 61 publications

(51 citation statements)

References 163 publications

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“…For detailed reviews on the priming and activation of the NLRP3 inflammasome, the reader is referred to articles by Swanson et al [31], Patel et al [49], and Herman et al [51]. Importantly, the aforementioned priming and activating stimuli have been implicated in the aftermath of TBI (see [52][53][54] reviews), and as such, may play a key role in generating a significant neuroinflammatory response (see Fig. 2).…”

Section: The Nlrp3 Inflammasomementioning

confidence: 99%

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

O’Brien

Pham

Symons

et al. 2020

J Neuroinflammation

141

108

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There is a great clinical need to identify the underlying mechanisms, as well as related biomarkers, and treatment targets, for traumatic brain injury (TBI). Neuroinflammation is a central pathophysiological feature of TBI. NLRP3 inflammasome activity is a necessary component of the innate immune response to tissue damage, and dysregulated inflammasome activity has been implicated in a number of neurological conditions. This paper introduces the NLRP3 inflammasome and its implication in the pathogenesis of neuroinflammatory-related conditions, with a particular focus on TBI. Although its role in TBI has only recently been identified, findings suggest that priming and activation of the NLRP3 inflammasome are upregulated following TBI. Moreover, recent studies utilizing specific NLRP3 inhibitors have provided further evidence that this inflammasome is a major driver of neuroinflammation and neurobehavioral disturbances following TBI. In addition, there is emerging evidence that circulating inflammasome-associated proteins may have utility as diagnostic biomarkers of neuroinflammatory conditions, including TBI. Finally, novel and promising areas of research will be highlighted, including the potential involvement of the NLRP3 inflammasome in mild TBI, how factors such as biological sex may affect NLRP3 activity in TBI, and the use of emerging biomarker platforms. Taken together, this review highlights the exciting potential of the NLRP3 inflammasome as a target for treatments and biomarkers that may ultimately be used to improve TBI management.

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Section: The Nlrp3 Inflammasomementioning

confidence: 99%

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

O’Brien

Pham

Symons

et al. 2020

J Neuroinflammation

141

108

View full text Add to dashboard Cite

show abstract

“…Three general methods to detect autophagic flux are Microtubule-associated protein 1A/1B-light chain 3 (LC3) turnover, protein p62 degradation, and tandem fluorescent tagged LC3 (tfLC3) assay [65]. Autophagy has a dual role in TBI, depending on its flux [66]. In mild cases, autophagy flux is increased, which is expected to be beneficial for cell survival.…”

Section: Post-tbi Cell Death Mechanismsmentioning

confidence: 99%

“…In mild cases, autophagy flux is increased, which is expected to be beneficial for cell survival. Conversely, flux is decreased in moderate to severe cases, which leads to neuronal death and aggravated pathological phenotypes [66]. Increased LC3-II and autophagosomes are observed in the experimental weight drop injury model of TBI [67], and caloric restriction after mild TBI results in increased Beclin 1, LC3, and mTOR [68].…”

Section: Post-tbi Cell Death Mechanismsmentioning

confidence: 99%

Traumatic Brain Injury and Blood–Brain Barrier (BBB): Underlying Pathophysiological Mechanisms and the Influence of Cigarette Smoking as a Premorbid Condition

Sivandzade

Alqahtani

Cucullo

2020

IJMS

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Traumatic brain injury (TBI) is among the most pressing global health issues and prevalent causes of cerebrovascular and neurological disorders all over the world. In addition to the brain injury, TBI may also alter the systemic immune response. Thus, TBI patients become vulnerable to infections, have worse neurological outcomes, and exhibit a higher rate of mortality and morbidity. It is well established that brain injury leads to impairments of the blood–brain barrier (BBB) integrity and function, contributing to the loss of neural tissue and affecting the response to neuroprotective drugs. Thus, stabilization/protection of the BBB after TBI could be a promising strategy to limit neuronal inflammation, secondary brain damage, and acute neurodegeneration. Herein, we present a review highlighting the significant post-traumatic effects of TBI on the cerebrovascular system. These include the loss of BBB integrity and selective permeability, impact on BBB transport mechanisms, post-traumatic cerebral edema formation, and significant pathophysiological factors that may further exacerbate post-traumatic BBB dysfunctions. Furthermore, we discuss the post-traumatic impacts of chronic smoking, which has been recently shown to act as a premorbid condition that impairs post-TBI recovery. Indeed, understanding the underlying molecular mechanisms associated with TBI damage is essential to better understand the pathogenesis and progression of post-traumatic secondary brain injury and the development of targeted treatments to improve outcomes and speed up the recovery process. Therapies aimed at restoring/protecting the BBB may reduce the post-traumatic burden of TBI by minimizing the impairment of brain homeostasis and help to restore an optimal microenvironment to support neuronal repair.

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“…TBI elicited further activation of autophagy in the brain of ASM KO mice that is consistent with ASM/sphingosine acting as an inhibitor of autophagy (63). Although the accurate role of autophagy in TBI remains to be established, many studies show that autophagy participates in the secondary mechanisms of brain injury after TBI and that activation of autophagy could provide neuroprotection and ameliorate brain impairments (59).…”

Section: Discussionmentioning

confidence: 62%

“…To curb the accumulation of damaged mitochondria, cells could trigger an elimination of dysfunctional mitochondria by stimulating autophagy and/or mitophagy, an autophagy process facilitated by activation of the PINK-1/Parkin pathway (58). Autophagy, a self-catabolic process by which cells recycle their proteins and organelles in response to stress or injury, has been demonstrated in human injured brain and animal models of TBI (59). Experimental evidence seems to support both a detrimental role of autophagy dysfunction promoting cell death and a protective role for autophagy activators in TBI.…”

Section: Elevated Autophagy In the Asm-deficient Brain Is Augmented Amentioning

confidence: 99%

Acid sphingomyelinase deficiency protects mitochondria and improves function recovery after brain injury

Novgorodov

Voltin

Wang

et al. 2019

Journal of Lipid Research

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Traumatic brain injury (TBI) is one of the leading causes of disability worldwide and a prominent risk factor for neurodegenerative diseases. The expansion of nervous tissue damage after the initial trauma involves a multifactorial cascade of events including excitotoxicity, oxidative stress, inflammation and deregulation of sphingolipid metabolism that further mitochondrial dysfunction and secondary brain damage. Our studies establish a fundamental role of acid sphingomyelinase (ASM) in the multi‐faceted mechanisms governing secondary brain injury after TBI. The data indicate that TBI‐triggered activation of ASM and upregulation of mitochondrial sphingosine resulted in mitochondrial respiratory chain malfunction leading to an enhanced assembly and activity of the NLRP3 inflammasome, a pivotal factor promoting the neuroinflammatory response to brain injury. The results of our studies provide further support for the emerging role of ASM in repressing the cell maintenance and quality control mechanism, autophagy, which is essential for the neural cell survival after the injury. Thus, knocking down ASM rescued mitochondrial defect, augmented the autophagic flux, downregulated the neuroinflammation and improved the brain function recovery after TBI. Importantly, ASM is involved in the initial stages of progression of astrogliosis, a brain defense mechanism wherein activated astrocytes minimize spread of the neuroinflammation and further tissue repair and regeneration in response to TBI. Our novel findings reveal that ASM, a critical player promoting secondary brain injury and neuroinflammation is uniquely positioned to be a promising target for the development of effective pharmacological treatment of patients with TBI. Support or Funding Information Supported by NIH grant R01NS083544 (TIG) and VA Merit Award I01BX002991 (TIG). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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Autophagy in Traumatic Brain Injury: A New Target for Therapeutic Intervention

Cited by 61 publications

References 163 publications

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

Traumatic Brain Injury and Blood–Brain Barrier (BBB): Underlying Pathophysiological Mechanisms and the Influence of Cigarette Smoking as a Premorbid Condition

Acid sphingomyelinase deficiency protects mitochondria and improves function recovery after brain injury

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