Autophagy Inhibitor 3-MA Weakens Neuroprotective Effects of Posttraumatic Brain Injury Moderate Hypothermia

Jin, Yichao; Jin, Lei; Lin, Yingying; Gao, Guoyi; Jiang, Jiyao

doi:10.1016/j.wneu.2015.10.055

Cited by 22 publications

(24 citation statements)

References 53 publications

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“…It is possible that the beneficial versus detrimental effects of mitophagy after TBI depend on timing after injury. 3-MA, an autophagy inhibitor, has been also tested as a response modifier after TBI (Luo et al, 2011) with conflicting results (Wang et al, 2012;Jin et al, 2016). However, the harmful effects of long-term autophagy and continued activation of LC3 cannot be completely excluded by our study focused on the early time points, from 1 to 24 h, after TBI (Kroemer and Levine, 2008;Liu and Levine, 2015).…”

Section: Discussionmentioning

confidence: 94%

Cardiolipin-Dependent Mitophagy Guides Outcome after Traumatic Brain Injury

Chao

Lin²,

Zuo

et al. 2019

J. Neurosci.

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Mitochondrial energy production is essential for normal brain function. Traumatic brain injury (TBI) increases brain energy demands, results in the activation of mitochondrial respiration, associated with enhanced generation of reactive oxygen species. This chain of events triggers neuronal apoptosis via oxidation of a mitochondria-specific phospholipid, cardiolipin (CL). One pathway through which cells can avoid apoptosis is via elimination of damaged mitochondria by mitophagy. Previously, we showed that externalization of CL to the mitochondrial surface acts as an elimination signal in cells. Whether CL-mediated mitophagy occurs in vivo or its significance in the disease processes are not known. In this study, we showed that TBI leads to increased mitophagy in the human brain, which was also detected using TBI models in male rats. Knockdown of CL synthase, responsible for de novo synthesis of CL, or phospholipid scramblase-3, responsible for CL translocation to the outer mitochondrial membrane, significantly decreased TBI-induced mitophagy. Inhibition of mitochondrial clearance by 3-methyladenine, mdivi-1, or phospholipid scramblase-3 knockdown after TBI led to a worse outcome, suggesting that mitophagy is beneficial. Together, our findings indicate that TBI-induced mitophagy is an endogenous neuroprotective process that is directed by CL, which marks damaged mitochondria for elimination, thereby limiting neuronal death and behavioral deficits.

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Section: Discussionmentioning

confidence: 94%

Cardiolipin-Dependent Mitophagy Guides Outcome after Traumatic Brain Injury

Chao

Lin²,

Zuo

et al. 2019

J. Neurosci.

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“…TTM was induced with a hypothermia therapy apparatus (HEMA, Shenzhen, China) by applying an ice blanket over the dorsum of prone rats until a body temperature of 32 ± 0.5°C was achieved. The temperature of 32°C for TTM was chosen according to previous studies in rats [23,24]. A similar degree of hypothermia is recommended by the American Association of Neurological Surgeons Guidelines for the management of severe TBI [25].…”

Section: Temperature Manipulationsmentioning

confidence: 99%

iTRAQ-Based Quantitative Proteomics Reveals the New Evidence Base for Traumatic Brain Injury Treated with Targeted Temperature Management

Cheng

et al. 2018

Neurotherapeutics

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This study aimed to investigate the effects of targeted temperature management (TTM) modulation on traumatic brain injury (TBI) and the involved mechanisms using quantitative proteomics technology. SH-SY5Y and HT-22 cells were subjected to moderate stretch injury using the cell injury controller (CIC), followed by incubation at TTM (mild hypothermia, 32°C), or normothermia (37°C). The real-time morphological changes, cell cycle phase distribution, death, and cell viability were evaluated. Moderate TBI was produced by the controlled cortical impactor (CCI), and the effects of TTM on the neurological damage, neurodegeneration, cerebrovascular histopathology, and behavioral outcome were determined in vivo. Results showed that TTM treatment prevented TBI-induced neuronal necrosis in the brain, achieved a substantial reduction in neuronal death both in vitro and in vivo, reduced cortical lesion volume and neuronal loss, attenuated cerebrovascular histopathological damage, brain edema, and improved behavioral outcome. Using an iTRAQ proteomics approach, proteins that were significantly associated with TTM in experimental TBI were identified. Importantly, changes in four candidate molecules (plasminogen [PLG], antithrombin III [AT III], fibrinogen gamma chain [FGG], transthyretin [TTR]) were verified using TBI rat brain tissues and TBI human cerebrospinal fluid (CSF) samples. This study is one of the first to investigate the neuroprotective effects of TTM on the proteome of human and experimental models of TBI, providing an overall landscape of the TBI brain proteome and a scientific foundation for further assessment of candidate molecules associated with TTM for the promotion of reparative strategies post-TBI.

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“…Furthermore, we demonstrated that post-TBI hypothermia could upregulate the autophagy pathway, modulate apoptosis, and reduce cell death in neurons and glial cells; a possible mechanism for this is the negative regulatory effect of autophagy on apoptosis [ 7 , 8 ]. We also found autophagy induction in microglia after TBI [ 9 ], but the regulatory effect of moderate hypothermia on microglial activation remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Moderate hypothermia inhibits microglial activation after traumatic brain injury by modulating autophagy/apoptosis and the MyD88-dependent TLR4 signaling pathway

Zhang

Dong

et al. 2018

J Neuroinflammation

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BackgroundComplex mechanisms participate in microglial activation after a traumatic brain injury (TBI). TBI can induce autophagy and apoptosis in neurons and glial cells, and moderate hypothermia plays a protective role in the acute phase of TBI. In the present study, we evaluated the effect of TBI and moderate hypothermia on microglial activation and investigated the possible roles of autophagy/apoptosis and toll-like receptor 4 (TLR4).MethodsThe TBI model was induced with a fluid percussion TBI device. Moderate hypothermia was achieved under general anesthesia by partial immersion in a water bath for 4 h. All rats were killed 24 h after the TBI.ResultsOur results showed downregulation of the microglial activation and autophagy, but upregulation of microglial apoptosis, upon post-TBI hypothermia treatment. The expression of TLR4 and downstream myeloid differentiation primary response 88 (MyD88) was attenuated. Moderate hypothermia reduced neural cell death post-TBI.ConclusionsModerate hypothermia can reduce the number of activated microglia by inhibiting autophagy and promoting apoptosis, probably through a negative modulation between autophagy and apoptosis. Moderate hypothermia may attenuate the pro-inflammatory function of microglia by inhibiting the MyD88-dependent TLR4 signaling pathway.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1315-1) contains supplementary material, which is available to authorized users.

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Autophagy Inhibitor 3-MA Weakens Neuroprotective Effects of Posttraumatic Brain Injury Moderate Hypothermia

Cited by 22 publications

References 53 publications

Cardiolipin-Dependent Mitophagy Guides Outcome after Traumatic Brain Injury

Cardiolipin-Dependent Mitophagy Guides Outcome after Traumatic Brain Injury

iTRAQ-Based Quantitative Proteomics Reveals the New Evidence Base for Traumatic Brain Injury Treated with Targeted Temperature Management

Moderate hypothermia inhibits microglial activation after traumatic brain injury by modulating autophagy/apoptosis and the MyD88-dependent TLR4 signaling pathway

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