Limits...
MCP-induced protein 1 mediates the minocycline-induced neuroprotection against cerebral ischemia/reperfusion injury in vitro and in vivo.

Jin Z, Liang J, Wang J, Kolattukudy PE - J Neuroinflammation (2015)

Bottom Line: Minocycline, a broad-spectrum tetracycline antibiotic, has shown anti-inflammatory and neuroprotective effects in ischemic brain injury.Similarly, in vitro data showed that minocycline significantly induced the expression of MCPIP1 in primary neuron-glial cells, cortical neurons, and reduced oxygen glucose deprivation (OGD)-induced cell death.Our in vitro and in vivo studies demonstrate that MCPIP1 is an important mediator of minocycline-induced protection from brain ischemia.

View Article: PubMed Central - PubMed

Affiliation: School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China. jinzq@hotmail.com.

ABSTRACT

Background: Minocycline, a broad-spectrum tetracycline antibiotic, has shown anti-inflammatory and neuroprotective effects in ischemic brain injury. The present study seeks to determine whether monocyte chemotactic protein-induced protein 1 (MCPIP1), a recently identified modulator of inflammatory reactions, is involved in the cerebral neuroprotection conferred by minocycline treatment in the animal model of focal cerebral ischemia and to elucidate the mechanisms of minocycline-induced ischemic brain tolerance.

Methods: Focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 2 h in male C57BL/6 mice and MCPIP1 knockout mice followed by 24- or 48-h reperfusion. Twelve hours before ischemia or 2 h after MCAO, mice were injected intraperitoneally with 90 mg/kg of minocycline hydrochloride. Thereafter, the animals were injected twice a day, at a dose of 90 mg/kg after ischemia until sacrificed. Transcription and expression of MCPIP1 gene was monitored by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry. The neurobehavioral scores, infarction volumes, and proinflammatory cytokines in brain and NF-κB signaling were evaluated after ischemia/reperfusion.

Results: MCPIP1 protein and mRNA levels significantly increased in mouse brain undergoing minocycline pretreatment. Minocycline treatment significantly attenuated the infarct volume, neurological deficits, and upregulation of proinflammatory cytokines in the brain of wild type mice after MCAO. MCPIP1-deficient mice failed to evoke minocycline-treatment-induced tolerance compared with that of the control MCPIP1-deficient group without minocycline treatment. Similarly, in vitro data showed that minocycline significantly induced the expression of MCPIP1 in primary neuron-glial cells, cortical neurons, and reduced oxygen glucose deprivation (OGD)-induced cell death. The absence of MCPIP1 blocked minocycline-induced protection on neuron-glial cells and cortical neurons treated with OGD.

Conclusions: Our in vitro and in vivo studies demonstrate that MCPIP1 is an important mediator of minocycline-induced protection from brain ischemia.

No MeSH data available.


Related in: MedlinePlus

Reduction in inflammatory cytokine expression in ischemic brain by minocycline treatment in the wild type, but not in MCPIP1-deficient mice. The results showed that the expression levels of TNFα, IL-1β, IL-6, and MCP-1 were significantly elevated in shams in MCPIP1-deficient mice than that of wild type and that the expression levels of TNFα, IL-1β, IL-6, and MCP-1 were significantly reduced at 24 h after MCAO in minocycline-pretreated wild type mice compared to that of the control. In the MCPIP1-deficient mice, there was no significant difference in proinflammatory cytokine expression between minocycline-pretreated and control group without minocycline treatment. The MCPIP1 mRNA level in mouse brain was significantly induced by minocycline treatment compared to controls in wild type mice. Significant increase of MCPIP1 transcript level was detected at 24 h after minocycline treatment after ischemic stroke (P < 0.01). Values represent mean ± SD, n = 6 mice per group. MCPIP1, monocyte chemotactic protein-induced protein 1; MCP-1, monocyte chemotactic protein 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4359584&req=5

Fig5: Reduction in inflammatory cytokine expression in ischemic brain by minocycline treatment in the wild type, but not in MCPIP1-deficient mice. The results showed that the expression levels of TNFα, IL-1β, IL-6, and MCP-1 were significantly elevated in shams in MCPIP1-deficient mice than that of wild type and that the expression levels of TNFα, IL-1β, IL-6, and MCP-1 were significantly reduced at 24 h after MCAO in minocycline-pretreated wild type mice compared to that of the control. In the MCPIP1-deficient mice, there was no significant difference in proinflammatory cytokine expression between minocycline-pretreated and control group without minocycline treatment. The MCPIP1 mRNA level in mouse brain was significantly induced by minocycline treatment compared to controls in wild type mice. Significant increase of MCPIP1 transcript level was detected at 24 h after minocycline treatment after ischemic stroke (P < 0.01). Values represent mean ± SD, n = 6 mice per group. MCPIP1, monocyte chemotactic protein-induced protein 1; MCP-1, monocyte chemotactic protein 1.

Mentions: We examined the expression of proinflammatory cytokine transcripts in the ischemic brain of the wild type and MCPIP1 knockout mice with or without minocycline treatment after MCAO. The results showed that the transcript levels of TNFα, IL-1β, IL-6, and MCP-1 were significantly elevated in shams in MCPIP1 knockout mice than that of wild type. The transcript levels of TNFα, IL-1β, IL-6, and MCP-1 were significantly reduced at 24 h after MCAO in minocycline-pretreated wild type mice compared to that of the control group. In the MCPIP1-deficient mice, there was no significant difference in the proinflammatory cytokine expression between the minocycline-pretreated and control group without minocycline treatment (Figure 5). Consistent with the results of Figure 1, the MCPIP1 mRNA level in mouse brain was significantly induced by minocycline treatment compared to the controls in wild type mice. Significant increase of the MCPIP1 transcript level was detected at 24 h after minocycline treatment after ischemic stroke (Figure 5).Figure 5


MCP-induced protein 1 mediates the minocycline-induced neuroprotection against cerebral ischemia/reperfusion injury in vitro and in vivo.

Jin Z, Liang J, Wang J, Kolattukudy PE - J Neuroinflammation (2015)

Reduction in inflammatory cytokine expression in ischemic brain by minocycline treatment in the wild type, but not in MCPIP1-deficient mice. The results showed that the expression levels of TNFα, IL-1β, IL-6, and MCP-1 were significantly elevated in shams in MCPIP1-deficient mice than that of wild type and that the expression levels of TNFα, IL-1β, IL-6, and MCP-1 were significantly reduced at 24 h after MCAO in minocycline-pretreated wild type mice compared to that of the control. In the MCPIP1-deficient mice, there was no significant difference in proinflammatory cytokine expression between minocycline-pretreated and control group without minocycline treatment. The MCPIP1 mRNA level in mouse brain was significantly induced by minocycline treatment compared to controls in wild type mice. Significant increase of MCPIP1 transcript level was detected at 24 h after minocycline treatment after ischemic stroke (P < 0.01). Values represent mean ± SD, n = 6 mice per group. MCPIP1, monocyte chemotactic protein-induced protein 1; MCP-1, monocyte chemotactic protein 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359584&req=5

Fig5: Reduction in inflammatory cytokine expression in ischemic brain by minocycline treatment in the wild type, but not in MCPIP1-deficient mice. The results showed that the expression levels of TNFα, IL-1β, IL-6, and MCP-1 were significantly elevated in shams in MCPIP1-deficient mice than that of wild type and that the expression levels of TNFα, IL-1β, IL-6, and MCP-1 were significantly reduced at 24 h after MCAO in minocycline-pretreated wild type mice compared to that of the control. In the MCPIP1-deficient mice, there was no significant difference in proinflammatory cytokine expression between minocycline-pretreated and control group without minocycline treatment. The MCPIP1 mRNA level in mouse brain was significantly induced by minocycline treatment compared to controls in wild type mice. Significant increase of MCPIP1 transcript level was detected at 24 h after minocycline treatment after ischemic stroke (P < 0.01). Values represent mean ± SD, n = 6 mice per group. MCPIP1, monocyte chemotactic protein-induced protein 1; MCP-1, monocyte chemotactic protein 1.
Mentions: We examined the expression of proinflammatory cytokine transcripts in the ischemic brain of the wild type and MCPIP1 knockout mice with or without minocycline treatment after MCAO. The results showed that the transcript levels of TNFα, IL-1β, IL-6, and MCP-1 were significantly elevated in shams in MCPIP1 knockout mice than that of wild type. The transcript levels of TNFα, IL-1β, IL-6, and MCP-1 were significantly reduced at 24 h after MCAO in minocycline-pretreated wild type mice compared to that of the control group. In the MCPIP1-deficient mice, there was no significant difference in the proinflammatory cytokine expression between the minocycline-pretreated and control group without minocycline treatment (Figure 5). Consistent with the results of Figure 1, the MCPIP1 mRNA level in mouse brain was significantly induced by minocycline treatment compared to the controls in wild type mice. Significant increase of the MCPIP1 transcript level was detected at 24 h after minocycline treatment after ischemic stroke (Figure 5).Figure 5

Bottom Line: Minocycline, a broad-spectrum tetracycline antibiotic, has shown anti-inflammatory and neuroprotective effects in ischemic brain injury.Similarly, in vitro data showed that minocycline significantly induced the expression of MCPIP1 in primary neuron-glial cells, cortical neurons, and reduced oxygen glucose deprivation (OGD)-induced cell death.Our in vitro and in vivo studies demonstrate that MCPIP1 is an important mediator of minocycline-induced protection from brain ischemia.

View Article: PubMed Central - PubMed

Affiliation: School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China. jinzq@hotmail.com.

ABSTRACT

Background: Minocycline, a broad-spectrum tetracycline antibiotic, has shown anti-inflammatory and neuroprotective effects in ischemic brain injury. The present study seeks to determine whether monocyte chemotactic protein-induced protein 1 (MCPIP1), a recently identified modulator of inflammatory reactions, is involved in the cerebral neuroprotection conferred by minocycline treatment in the animal model of focal cerebral ischemia and to elucidate the mechanisms of minocycline-induced ischemic brain tolerance.

Methods: Focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 2 h in male C57BL/6 mice and MCPIP1 knockout mice followed by 24- or 48-h reperfusion. Twelve hours before ischemia or 2 h after MCAO, mice were injected intraperitoneally with 90 mg/kg of minocycline hydrochloride. Thereafter, the animals were injected twice a day, at a dose of 90 mg/kg after ischemia until sacrificed. Transcription and expression of MCPIP1 gene was monitored by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry. The neurobehavioral scores, infarction volumes, and proinflammatory cytokines in brain and NF-κB signaling were evaluated after ischemia/reperfusion.

Results: MCPIP1 protein and mRNA levels significantly increased in mouse brain undergoing minocycline pretreatment. Minocycline treatment significantly attenuated the infarct volume, neurological deficits, and upregulation of proinflammatory cytokines in the brain of wild type mice after MCAO. MCPIP1-deficient mice failed to evoke minocycline-treatment-induced tolerance compared with that of the control MCPIP1-deficient group without minocycline treatment. Similarly, in vitro data showed that minocycline significantly induced the expression of MCPIP1 in primary neuron-glial cells, cortical neurons, and reduced oxygen glucose deprivation (OGD)-induced cell death. The absence of MCPIP1 blocked minocycline-induced protection on neuron-glial cells and cortical neurons treated with OGD.

Conclusions: Our in vitro and in vivo studies demonstrate that MCPIP1 is an important mediator of minocycline-induced protection from brain ischemia.

No MeSH data available.


Related in: MedlinePlus