The Role of Posttraumatic Hypothermia in Preventing Dendrite Degeneration and Spine Loss after Severe Traumatic Brain Injury

Wang, Chuanfang; Zhao, Chengcheng; Jiang, Gan; Gu, Xiao; Feng, Junfeng; Jiang, Jiyao

doi:10.1038/srep37063

Cited by 28 publications

(17 citation statements)

References 39 publications

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“…In this study, surgical preparation and moderate CCI TBI was performed as previously described with only slight modification . In brief, mice were anesthetized with sodium pentobarbital (70 mg/kg) and mounted in a stereotaxic frame (Stoelting, Varese, Italy).…”

Section: Methodsmentioning

confidence: 99%

“…In this study, surgical preparation and moderate CCI TBI was performed as previously described with only slight modification. 20,21 In brief, mice were anesthetized with sodium pentobarbital (70 mg/kg) and mounted in a stereotaxic frame (Stoelting, Varese, Italy). A sagittal incision was then made in the scalp and a circular craniotomy (4-mm diameter) was performed on the left side, midway between the bregma and the lambda with the medial edge 2 mm lateral to the midline.…”

Section: Model and Drug Administrationmentioning

confidence: 99%

“…The learning and memory functions of mice were evaluated 2 weeks after TBI with the Morris water maze, as previously described. 20,25 The maze was a round pool, which was 120 cm in diameter and 50 cm in depth. A white platform, 6 cm in diameter and 30 cm in height, lay in the southwest quadrant of the pool.…”

Section: Morris Water Mazementioning

confidence: 99%

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Inhibition of ferroptosis attenuates tissue damage and improves long‐term outcomes after traumatic brain injury in mice

et al. 2018

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Summary Aims Ferroptosis, a new form of iron‐dependent programmed cell death, has been shown to be involved in a range of diseases. However, the role of ferroptosis in traumatic brain injury (TBI) has yet to be elucidated. We aimed to investigate whether ferroptosis is induced after TBI and whether the inhibition of ferroptosis would protect against traumatic brain injury in a controlled cortical impact injury (CCI) mouse model. Methods After establishing the TBI model in mice, we determined the biochemical and morphological changes associated with ferroptosis, including iron accumulation with Perl's staining, neuronal cell death with Fluoro‐Jade B (FJB) staining, iron metabolism dysfunction with Western blotting, reactive oxygen species (ROS) accumulation with malondialdehyde (MDA) assays, and shrunken mitochondria with transmission electron microscopy. Furthermore, a specific inhibitor of ferroptosis, ferrostatin‐1(fer‐1), was administrated by cerebral ventricular injection after CCI. We used cresyl violet (CV) staining to assess lesion volume, along with the Morris water maze and beam walk test to evaluate long‐term outcomes. Results TBI was followed by iron accumulation, dysfunctional iron metabolism, the upregulation of ferroptosis‐related genes, reduced glutathione peroxidase (GPx) activity, and the accumulation of lipid‐reactive oxygen species (ROS). Three days (d) after TBI, transmission electron microscopy (TEM) confirmed that the mitochondria had shrunk a typical characteristic of ferroptosis. Importantly, the administration of Fer‐1 by cerebral ventricular injection significantly reduced iron deposition and neuronal degeneration while attenuating injury lesions and improving long‐term motor and cognitive function. Conclusion This study demonstrated an effective method with which to treat TBI by targeting ferroptosis.

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Section: Methodsmentioning

confidence: 99%

Section: Model and Drug Administrationmentioning

confidence: 99%

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Inhibition of ferroptosis attenuates tissue damage and improves long‐term outcomes after traumatic brain injury in mice

et al. 2018

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“…Behavioral testing. The Morris water maze (MWM) test was performed for TgSwDI mice to assess learning and memory performance at the end of the treatment using protocols similar to those described previously 61 . All mice underwent training 3 times a day for 4 consecutive days.…”

Section: Scientific Reports |mentioning

confidence: 99%

Amylin and pramlintide modulate γ-secretase level and APP processing in lipid rafts

Mousa

Abdallah

Hwang

et al. 2020

Sci Rep

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A major characteristic of Alzheimer's disease (AD) is the accumulation of misfolded amyloid-β (Aβ) peptide. Several studies linked AD with type 2 diabetes due to similarities between Aβ and human amylin. This study investigates the effect of amylin and pramlintide on Aβ pathogenesis and the predisposing molecular mechanism(s) behind the observed effects in TgSwDI mouse, a cerebral amyloid angiopathy (CAA) and AD model. Our findings showed that thirty days of intraperitoneal injection with amylin or pramlintide increased Aβ burden in mice brains. Mechanistic studies revealed both peptides altered the amyloidogenic pathway and increased Aβ production by modulating amyloid precursor protein (App) and γ-secretase levels in lipid rafts. in addition, both peptides increased levels of B4GALNT1 enzyme and GM1 ganglioside, and only pramlintide increased the level of GM2 ganglioside. Increased levels of GM1 and GM2 gangliosides play an important role in regulating amyloidogenic pathway proteins in lipid rafts. increased brain Aβ burden by amylin and pramlintide was associated with synaptic loss, apoptosis, and microglia activation. In conclusion, our findings showed amylin or pramlintide increase Aβ levels and related pathology in tgSwDi mice brains, and suggest that increased amylin levels or the therapeutic use of pramlintide could increase the risk of AD.Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by multiple dysregulated neurobiological networks and cellular functions, neuronal death, and memory loss 1 . The major hallmarks for AD include amyloid-β (Aβ) deposits and neurofibrillary tangles of hyper-phosphorylated tau protein 1,2 . Aβ is produced from the amyloid-β precursor protein (APP), which, after synthesis, traffics to the Golgi apparatus and eventually to plasma membrane 3 . The majority of plasma membrane bound APP is rapidly endocytosed 3 , while approximately 10% of the total APP is processed in the plasma membrane by α-secretase to release soluble APP-α (sAPP-α) 4 . Alternatively, APP can be processed by β-site APP cleaving enzyme 1 (BACE1) in plasma membrane, trans-Golgi, and early endosomes to produce soluble APP-β (sAPP-β) and β-C-terminal fragments (β-CTF), followed by subsequent proteolytic cleavage of β-CTF by γ-secretase to release Aβ 4 . Besides Aβ production, another contributing factor to Aβ accumulation in AD is the failure to clear Aβ from the brain 5 , and across the blood-brain barrier (BBB) 6 .The accumulation of Aβ due to decreased clearance or increased production leads to multiple dysregulated cellular functions including synaptic loss and neuroinflammation 7,8 . Aβ initiates synaptic loss by down-regulating synaptic markers in AD including the pre-synaptic marker SNAP-25 and synapsin I and post-synaptic marker PSD-95 9 . Moreover, the accumulation of Aβ in the brain parenchyma of AD patients is associated with strong inflammatory processes and glial cells activation 7 .Mounting evidence supports the localization of APP, BACE1 and each of the four core subu...

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“…The animal model of CCI injury and temperature manipulation were performed as previous described (Wang et al., ). Briefly, the mice were anesthetized with isoflurane and fixed in a stereotactic frame (Stoelting, Varese, Italy) prior to TBI.…”

Section: Methodsmentioning

confidence: 99%

Mild hypothermia reduces endoplasmic reticulum stress‐induced apoptosis and improves neuronal functions after severe traumatic brain injury

Wang

Zhao

et al. 2019

Brain and Behavior

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Background Mild hypothermia is wildly used in clinical treatment of traumatic brain injury (TBI). However, the effect of mild hypothermia on endoplasmic reticulum (ER) stress‐induced apoptosis after severe TBI is still unknown. Methods In the present study, we used BALB/c mice to investigate the efficacy of posttraumatic mild hypothermia in reducing ER stress. Severe TBI was induced by controlled cortical impact injury. Mild hypothermia treatment was performed immediately after surgery and maintained for 4 hr. The animals were euthanized at 1 and 7 days after severe TBI. The expression levels of ER stress marker proteins were evaluated using Western blot and immunofluorescence. Cell apoptosis rate was analyzed by TUNEL staining. Neuronal functions of the mice were assessed using rotarod test and Morris water maze. Results Our results revealed that mild hypothermia significantly attenuated ER stress marker proteins, including p‐eIF2α/eIF2α, ATF4, CHOP and IRE‐1α, and reduced apoptosis rate in the pericontusion region at 1 and 7 days after severe TBI. Interestingly, mild hypothermia also prevented the translocation of CHOP into nucleus. In addition, posttraumatic mild hypothermia significantly improved neuronal functions after severe TBI. Conclusions Our findings illustrated that mild hypothermia could reduce ER stress‐induced apoptosis and improve neuronal functions after severe traumatic brain injury.

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The Role of Posttraumatic Hypothermia in Preventing Dendrite Degeneration and Spine Loss after Severe Traumatic Brain Injury

Cited by 28 publications

References 39 publications

Inhibition of ferroptosis attenuates tissue damage and improves long‐term outcomes after traumatic brain injury in mice

Inhibition of ferroptosis attenuates tissue damage and improves long‐term outcomes after traumatic brain injury in mice

Amylin and pramlintide modulate γ-secretase level and APP processing in lipid rafts

Mild hypothermia reduces endoplasmic reticulum stress‐induced apoptosis and improves neuronal functions after severe traumatic brain injury

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