Therapeutic application of gene silencing MMP-9 in a middle cerebral artery occlusion-induced focal ischemia rat model

Hu, Qin; Chen, Chunhua; Yan, Junhao; Yang, Xiaomei; Shi, Xiaoming; Zhao, Jing; Lei, Jiliang; Yang, Lei; Wang, Ke; Chen, Lin; Huang, Hongyun; Han, Jing‐Yan; Zhang, Junyi; Zhou, Changman

doi:10.1016/j.expneurol.2008.11.007

Cited by 84 publications

(79 citation statements)

References 58 publications

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“…Moreover, it has been reported that the inhibition of LFA-1 could be a potential therapeutic pathway to both inflammation and autoimmune diseases [18]. Moreover, MMP-9 gene silencing has been applied as an important therapeutic alternative for patients with cerebral ischemia, and the treatment was very effective in decreasing the brain water content of patients [7]. Based on the aforementioned information, we inferred that lentivirus-mediated gene silencing of LFA-1 could result in the reduction of brain water content in ischemia area of rats.…”

Section: Discussionmentioning

confidence: 99%

“…LFA-1 plays an essential role in immune cell trafficking and activation, and is a major contributor to the hots defense [6]. Based on a previously conducted study on the therapeutic application of MMP-9 gene silencing in focal ischemia presented us with the disruption of blood-brain barrier, brain water content, and reduction of neurological deficits due to MMP-9 siRNA treatment, indicating that the gene silencing of specific gene could provide an effective strategy in the treatment of cerebral ischemia [7]. Therefore, we came up with the hypothesis that the LFA-1 gene silencing mediated by lentivirus may have pro-regulatory effects on the hippocampal neurons in rats with acute cerebral ischemia after cerebral lymphatic blockage.…”

Section: Introductionmentioning

confidence: 99%

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Lentivirus-Mediated Gene Silencing of Lymphocyte Function-Associated Antigen 1 Inhibits Apoptosis of Hippocampal Neurons in Rats with Acute Cerebral Ischemia After Cerebral Lymphatic Blockage

Yu¹,

Li²,

Che³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cerebral ischemia is considered to be the most common cause of stroke with high mortality. It occurs as a result of the damage of the hippocampal neurons with lymphocyte function–associated antigen (LFA)-1 being emphasized to play a role in the biological functions of hippocampal neurons. This study was conducted in order to investigate the effects of specific knockdown of LFA-1 expression by lentivirus had on the apoptosis of the hippocampal neurons, simulated by rat models of acute cerebral ischemia after cerebral lymphatic blockage. Methods: A total of 60 Wistar rats were selected as subjects, among which 50 were used to establish models of the acute cerebral ischemia after cerebral lymphatic blockage, while the remaining 10 rats were treated with the sham operation. The underlying regulatory mechanisms regarding LFA-1 were analyzed with the treatment of si-LFA-1 and LFA-1 vector in the hippocampal CA1 area of brain tissues isolated from the rats with acute cerebral ischemia. The brain water content, electrolyte content, and blood-brain barrier permeability located in ischemic area of rats were measured. TUNEL staining and immunochemistry methods were employed in order to determine the apoptosis rate and positive levels of LFA-1, MMP-9, and Caspase-3. The mRNA and protein levels of related genes were also detected by means of RT-qPCR and western blot assay. Results: The brain water content, Na⁺ and Ca⁺ contents, blood-brain barrier permeability, apoptosis rate, positive levels of LFA-1, MMP-9, and Caspase-3 were decreased, and the K⁺ content was increased in ischemic tissues treated with si-LFA-1. The mRNA and protein levels of LFA-1, MMP-9, Caspase-3, and Bax had all decreased, while the mRNA and protein levels of Bcl-2 were elevated in the hippocampal CA1 area of rat brain tissues treated with si-LFA-1. These situations could be reversed through the up-regulation of LFA-1. Conclusion: In conclusion, LFA-1 gene silencing could improve the acute cerebral ischemia after cerebral lymphatic blockage by inhibiting apoptosis of the hippocampal neurons in rats.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lentivirus-Mediated Gene Silencing of Lymphocyte Function-Associated Antigen 1 Inhibits Apoptosis of Hippocampal Neurons in Rats with Acute Cerebral Ischemia After Cerebral Lymphatic Blockage

Yu¹,

Li²,

Che³

et al. 2018

Cell Physiol Biochem

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“…Manipulation of either MMP-9 or MMP-12 by neutralizing antibodies or siRNA-/shRNAmediated gene silencing attenuated the brain damage in rats after ischemic stroke [4][5][6][7][8]. HUCB-MSCs treatment in spinal cord injured rats prevented the dysregulation of various MMPs including MMP-9 and MMP-12 as well as improved their locomotor recovery [9,31].…”

Section: Discussionmentioning

confidence: 99%

“…The temporal expression profile of various MMPs in ischemic rat brains after focal cerebral ischemia and reperfusion revealed that MMP-9 and MMP-12 were upregulated (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) fold in case of MMP-9 and 47-265 fold in case of MMP-12 through days 1 to 7 after reperfusion) several fold higher than any other MMPs tested [4]. Evidence also suggests the detrimental role of MMP-9 and MMP-12 on post-stroke brain damage [4][5][6][7][8]. In the recent past, we demonstrated the prevention of MMPs induction in human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) treated spinal cord injured rats [9].…”

Section: Introductionmentioning

confidence: 97%

Mesenchymal Stem Cell Treatment Prevents Post-Stroke Dysregulation of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases

Chelluboina

Nalamolu

Mendez

et al. 2017

Cell Physiol Biochem

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Background/Aims: Stem cell treatment is one of the potential treatment options for ischemic stroke. We recently demonstrated a protective effect of human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) in a rat model of ischemic stroke. The treatment attenuated apoptosis and prevented DNA damage. A collection of published studies, including several from our laboratory, indicated the induction and detrimental role for several matrix metalloproteinases (MMPs) in post-stroke brain injury. We hypothesized that the HUCB-MSCs treatment after focal cerebral ischemia prevents the dysregulation of MMPs and induces the expression of endogenous tissue inhibitors of metalloproteinases (TIMPs) to neutralize the elevated activity of MMPs. Methods: To test our hypothesis, we administered HUCBMSCs (0.25 million cells/animal and 1 million cells/animal) intravenously via tail vein to male Sprague-Dawley rats that were subjected to a transient (two-hour) right middle cerebral artery occlusion (MCAO) and one-day reperfusion. Ischemic brain tissues obtained from various groups of rats seven days after reperfusion were subjected to real-time PCR, immunoblot, and immunofluorescence analysis. Results: HUCB-MSCs treatment prevented the induction of MMPs, which were upregulated in ischemia-induced rats that received no treatment. HUCBMSCs treatment also prevented the induction of TIMPs expression. The extent of prevention of MMPs and TIMPs induction by HUCB-MSCs treatment is similar at both the doses tested. Conclusion: Prevention of stroke-induced MMPs upregulation after HUCB-MSCs treatment is not mediated through TIMPs upregulation.

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“…MMP-9 knockout in mice protected from BBB disruption in a cerebral ischemia model [58]. MMP-9 siRNA or shRNA treatment reduced Evans blue and IgG extravasation at 24 h of reperfusion in rodent ischemic stroke models [60,61]. In addition, broad-spectrum or specific MMP-9 inhibitors also reduced BBB damage in cerebral ischemia models [49,56,62].…”

Section: Mechanisms Of T-pa-induced Htmentioning

confidence: 99%

Targeting ONOO<sup>-</sup>/HMGB1/MMP-9 Signaling Cascades: Potential for Drug Development from Chinese Medicine to Attenuate Ischemic Brain Injury and Hemorrhagic Transformation Induced by Thrombolytic Treatment

Chen¹,

Guan²,

Shen³

2016

Integr Med Int

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Stroke is the leading cause of death and disability worldwide, and ischemic stroke accounts for more than 85% of the stroke incidence. Tissue plasminogen activator (t-PA) is the only FDA-approved drug for ischemic stroke treatment with a narrow treatment time window of 4.5 h. Hemorrhagic transformation (HT) is a severe complication of delayed t-PA treatment in ischemic stroke. Thus, it is critically important to develop combination therapies to reduce HT and extend the therapeutic time window of t-PA. Current progress suggests that peroxynitrite (ONOO^-)/high-mobility group box 1 protein (HMGB1)/matrix metalloproteinase-9 (MMP-9) signaling cascades could be important for attenuating HT during thrombolytic treatment for acute ischemic stroke. Recently, important progress has been made in seeking for natural compounds from Chinese medicine for reducing ischemic stroke injury, with some of them targeting ONOO^-/HMGB1/MMP-9 signaling cascades. Herein, we analyze the roles and interactions of these three targets in mediating HT; subsequently, we summarize the potential compounds from Chinese herbal medicine for attenuating HT and analyze the related targets. Finally, we raise the potential issues to be addressed in further development of these compounds as combination therapy.

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Therapeutic application of gene silencing MMP-9 in a middle cerebral artery occlusion-induced focal ischemia rat model

Cited by 84 publications

References 58 publications

Lentivirus-Mediated Gene Silencing of Lymphocyte Function-Associated Antigen 1 Inhibits Apoptosis of Hippocampal Neurons in Rats with Acute Cerebral Ischemia After Cerebral Lymphatic Blockage

Lentivirus-Mediated Gene Silencing of Lymphocyte Function-Associated Antigen 1 Inhibits Apoptosis of Hippocampal Neurons in Rats with Acute Cerebral Ischemia After Cerebral Lymphatic Blockage

Mesenchymal Stem Cell Treatment Prevents Post-Stroke Dysregulation of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases

Targeting ONOO<sup>-</sup>/HMGB1/MMP-9 Signaling Cascades: Potential for Drug Development from Chinese Medicine to Attenuate Ischemic Brain Injury and Hemorrhagic Transformation Induced by Thrombolytic Treatment

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