Synthetic gelatinases inhibitor attenuates electromagnetic pulse-induced blood–brain barrier disruption by inhibiting gelatinases-mediated ZO-1 degradation in rats

Qiu, Lian-Bo; Zhou, Yan; Wang, Qi; Yang, Longlong; Liu, Haiqiang; Xu, Shenglong; Qi, Yuhong; Ding, Gui‐Rong; Guo, Guozhen

doi:10.1016/j.tox.2011.03.019

Cited by 27 publications

(14 citation statements)

References 41 publications

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“…In addition, the protein levels of MMP-9 and its endogenous inhibitor TIMP-1 didn't change significantly after EMP exposure. These data suggested that EMP exposure could increase the protein level of MMP-2, but had no effect on MMP-9, TIMP-1 and TIMP-2 in the BBB model, which was consistent with our previous study in vivo (Qiu et al, 2011).…”

Section: Electromagnetic Biology and Medicinesupporting

confidence: 92%

“…Further study showed that the decrease of the TJ protein ZO-1 level resulted from the increased activity of gelatinase after EMP exposure (Qiu et al, 2011). To further explore the mechanism of EMP-induced BBB permeability change, especially the role of gelatinase in this process, we established the BBB model in vitro, and observed the protein level and activity of gelatinase.…”

Section: Electromagnetic Biology and Medicinementioning

confidence: 99%

“…In our previous in vivo studies, we found that EMPinduced BBB opening was related to gelatinasemediated ZO-1 degradation (Qiu et al, 2011). In order to further explore the mechanism of EMPinduced BBB permeability change, in this study, an in vitro BBB model was established.…”

Section: Introductionmentioning

confidence: 99%

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Effects of electromagnetic pulse exposure on gelatinase of blood–brain barrierin vitro

Zhou

Qiu

et al. 2016

Electromagnetic Biology and Medicine

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The biological effects of electromagnetic pulse (EMP) on the brain have been focused on for years. It was reported that gelatinase played an important role in maintaining brain function through regulating permeability in the blood-brain barrier (BBB). To investigate the effects of EMP on gelatinase of BBB, an in vitro BBB model was established using primary cultured rat brain microvascular endothelial cells (BMVEC), astrocytes and half-contact culture of these cells in a transwell chamber. Cultured supernatant and cells were collected at different time points after exposure to EMP (peak intensity 400 kV/m, rise time 10 ns, pulse width 350 ns, 0.5 pps and 200 pulses). Protein levels of cellular gelatinase MMP-2 and MMP-9, and endogenous inhibitor TIMP-1 and TIMP-2 were detected by Western blot. The activity of gelatinase in culture supernatant was detected by gelatin zymography. It was found that compared with the sham-exposed group, the protein level of MMP-2 was significantly increased at 6 h (p < 0.05), and the protein level of its endogenous inhibitor TIMP-2 did not change after EMP exposure. In addition, the protein levels of MMP-9 and its endogenous inhibitor TIMP-1 did not change after EMP exposure. Gelatin zymography results showed that the activity of MMP-2 in the inner pool and the outer pool of the transwell chamber was significantly increased at 6 h after EMP exposure compared with that of the sham group. These results suggested that EMP exposure could affect the expression and activity of MMP-2 in the BBB model.

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Section: Electromagnetic Biology and Medicinesupporting

confidence: 92%

Section: Electromagnetic Biology and Medicinementioning

confidence: 99%

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Effects of electromagnetic pulse exposure on gelatinase of blood–brain barrierin vitro

Zhou

Qiu

et al. 2016

Electromagnetic Biology and Medicine

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“…This dose has been shown to be effective against both gelatinases in vivo. SB-3CT has been used in vivo at concentrations ranging from 5 to 25 mg/kg [29, 33–35]. In our study, SB-3CT (25 mg/kg/day, i.v.)…”

Section: Resultsmentioning

confidence: 99%

MMPs 2 and 9 are essential for coronary collateral growth and are prominently regulated by p38 MAPK

Dodd¹,

Jadhav²,

Wiggins³

et al. 2011

Journal of Molecular and Cellular Cardiology

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Transient, repetitive ischemia (RI) stimulates coronary collateral growth (CCG) in normal, healthy (SD) rats, which requires p38 MAPK activation. In contrast, RI does not induce CCG in the metabolic syndrome (JCR) rats, which is associated with lack of p38 MAPK activation. The functional consequences of p38 MAPK activation in CCG remain unknown. Theoretically, effective collateral growth would require extracellular matrix remodeling; however, direct assessment as well as identification of proteases responsible for this degradation are lacking. In this study, we investigated the role of p38 MAPK in the regulation of matrix metalloproteinases 2 and 9 (MMPs 2 and 9) and their requirement for CCG in SD vs. JCR rats. The rats underwent the RI protocol (8 LAD occlusions, 40 sec each, every 20 min, in 8 hr cycles for 0, 3, 6, or 9 days). MMP expression was measured in the ischemic, collateral-dependent zone (CZ) and the normal zone (NZ) by Western blot, and MMP activity by zymography. Expression and activation of MMP 2 and 9 were significantly increased (~3.5 fold) on day 3 of RI in the CZ of SD rats. In vivo p38 MAPK inhibition completely blocked RI-induced MMP 2 and 9 expression and activation. MMP activation correlated with increased degradation of components of the basement membrane and the vascular elastic laminae: elastin (~3 fold), laminin (~3 fold) and type IV collagen (~2 fold). This was blocked by MMP 2 and 9 inhibition, which also abolished RI-induced CCG. In contrast, in JCR rats, RI did not induce expression or activation of MMP 2 or 9 and there was no associated degradation of elastin, laminin or type IV collagen. In conclusion, MMP 2 and 9 activation is essential for CCG and is mediated, in part, by p38 MAPK. Furthermore, compromised CCG in the metabolic syndrome may be partially due to the lack of p38 MAPK-dependent activation of MMP 2 and 9 and resultant decreased extracellular matrix degradation.

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“…MMP-2, MMP-3, MMP-7 and MMP-9), which raises the possibility that MMP activity on these substrates can enhance the permeability of endothelial barriers by destroying these junctions [203-209]. Therefore, enhanced MMP levels in malaria might facilitate BBB leakage.…”

Section: Introductionmentioning

confidence: 99%

Host matrix metalloproteinases in cerebral malaria: new kids on the block against blood–brain barrier integrity?

Polimeni

Prato

2014

Fluids Barriers CNS

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Cerebral malaria (CM) is a life-threatening complication of falciparum malaria, associated with high mortality rates, as well as neurological impairment in surviving patients. Despite disease severity, the etiology of CM remains elusive. Interestingly, although the Plasmodium parasite is sequestered in cerebral microvessels, it does not enter the brain parenchyma: so how does Plasmodium induce neuronal dysfunction? Several independent research groups have suggested a mechanism in which increased blood–brain barrier (BBB) permeability might allow toxic molecules from the parasite or the host to enter the brain. However, the reported severity of BBB damage in CM is variable depending on the model system, ranging from mild impairment to full BBB breakdown. Moreover, the factors responsible for increased BBB permeability are still unknown. Here we review the prevailing theories on CM pathophysiology and discuss new evidence from animal and human CM models implicating BBB damage. Finally, we will review the newly-described role of matrix metalloproteinases (MMPs) and BBB integrity. MMPs comprise a family of proteolytic enzymes involved in modulating inflammatory response, disrupting tight junctions, and degrading sub-endothelial basal lamina. As such, MMPs represent potential innovative drug targets for CM.

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Synthetic gelatinases inhibitor attenuates electromagnetic pulse-induced blood–brain barrier disruption by inhibiting gelatinases-mediated ZO-1 degradation in rats

Cited by 27 publications

References 41 publications

Effects of electromagnetic pulse exposure on gelatinase of blood–brain barrierin vitro

Effects of electromagnetic pulse exposure on gelatinase of blood–brain barrierin vitro

MMPs 2 and 9 are essential for coronary collateral growth and are prominently regulated by p38 MAPK

Host matrix metalloproteinases in cerebral malaria: new kids on the block against blood–brain barrier integrity?

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