Modeling traumatic brain injury in vitro: Functional changes in the absence of cell death

2009 ◽  
Author(s):  
Zhe Yu ◽  
Benjamin S. Elkin ◽  
Barclay Morrison
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Functional Changes

scholarly journals Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhongyuan Bao ◽  
Yinlong Liu ◽  
Binglin Chen ◽  
Zong Miao ◽  
Yiming Tu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Brain Injury ◽  
Neuronal Degeneration ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Prokineticin 2

AbstractProkineticin-2 (Prok2) is an important secreted protein likely involved in the pathogenesis of several acute and chronic neurological diseases through currently unidentified regulatory mechanisms. The initial mechanical injury of neurons by traumatic brain injury triggers multiple secondary responses including various cell death programs. One of these is ferroptosis, which is associated with dysregulation of iron and thiols and culminates in fatal lipid peroxidation. Here, we explore the regulatory role of Prok2 in neuronal ferroptosis in vitro and in vivo. We show that Prok2 prevents neuronal cell death by suppressing the biosynthesis of lipid peroxidation substrates, arachidonic acid-phospholipids, via accelerated F-box only protein 10 (Fbxo10)-driven ubiquitination, degradation of long-chain-fatty-acid-CoA ligase 4 (Acsl4), and inhibition of lipid peroxidation. Mice injected with adeno-associated virus-Prok2 before controlled cortical impact injury show reduced neuronal degeneration and improved motor and cognitive functions, which could be inhibited by Fbxo10 knockdown. Our study shows that Prok2 mediates neuronal cell deaths in traumatic brain injury via ferroptosis.

scholarly journals Comparing effects of CDK inhibition and E2F1/2 ablation on neuronal cell death pathways in vitro and after traumatic brain injury

2018 ◽  
Vol 9 (11) ◽  
Author(s):  
Taryn G. Aubrecht ◽  
Alan I. Faden ◽  
Boris Sabirzhanov ◽  
Ethan P. Glaser ◽  
Brian A. Roelofs ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cell Death Pathways

scholarly journals Experimental Mild Traumatic Brain Injury Induces Functional Alteration of the Developing Hippocampus

2010 ◽  
Vol 103 (1) ◽  
pp. 499-510 ◽  
Author(s):  
Zhe Yu ◽  
Barclay Morrison
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Neuronal Function ◽  
Mild Tbi ◽  
Functional Deficits ◽  
Biaxial Deformation ◽  
Safe Limits ◽  
Pediatric Tbi

It is estimated that ∼1.5 million Americans suffer a traumatic brain injury (TBI) every year, of which ∼80% are considered mild injuries. Because symptoms caused by mild TBI last less than half an hour by definition and apparently resolve without treatment, the study of mild TBI is often neglected resulting in a significant knowledge gap for this wide-spread problem. In this work, we studied functional (electrophysiological) alterations of the neonatal/juvenile hippocampus after experimental mild TBI. Our previous work reported significant cell death after in vitro injury >10% biaxial deformation. Here we report that biaxial deformation as low as 5% affected neuronal function during the first week after in vitro mild injury of hippocampal slice cultures. These results suggest that even very mild mechanical events may lead to a quantifiable neuronal network dysfunction. Furthermore, our results highlight that safe limits of mechanical deformation or tolerance criteria may be specific to a particular outcome measure and that neuronal function is a more sensitive measure of injury than cell death. In addition, the age of the tissue at injury was found to be an important factor affecting posttraumatic deficits in electrophysiological function, indicating a relationship between developmental status and vulnerability to mild injury. Our findings suggest that mild pediatric TBI could result in functional deficits that are more serious than currently appreciated.

scholarly journals Caspase Inhibitor z-DEVD-fmk Attenuates Calpain and Necrotic Cell Death in Vitro and after Traumatic Brain Injury

2004 ◽  
Vol 24 (10) ◽  
pp. 1119-1132 ◽  
Author(s):  
Susan M. Knoblach ◽  
Daniel A. Alroy ◽  
Maria Nikolaeva ◽  
Ibolja Cernak ◽  
Bogdan A. Stoica ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Caspase 3 ◽  
Therapeutic Window ◽  
Necrotic Cell Death ◽  
Type I ◽  
Necrotic Cell ◽  
Neuronal Necrosis

In studies designed to evaluate the therapeutic window for treatment of traumatic brain injury, the caspase 3 inhibitor z-DEVD-fmk improved neurologic function and reduced lesion volumes when administered at 1 but not at 4, 8, or 24 hours after injury. Moreover, neither caspase 3 nor PARP, a caspase 3 substrate, were cleaved in injured, untreated cortex from 1 to 72 hours after injury. Few cortical neurons expressed active caspase 3 or were TUNEL positive from 6 to 24 hours after injury, and TUNEL staining was primarily Type I (necrotic). Nissl staining revealed extensive neuronal necrosis in the injured cortex from 6 to 24 hours after impact. Considered together, these data suggested that z-DEVD-fmk may reduce neuronal necrosis, so we used an in vitro model of necrotic cell death induced by maitotoxin to test this further and explore the potential mechanism(s) involved. Z-DEVD-fmk (1 nM-100 μM) significantly attenuated maitotoxin induced neuronal cell death and markedly reduced expression of the 145 kD calpain-mediated α-spectrin breakdown product after maitotoxin injury. Neither the 120 kD caspase-mediated α-spectrin cleavage product nor cathepsin B were expressed after maitotoxin injury. In a cell free assay, z-DEVD-fmk reduced hydrolysis of casein by purified calpain I. Finally, z-DEVD-fmk reduced expression of the 145 kD calpain-mediated α-spectrin cleavage fragment after traumatic brain injury in vivo. These data suggest that neuroprotection by z-DEVD-fmk may, in part, reflect inhibition of calpain-related necrotic cell death.

scholarly journals Novel Diketopiperazine Enhances Motor and Cognitive Recovery after Traumatic Brain Injury in Rats and Shows Neuroprotection In Vitro and In Vivo

2003 ◽  
Vol 23 (3) ◽  
pp. 342-354 ◽  
Author(s):  
Alan I. Faden ◽  
Susan M. Knoblach ◽  
Ibolja Cernak ◽  
Lei Fan ◽  
Robert Vink ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Apoptotic Cell ◽  
Thyroid Stimulating Hormone ◽  
Neuroprotective Activity ◽  
Magnesium Concentration ◽  
Binding Studies

The authors developed a novel diketopiperazine that shows neuroprotective activity in a variety of in vitro models, as well as in a clinically relevant experimental model of traumatic brain injury (TBI) in rats. Treatment with 1-ARA-35b (35b), a cyclized dipeptide derived from a modified thyrotropin-releasing hormone (TRH) analog, significantly reduced cell death associated with necrosis (maitotoxin), apoptosis (staurosporine), or mechanical injury in neuronal–glial cocultures. Rats subjected to lateral fluid percussion–induced TBI and then treated with 1 mg/kg intravenous 35b thirty minutes after trauma showed significantly improved motor recovery and spatial learning compared with vehicle-treated controls. Treatment also significantly reduced lesion volumes as shown by magnetic resonance imaging, and decreased the number of TUNEL-positive neurons observed in ipsilateral hippocampus. Unlike TRH or traditional TRH analogs, 35b treatment did not change mean arterial pressure, body temperature, or thyroid-stimulating hormone release, and did not have analeptic activity. Moreover, in contrast to TRH or typical TRH analogs, 35b administration after TBI did not alter free-magnesium concentration or cellular bioenergetic state. Receptor-binding studies showed that 35b did not act with high affinity at 50 classical receptors, channels, or transporters. Thus, 35b shows none of the typical physiologic actions associated with TRH, but possesses neuroprotective actions in vivo and in vitro, and appears to attenuate both necrotic and apoptotic cell death.

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