Traumatic brain injury-induced downregulation of Nrf2 activates inflammatory response and apoptotic cell death

2019 ◽  
Vol 97 (12) ◽  
pp. 1627-1641 ◽  
Author(s):  
Saurav Bhowmick ◽  
Veera D’Mello ◽  
Danielle Caruso ◽  
P. M. Abdul-Muneer
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death

Minimal Traumatic Brain Injury Induce Apoptotic Cell Death in Mice

2008 ◽  
Vol 37 (1) ◽  
pp. 16-24 ◽  
Author(s):  
V. Tashlykov ◽  
Y. Katz ◽  
A. Volkov ◽  
V. Gazit ◽  
S. Schreiber ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death

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

2000 ◽  
Vol 20 (4) ◽  
pp. 669-677 ◽  
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.

scholarly journals 17β-Estradiol Abrogates Oxidative Stress and Neuroinflammation after Cortical Stab Wound Injury

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1682
Author(s):  
Kamran Saeed ◽  
Myeung Hoon Jo ◽  
Jun Sung Park ◽  
Sayed Ibrar Alam ◽  
Ibrahim Khan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Oxidative Damage ◽  
Stab Wound ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Estradiol Treatment ◽  
17Β Estradiol

Disruptions in brain energy metabolism, oxidative damage, and neuroinflammation are commonly seen in traumatic brain injury (TBI). Microglial activation is the hallmark of neuroinflammation. After brain injury, microglia also act as a double-edged sword with distinctive phenotypic changes. Therefore, therapeutic applications to potentiate microglia towards pro-inflammatory response following brain injury have become the focus of attention in recent years. Here, in the current study, we investigated the hypothesis that 17β-estradiol could rescue the mouse brain against apoptotic cell death and neurodegeneration by suppressing deleterious proinflammatory response probably by abrogating metabolic stress and oxidative damage after brain injury. Male C57BL/6N mice were used to establish a cortical stab wound injury (SWI) model. Immediately after brain injury, the mice were treated with 17β-estradiol (10 mg/kg, once every day via i.p. injection) for one week. Immunoblotting and immunohistochemical analysis was performed to examine the cortical and hippocampal brain regions. For the evaluation of reactive oxygen species (ROS), reduced glutathione (GSH), and oxidized glutathione (GSSG), we used specific kits. Our findings revealed that 17β-estradiol treatment significantly alleviated SWI-induced energy dyshomeostasis and oxidative stress by increasing the activity of phospho-AMPK (Thr172) and by regulating the expression of an antioxidant gene (Nrf2) and cytoprotective enzymes (HO-1 and GSH) to mitigate ROS. Importantly, 17β-estradiol treatment downregulated gliosis and proinflammatory markers (iNOS and CD64) while significantly augmenting an anti-inflammatory response as evidenced by the robust expression of TGF-β and IGF-1 after brain injury. The treatment with 17β-estradiol also reduced inflammatory mediators (Tnf-α, IL-1β, and COX-2) in the injured mouse. Moreover, 17β-estradiol administration rescued p53-associated apoptotic cell death in the SWI model by regulating the expression of Bcl-2 family proteins (Bax and Bcl-2) and caspase-3 activation. Finally, SWI + 17β-estradiol-treated mice illustrated reduced brain lesion volume and enhanced neurotrophic effect and the expression of synaptic proteins. These findings suggest that 17β-estradiol is an effective therapy against the brain secondary injury-induced pathological cascade following trauma, although further studies may be conducted to explore the exact mechanisms.

scholarly journals Agmatine Attenuates Brain Edema and Apoptotic Cell Death after Traumatic Brain Injury

2015 ◽  
Vol 30 (7) ◽  
pp. 943 ◽  
Author(s):  
Jae Young Kim ◽  
Yong Woo Lee ◽  
Jae Hwan Kim ◽  
Won Taek Lee ◽  
Kyung Ah Park ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Brain Edema ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death

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

ASN NEURO ◽  
2020 ◽  
Vol 12 ◽  
pp. 175909142093086
Author(s):  
Laura E. Montroull ◽  
Deborah E. Rothbard ◽  
Hur D. Kanal ◽  
Veera D’Mello ◽  
Vincent Dodson ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Neuronal Death ◽  
Apoptotic Cell ◽  
Neuronal Cell ◽  
Adult Brain ◽  
Neurotrophin Receptor ◽  
Cortical Impact ◽  
Impact Injury

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.

scholarly journals Ischemic Brain Injury is Mediated by the Activation of Poly(ADP-Ribose)Polymerase

1997 ◽  
Vol 17 (11) ◽  
pp. 1143-1151 ◽  
Author(s):  
Matthias Endres ◽  
Zhao-Qi Wang ◽  
Shobu Namura ◽  
Christian Waeber ◽  
Michael A. Moskowitz
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Tissue Injury ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Ischemic Brain Injury ◽  
Cell Nuclei ◽  
Ischemic Brain ◽  
Nad Depletion

Poly(ADP-ribose)polymerase (PARP, EC 2.4.2.30), an abundant nuclear protein activated by DNA nicks, mediates cell death in vitro by nicotinamide adenine dinucleotide (NAD) depletion after exposure to nitric oxide. The authors examined whether genetic deletion of PARP (PARP null mice) or its pharmacologic inhibition by 3-aminobenzamide (3-AB) attenuates tissue injury after transient cerebral ischemia. Twenty-two hours after reperfusion following 2 hours of filamentous middle cerebral artery occlusion, ischemic injury was decreased in PARP−/− and PARP+/− mice compared with PARP+/+ litter mates, and also was attenuated in 129/SV wild-type mice after 3-AB treatment compared with controls. Infarct sparing was accompanied by functional recovery in PARP−/− and 3-AB–treated mice. Increased poly(ADP-ribose) immunostaining observed in ischemic cell nuclei 5 minutes after reperfusion was reduced by 3-AB treatment. Levels of NAD—the substrate of PARP—were reduced 2 hours after reperfusion and were 35% of contralateral levels at 24 hours. The decreases were attenuated in PARP−/− mice and in 3-AB–treated animals. Poly(ADP-ribose)polymerase cleavage by caspase-3 (CPP-32) has been proposed as an important step in apoptotic cell death. Markers of apoptosis, such as oligonucleosomal DNA damage, total DNA fragmentation, and the density of terminal deoxynucleotidyl transferase dUTP nick-end–labelled (TUNEL +) cells, however, did not differ in ischemic brain tissue of PARP−/− mice or in 3-AB–treated animals versus controls, although there were differences in the number of TUNEL-stained cells reflecting the decrease in infarct size. Thus, ischemic brain injury activates PARP and contributes to cell death most likely by NAD depletion and energy failure, although the authors have not excluded a role for PARP in apoptotic cell death at earlier or later stages in ischemic cell death. Inhibitors of PARP activation could provide a potential therapy in acute stroke.

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