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

Abstract

BackgroundMinocycline, 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.MethodsFocal 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.ResultsMCPIP1 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.ConclusionsOur in vitro and in vivo studies demonstrate that MCPIP1 is an important mediator of minocycline-induced protection from brain ischemia.

Minocycline Suppresses NLRP3 Inflammasome Activation in Experimental Ischemic Stroke

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Minocycline Inhibits Inflammation and Squamous Metaplasia of Conjunctival Tissue Culture in Airlift Conditions

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Modulation of Sox10, HIF-1α, Survivin, and YAP by Minocycline in the Treatment of Neurodevelopmental Handicaps following Hypoxic Insult

“…These studies i) demonstrate the beneficial effects of minocycline treatment following hypoxic insult and add to the growing literature of this repurposed therapeutic as a beneficial agent in promoting neuroprotection, neuronal remodeling, and improving neuronal behaviors 64,66,67 ; ii) document the up-regulation of Sox10, HIF1A, and several of the genes associated with proliferation and apoptosis (survivin and YAP), myelination in neurogenic zones and improved cognitive function; and iii) support the possibility of minocycline as a potential transient therapeutic drug in the treatment of the neurodevelopmental handicaps observed in the very premature newborn population. In addition, these studies may aid in the further interpretation of minocycline's effects in the ongoing treatment trials and animal model studies of fragile X syndrome and multiple sclerosis.…”