Proneurotrophins Induce Apoptotic Neuronal Death After Controlled Cortical Impact Injury in Adult Mice

The p75 neurotrophin receptor (p75NTR) can regulate multiple cellular functions including proliferation, survival, and apoptotic cell death. The p75NTR is widely expressed in the developing brain and is downregulated as the nervous system matures, with only a few neuronal subpopulations retaining expression into adulthood. However, p75NTR expression is induced following damage to the adult brain, including after traumatic brain injury, which is a leading cause of mortality and disability worldwide. A major consequence of traumatic brain injury is the progressive neuronal loss that continues secondary to the initial trauma, which ultimately contributes to cognitive decline. Understanding mechanisms governing this progressive neuronal death is key to developing targeted therapeutic strategies to provide neuroprotection and salvage cognitive function. In this study, we demonstrate that a cortical impact injury to the sensorimotor cortex elicits p75NTR expression in apoptotic neurons in the injury penumbra, confirming previous studies. To establish whether preventing p75NTR induction or blocking the ligands would reduce the extent of secondary neuronal cell death, we used a noninvasive intranasal strategy to deliver either siRNA to block the induction of p75NTR, or function-blocking antibodies to the ligands pro-nerve growth factor and pro-brain-derived neurotrophic factor. We demonstrate that either preventing the induction of p75NTR or blocking the proneurotrophin ligands provides neuroprotection and preserves sensorimotor function.

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Expression of Fas and Fas Ligand After Experimental Traumatic Brain Injury in the Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200004000-00004 ◽

2000 ◽

Vol 20 (4) ◽

pp. 669-677 ◽

Cited By ~ 90

Author(s):

Ronny Beer ◽

Franz Gerhard ◽

Marion Schöpf ◽

Markus Reindl ◽

Bernhard Zelger ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Brain Injury ◽

Fas Ligand ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Fasl Expression ◽

Double Labeling ◽

Injury Site ◽

Impact Injury

Apoptotic cell death plays an important role in the cascade of neuronal degeneration after traumatic brain injury (TBI), but the underlying mechanisms are not fully understood. However, increasing evidence suggests that expression of Fas and its ligand (FasL) could play a major role in mediating apoptotic cell death in acute and chronic neurologic disorders. To further investigate the temporal pattern of Fas and FasL expression after experimental TBI in the rat, male Sprague Dawley rats were subjected to unilateral cortical impact injury. The animals were killed and examined for Fas and FasL protein expression and for immunohistologic analysis at intervals from 15 minutes to 14 days after injury. Increased Fas and FasL immunoreactivity was seen in the cortex ipsilateral to the injury site from 15 minutes to 72 hours after the trauma, respectively. Immunohistologic investigation demonstrated a differential pattern of Fas and FasL expression in the cortex, respectively: increased Fas immunoreactivity was seen in cortical astrocytes and neurons from 15 minutes to 72 hours after the injury. In contrast, increased expression of FasL was seen in cortical neurons, astrocytes, and microglia from 15 minutes to 72 hours after impact injury. Concurrent double-labeling examinations using terminal deoxynucleotidyl tranferase-mediated deoxyuridine-biotin nick end labeling identified Fas- and FasL-immunopostive cells with high frequency in the cortex ipsilateral to the injury site. In contrast, there was no evidence of Fas- and FasL-immunopositive cells in the hippocampus ipsilateral to the injury site up to 14 days after the trauma. Further, Fas and FasL immunoreactivity was absent in the contralateral cortex and hippocampus at all time points investigated. These results reveal induction of Fas and FasL expression in the cortex after TBI in the rat. Further, these data implicate an involvement of Fas and FasL in the pathophysiologic mechanism of apoptotic neurodegeneration after TBI. Last, these data suggest that strategies aimed to repress posttraumatic Fas- and FasL-induced apoptosis may open new perspectives for the treatment of TBI.

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Improvement of Cognitive Deficits and Decreased Cholinergic Neuronal Cell Loss and Apoptotic Cell Death Following Neurotrophin Infusion after Experimental Traumatic Brain Injury

Journal of Neuro-Ophthalmology ◽

10.1097/00041327-199712000-00027 ◽

1997 ◽

Vol 17 (4) ◽

pp. 283

Author(s):

G Sinson ◽

B R Perri ◽

J Q Trojanowski ◽

E S Flamm ◽

T K McIntosh

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Brain Injury ◽

Cognitive Deficits ◽

Apoptotic Cell ◽

Neuronal Cell ◽

Cell Loss ◽

Apoptotic Cell Death ◽

Neuronal Cell Loss ◽

Experimental Traumatic Brain Injury

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Effects of Transient Receptor Potential Cation 5 (TRPC5) Inhibitor, NU6027, on Hippocampal Neuronal Death after Traumatic Brain Injury

International Journal of Molecular Sciences ◽

10.3390/ijms21218256 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8256 ◽

Cited By ~ 1

Author(s):

Min Kyu Park ◽

Bo Young Choi ◽

A Ra Kho ◽

Song Hee Lee ◽

Dae Ki Hong ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Neuronal Death ◽

Transient Receptor Potential ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Treated Group ◽

Therapeutic Window ◽

Permanent Disability ◽

Fluoro Jade B

Traumatic brain injury (TBI) can cause physical, cognitive, social, and behavioral changes that can lead to permanent disability or death. After primary brain injury, translocated free zinc can accumulate in neurons and lead to secondary events such as oxidative stress, inflammation, edema, swelling, and cognitive impairment. Under pathological conditions, such as ischemia and TBI, excessive zinc release, and accumulation occurs in neurons. Based on previous research, it hypothesized that calcium as well as zinc would be influx into the TRPC5 channel. Therefore, we hypothesized that the suppression of TRPC5 would prevent neuronal cell death by reducing the influx of zinc and calcium. To test our hypothesis, we used a TBI animal model. After the TBI, we immediately injected NU6027 (1 mg/kg, intraperitoneal), TRPC5 inhibitor, and then sacrificed animals 24 h later. We conducted Fluoro-Jade B (FJB) staining to confirm the presence of degenerating neurons in the hippocampal cornus ammonis 3 (CA3). After the TBI, the degenerating neuronal cell count was decreased in the NU6027-treated group compared with the vehicle-treated group. Our findings suggest that the suppression of TRPC5 can open a new therapeutic window for a reduction of the neuronal death that may occur after TBI.

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miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

Molecular Brain ◽

10.1186/s13041-019-0501-0 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 9

Author(s):

Xiao Xiao ◽

Youjing Jiang ◽

Weibo Liang ◽

Yanyun Wang ◽

Shuqiang Cao ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Brain Injury ◽

Neuronal Death ◽

Sham Group ◽

Ferrous Ion ◽

Post Injury ◽

Regulated Cell Death ◽

Prostaglandin Endoperoxide Synthase ◽

Improved Learning

Abstract Ferroptosis, a newly discovered form of iron-dependent regulated cell death, has been implicated in traumatic brain injury (TBI). MiR-212-5p has previously been reported to be downregulated in extracellular vesicles following TBI. To investigate whether miR-212-5p is involved in the ferroptotic neuronal death in TBI mice, we first examined the accumulation of malondialdehyde (MDA) and ferrous ion, and the expression of ferroptosis-related molecules at 6 h, 12 h, 24 h, 48 h and 72 h following controlled cortical impact (CCI) in mice. There was a significant upregulation in the expression of Gpx4 and Acsl4 at 6 h, Slc7a11 from 12 h to 72 h, and Nox2 and Sat1 from 6 h to 72 h post injury. Similarly, an upregulation in the expression of Gpx4 at 6 h, Nox2 from 6 h to 72 h, xCT from 12 h to 72 h, and Sat1 at 72 h after CCI was observed at the protein level. Interestingly, MDA and ferrous ion were increased whereas miR-212-5p was decreased in the CCI group compared to the sham group. Furthermore, we found that overexpression of miR-212-5p attenuated ferroptosis while downregulation of miR-212-5p promoted ferroptotic cell death partially by targeting prostaglandin-endoperoxide synthase-2 (Ptgs2) in HT-22 and Neuro-2a cell lines. In addition, administration of miR-212-5p in CCI mice significantly improved learning and spatial memory. Collectively, these findings indicate that miR-212-5p may protect against ferroptotic neuronal death in CCI mice partially by targeting Ptgs2.

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Disruption of Bax Protein Prevents Neuronal Cell Death but Produces Cognitive Impairment in Mice following Traumatic Brain Injury

Journal of Neurotrauma ◽

10.1089/neu.2007.0441 ◽

2008 ◽

Vol 25 (7) ◽

pp. 755-767 ◽

Cited By ~ 39

Author(s):

Roya Tehranian ◽

Marie E. Rose ◽

Vincent Vagni ◽

Alicia M. Pickrell ◽

Raymond P. Griffith ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Cognitive Impairment ◽

Brain Injury ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Bax Protein

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Therapeutic Time Window for Edaravone Treatment of Traumatic Brain Injury in Mice

BioMed Research International ◽

10.1155/2013/379206 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 11

Author(s):

Kazuyuki Miyamoto ◽

Hirokazu Ohtaki ◽

Kenji Dohi ◽

Tomomi Tsumuraya ◽

Dandan Song ◽

...

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Neuronal Death ◽

Time Window ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Free Radical Scavenger ◽

Radical Scavenger ◽

Therapeutic Time Window

Traumatic brain injury (TBI) is a major cause of death and disability in young people. No effective therapy is available to ameliorate its damaging effects. Our aim was to investigate the optimal therapeutic time window of edaravone, a free radical scavenger which is currently used in Japan. We also determined the temporal profile of reactive oxygen species (ROS) production, oxidative stress, and neuronal death. Male C57Bl/6 mice were subjected to a controlled cortical impact (CCI). Edaravone (3.0 mg/kg), or vehicle, was administered intravenously at 0, 3, or 6 hours following CCI. The production of superoxide radicals (O2∙-) as a marker of ROS, of nitrotyrosine (NT) as an indicator of oxidative stress, and neuronal death were measured for 24 hours following CCI. Superoxide radical production was clearly evident 3 hours after CCI, with oxidative stress and neuronal cell death becoming apparent after 6 hours. Edaravone administration after CCI resulted in a significant reduction in the injury volume and oxidative stress, particularly at the 3-hour time point. Moreover, the greatest decrease inO2∙-levels was observed when edaravone was administered 3 hours following CCI. These findings suggest that edaravone could prove clinically useful to ameliorate the devastating effects of TBI.

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