Traumatic scratch injury in astrocytes triggers calcium influx to activate the JNK/c-Jun/AP-1 pathway and switch on GFAP expression

Gao, Kai; Wang, Chen Ran; Jiang, Feng; Wong, Ann Y.K.; Su, Na; Jiang, Jiao; Chai, Rui; Vatcher, Greg; Jiang, Teng; Chen, Jianguo; Jiang, Yuwu; Yu, Albert Cheung Hoi

doi:10.1002/glia.22577

Cited by 116 publications

(96 citation statements)

References 109 publications

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“…65,67 A recent study showed that traumatic scratch injury to astrocytes triggers Ca 2 + influx, resulting in an increase in GFAP expression and increase in the size of glial scars. 68 It suggests that Ca 2 + provides the early injury signal that triggers the signal transduction cascades for astrogliosis through ER Ca 2 + store release and this is consistent with our results. We provided direct evidence of such a Ca 2 + pathway, and we further showed that activation of such Ca 2 + responses is heterogeneous, depending on the stimulus properties.…”

Section: Discussionsupporting

confidence: 91%

A Threshold Shear Force for Calcium Influx in an Astrocyte Model of Traumatic Brain Injury

Maneshi

Sachs

Hua

2015

Journal of Neurotrauma

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Traumatic brain injury (TBI) refers to brain damage resulting from external mechanical force, such as a blast or crash. Our current understanding of TBI is derived mainly from in vivo studies that show measurable biological effects on neurons sampled after TBI. Little is known about the early responses of brain cells during stimuli and which features of the stimulus are most critical to cell injury. We generated defined shear stress in a microfluidic chamber using a fast pressure servo and examined the intracellular Ca 2 + levels in cultured adult astrocytes. Shear stress increased intracellular Ca 2 + depending on the magnitude, duration, and rise time of the stimulus. Square pulses with a fast rise time (*2 ms) caused transient increases in intracellular Ca 2 + , but when the rise time was extended to 20 ms, the response was much less. The threshold for a response is a matrix of multiple parameters. Cells can integrate the effect of shear force from repeated challenges: A pulse train of 10 narrow pulses (11.5 dyn/cm 2 and 10 ms wide) resulted in a 4-fold increase in Ca 2 + relative to a single pulse of the same amplitude 100 ms wide. The Ca 2 + increase was eliminated in Ca 2 + -free media, but was observed after depleting the intracellular Ca 2 + stores with thapsigargin suggesting the need for a Ca 2 + influx. The Ca 2 + influx was inhibited by extracellular Gd 3 + , a nonspecific inhibitor of mechanosensitive ion channels, but it was not affected by the more specific inhibitor, GsMTx4. The voltage-gated channel blockers, nifedipine, diltiazem, and verapamil, were also ineffective. The data show that the mechanically induced Ca 2 + influx commonly associated with neuron models for TBI is also present in astrocytes, and there is a viscoelastic/plastic coupling of shear stress to the Ca 2 + influx. The site of Ca 2 + influx has yet to be determined.

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Section: Discussionsupporting

confidence: 91%

A Threshold Shear Force for Calcium Influx in an Astrocyte Model of Traumatic Brain Injury

Maneshi

Sachs

Hua

2015

Journal of Neurotrauma

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“…The most crucial of elements in GFAP gene is a consensus AP-1 sequence, the binding site for the Fos and Jun families of transcription factors (Masood et al 1993). Gao et al reported that calcium influx triggered by scratch could activate the c-Jun/AP-1 signaling pathway to switch on GFAP expression (Gao et al 2013).…”

Section: Resultsmentioning

confidence: 99%

Scorpion Venom Heat-Resistant Peptide Attenuates Glial Fibrillary Acidic Protein Expression via c-Jun/AP-1

Cao

Peng

et al. 2015

Cell Mol Neurobiol

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Scorpion venom has been used in the Orient to treat central nervous system diseases for many years, and the protein/peptide toxins in Buthus martensii Karsch (BmK) venom are believed to be the effective components. Scorpion venom heat-resistant peptide (SVHRP) is an active component of the scorpion venom extracted from BmK. In a previous study, we found that SVHRP could inhibit the formation of a glial scar, which is characterized by enhanced glial fibrillary acidic protein (GFAP) expression, in the epileptic hippocampus. However, the cellular and molecular mechanisms underlying this process remain to be clarified. The results of the present study indicate that endogenous GFAP expression in primary rat astrocytes was attenuated by SVHRP. We further demonstrate that the suppression of GFAP was primarily mediated by inhibiting both c-Jun expression and its binding with AP-1 DNA binding site and other factors at the GFAP promoter. These results support that SVHRP contributes to reducing GFAP at least in part by decreasing the activity of the transcription factor AP-1. In conclusion, the effects of SVHRP on astrocytes with respect to the c-Jun/AP-1 signaling pathway in vitro provide a practical basis for studying astrocyte activation and inhibition and a scientific basis for further studies of traditional medicine.

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“…The method we used to make a stab wound injury model was modified based on previous studies. [47][48][49] Mice were anesthetized by intraperitoneal injection of 4% chloral hydrate (1 mL/100 g). We use a needle diameter of 0.7 mm and the injury point was 2 mm left of themed line and 2.5 mm underneath the lambdoid suture (Fig.…”

Section: Animal Modelmentioning

confidence: 99%

Osthole Enhances the Therapeutic Efficiency of Stem Cell Transplantation in Neuroendoscopy Caused Traumatic Brain Injury

Tao

Gao

Yan

et al. 2017

Biological & Pharmaceutical Bulletin

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Neuroendoscopy processes can cause severe traumatic brain injury. Existing therapeutic methods, such as neural stem cell transplantation and osthole have not been proven effective. Therefore, there is an emerging need on the development of new techniques for the treatment of brain injuries. In this study we propose to combine the above stem cell based methods and then evaluate the efficiency and accuracy of the new method. Mice were randomly divided into four groups: group 1 (brain injury alone); group 2 (osthole); group 3 (stem cell transplantation); and group 4 (osthole combined with stem cell transplantation). We carried out water maze task to exam spatial memory. Immunocytochemistry was used to test the inflammatory condition of each group, and the differentiation of stem cells. To evaluate the condition of the damaged blood brain barrier restore, we detect the Evans blue (EB) extravasation across the blood brain barrier. The result shows that osthole and stem cell transplantation combined therapeutic method has a potent effect on improving the spatial memory. This combined method was more effective on inhibiting inflammation and preventing neuronal degeneration than the single treated ones. In addition, there was a distinct decline of EB extravasation in the combined treatment groups, which was not observed in single treatment groups. Most importantly, the combined usage of osthole and stem cell transplantation provide a better treatment for the traumatic brain injury caused by neuroendoscopy. The collective evidence indicates osthole combined with neural stem cell transplantation is superior than either method alone for the treatment of traumatic brain injury caused by neuroendoscopy.

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Traumatic scratch injury in astrocytes triggers calcium influx to activate the JNK/c-Jun/AP-1 pathway and switch on GFAP expression

Cited by 116 publications

References 109 publications

A Threshold Shear Force for Calcium Influx in an Astrocyte Model of Traumatic Brain Injury

A Threshold Shear Force for Calcium Influx in an Astrocyte Model of Traumatic Brain Injury

Scorpion Venom Heat-Resistant Peptide Attenuates Glial Fibrillary Acidic Protein Expression via c-Jun/AP-1

Osthole Enhances the Therapeutic Efficiency of Stem Cell Transplantation in Neuroendoscopy Caused Traumatic Brain Injury

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