Targeting the blood-spinal cord barrier: A therapeutic approach to spinal cord protection against ischemia-reperfusion injury

Ji, Hu; Yu, Qijing; Xie, Li-Jie; Zhu, Hongfei

doi:10.1016/j.lfs.2016.06.018

Cited by 27 publications

(15 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Spinal cord IR injury elicits a concomitant increase in blood-spinal cord barrier (BSCB) permeability, accompanied by the subsequent activation of proinflammatory responses and cellular programmed or autophagy-associated death [2, 3]. Commonly, these responses are regulated by separate signalling pathways, and recent emerging evidence indicates that they may coordinate and integrate into a signalling network in response to ischaemia [4, 5].…”

Section: Introductionmentioning

confidence: 99%

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway

Chen

et al. 2018

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundIschaemia reperfusion (IR) induces multiple pathophysiological changes. In addition to its classical role in regulating tumourigenesis, the feedback loop formed by p53 and its driven target p53-upregulated modulator of apoptosis (PUMA) was recently demonstrated to be the common node tightly controlling various cellular responses during myocardial IR. However, the roles of the p53-PUMA feedback loop in the spinal cord remain unclear. This study aimed to elucidate the roles of p53-PUMA feedback interactions in the spinal cord after IR, specifically investigating their regulation of caspase 3-mediated apoptosis and nuclear factor (NF)-κB-mediated cytokine release.MethodsSD rats subjected to 12 min of aortic arch occlusion served as IR models. Neurological assessment as well as p53 and PUMA mRNA and protein expression analyses were performed at 12-h intervals during a 48-h reperfusion period. The cellular distributions of p53 and PUMA were determined via double immunofluorescence staining. The effects of the p53-PUMA feedback loop on modulating hind-limb function; the number of TUNEL-positive cells; and protein levels of caspase 3, NF-κB and cytokines interleukin (IL)-1β and tumour necrosis factor (TNF)-α, were evaluated by intrathecal treatment with PUMA-specific or scramble siRNA and pifithrin (PFT)-α. Blood-spinal cord barrier (BSCB) breakdown was examined by Evans blue (EB) extravasation and water content analyses.ResultsIR induced significant behavioural deficits as demonstrated by deceased Tarlov scores, which displayed trends opposite those of PUMA and p53 protein and mRNA expression. Upregulated PUMA and p53 fluorescent labels were widely distributed in neurons, astrocytes and microglia. Injecting si-PUMA and PFT-α exerted significant anti-apoptosis effects as shown by the reduced number of TUNEL-positive cells, nuclear abnormalities and cleaved caspase 3 levels at 48 h post-IR. Additionally, p53 colocalized with NF-κB within the cell. Similarly, injecting si-PUMA and PFT-α exerted anti-inflammatory effects as shown by the decreased NF-κB translocation and release of IL-1β and TNF-α. Additionally, injecting si-PUMA and PFT-α preserved the BSCB integrity as determined by decreased EB extravasation and spinal water content. However, injecting si-Con did not induce any of the abovementioned effects.ConclusionsInhibition of aberrant p53-PUMA feedback loop activation by intrathecal treatment with si-PUMA and PFT-α prevented IR-induced neuroapoptosis, inflammatory responses and BSCB breakdown by inactivating caspase 3-mediated apoptosis and NF-κB-mediated cytokine release.

show abstract

Section: Introductionmentioning

confidence: 99%

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway

Chen

et al. 2018

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…These results demonstrate that in addition to the BBB, TGF-β1 signaling is involved in TJ protein expression at the BSCB. Spinal cord injury causes increased BSCB permeability to Evans blue and induces edema in the spinal cord [110]. These changes are attenuated by pre-treatment with p -chlorophenylalanine, indomethacin, ibuprofen, and nimodipine, indicating a role for serotonin, COX signaling, and calcium channels in BSCB changes induced by spinal cord injury.…”

Section: Future Directionsmentioning

confidence: 99%

“…These changes are attenuated by pre-treatment with p -chlorophenylalanine, indomethacin, ibuprofen, and nimodipine, indicating a role for serotonin, COX signaling, and calcium channels in BSCB changes induced by spinal cord injury. Spinal cord ischemia-reperfusion injury has been shown to increase the extravasation of Evans blue into the spinal parenchyma and is associated with upregulation of MMP-9 and a reduction in claudin-5, occludin, and ZO-1 [110]. Understanding mechanisms which disrupt the BCSFB or BSCB following hypoxia, pain, or inflammation may lead to novel treatments targeting cells throughout the brain or spinal cord.…”

Section: Future Directionsmentioning

confidence: 99%

Hypoxic Stress and Inflammatory Pain Disrupt Blood-Brain Barrier Tight Junctions: Implications for Drug Delivery to the Central Nervous System

Lochhead

Ronaldson

Davis

2017

AAPS J

View full text Add to dashboard Cite

A functional blood-brain barrier (BBB) is necessary to maintain central nervous system (CNS) homeostasis. Many diseases affecting the CNS, however, alter the functional integrity of the BBB. It has been shown that various diseases and physiological stressors can impact the BBB’s ability to selectively restrict passage of substances from the blood to the brain. Modifications of the BBB’s permeability properties can potentially contribute to the pathophysiology of CNS diseases and result in altered brain delivery of therapeutic agents. Hypoxia and/or inflammation are central components of a number of diseases affecting the CNS. A number of studies indicate hypoxia or inflammatory pain increase BBB paracellular permeability, induce changes in the expression and/or localization of tight junction proteins, and affect CNS drug uptake. In this review, we look at what is currently known with regard to BBB disruption following a hypoxic or inflammatory insult in vivo. Potential mechanisms involved in altering tight junction components at the BBB are also discussed. A more detailed understanding of the mediators involved in changing BBB functional integrity in response to hypoxia or inflammatory pain could potentially lead to new treatments for CNS diseases with hypoxic or inflammatory components. Additionally, greater insight into the mechanisms involved in TJ rearrangement at the BBB may lead to novel strategies to pharmacologically increase delivery of drugs to the CNS.

show abstract

“…Pathological studies have shown that secondary SCI is a vicious circle caused by multiple mechanisms such as inflammation, acid‐induced oxidative injury, calcium overload and so on, the damage from which is even more severe than the original damage. The blood–spinal cord barrier (BSCB) is composed of glial membrane, endothelial cells and close connections between them, which changes badly after SCI, and it is an important pathophysiological basis of secondary damage . Presently, it is generally believed that edema is a key process in SCI pathophysiology, and is strongly correlated with clinical outcome, especially in terms of motor recovery.…”

Section: Introductionmentioning

confidence: 99%

“…The blood-spinal cord barrier (BSCB) is composed of glial membrane, endothelial cells and close connections between them, which changes badly after SCI, and it is an important pathophysiological basis of secondary damage. 4 Presently, it is generally believed that edema is a key process in SCI pathophysiology, and is strongly correlated with clinical outcome, especially in terms of motor recovery. Aquaporin (AQP) is a series of small hydrophobic protein molecules across the cytomembrane of various systems in mammals, among which AQP4 is the most abundant in the central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 99%

Aquaporin‐4 expression dynamically varies after acute spinal cord injury‐induced disruption of blood spinal cord barrier in rats

Pan

Guo

et al. 2019

Neuropathology

View full text Add to dashboard Cite

The blood–spinal cord barrier (BSCB) changes badly after spinal cord injury (SCI), and it is an important pathophysiological basis of SCI secondary damage. Aquaporin‐4 (AQP4), one of the transmembrane proteins in spinal cord, has been shown to be closely related to the development of the BSCB and edema. We established a SCI model in rats using a free‐falling weight drop device to subsequently investigate AQP4 expression. AQP4 messenger RNA (mRNA) and protein expression and immunoreactivity were detected in spinal cord tissue using reverse transcription‐real‐time quantitative polymerase chain reaction (RT‐qPCR), immunohistochemistry and Western blot analysis. We found the water content and edema of the spinal cord were significantly higher than the control group after SCI, which was related to the growth of BSCB permeability; both reached their peak on the third day after injury. One, 3, 5, 7 days after injury, the immune response and protein expression in the model group increased from 1 to 3 days, with a plateau period from 3 to 5 days and a decline from 5 to 7 days, showing a significant difference compared with the sham group at each time point (P < 0.05), while the RT‐qPCR results showed a decline of mRNA just after 3 days. In conclusion, after SCI, the water content of the spinal cord and the BSCB permeability increases, together with the excessive expression of AQP4, which reached a peak on the third day. AQP4 expression is closely relative to the permeability of BSCB and the water content of the spinal cord.

show abstract

Targeting the blood-spinal cord barrier: A therapeutic approach to spinal cord protection against ischemia-reperfusion injury

Cited by 27 publications

References 71 publications

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway

Hypoxic Stress and Inflammatory Pain Disrupt Blood-Brain Barrier Tight Junctions: Implications for Drug Delivery to the Central Nervous System

Aquaporin‐4 expression dynamically varies after acute spinal cord injury‐induced disruption of blood spinal cord barrier in rats

Contact Info

Product

Resources

About