After Ischemic Stroke, Minocycline Promotes a Protective Response in Neurons via the RNA-Binding Protein HuR, with a Positive Impact on Motor Performance

Abstract

Ischemic stroke is the most common cause of adult disability and one of the leading causes of death worldwide, with a serious socio-economic impact. In the present work, we used a new thromboembolic model, recently developed in our lab, to induce focal cerebral ischemic (FCI) stroke in rats without reperfusion. We analyzed selected proteins implicated in the inflammatory response (such as the RNA-binding protein HuR, TNFα, and HSP70) via immunohistochemistry and western blotting techniques. The main goal of the study was to evaluate the beneficial effects of a single administration of minocycline at a low dose (1 mg/kg intravenously administered 10 min after FCI) on the neurons localized in the penumbra area after an ischemic stroke. Furthermore, given the importance of understanding the crosstalk between molecular parameters and motor functions following FCI, motor tests were also performed, such as the Horizontal Runway Elevated test, CatWalk™ XT, and Grip Strength test. Our results indicate that a single administration of a low dose of minocycline increased the viability of neurons and reduced the neurodegeneration caused by ischemia, resulting in a significant reduction in the infarct volume. At the molecular level, minocycline resulted in a reduction in TNFα content coupled with an increase in the levels of both HSP70 and HuR proteins in the penumbra area. Considering that both HSP70 and TNF-α transcripts are targeted by HuR, the obtained results suggest that, following FCI, this RNA-binding protein promotes a protective response by shifting its binding towards HSP70 instead of TNF-α. Most importantly, motor tests showed that reduced inflammation in the brain damaged area after minocycline treatment directly translated into a better motor performance, which is a fundamental outcome when searching for new therapeutic options for clinical practice.

LOX-1 and MMP-9 Inhibition Attenuates the Detrimental Effects of Delayed rt-PA Therapy and Improves Outcomes After Acute Ischemic Stroke

“…These previous data in Supplemental Material demonstrate that targeting the vasculature can lead to improved stroke outcomes. 74,77,78 BI-0115 is a selective LOX-1 inhibitor that prevents the binding of the LOX-1 receptor and therefore inhibits the signaling cascade and possibly the upregulation of MMP-9. In comparison, JNJ0966 is a direct MMP-9 inhibitor that prevents the activation of MMP-9 by binding allosterically to the protease.…”

Histopathological lesions induced by stroke in the encephalon

“…Stroke is one of the leading causes of death worldwide and the most common cause of disability among adults, having a serious impact on the patient and family, but also upon the social and economic life [ 15 ]. The average cost of ischemic stroke per person, which includes inpatient care, rehabilitation, and aftercare, is estimated at 140 048 dollars in the United States [ 16 , 17 ].…”

Minocycline alleviates LPS-induced cognitive dysfunction in mice by inhibiting the NLRP3/caspase-1 pathway

“…Its neuroprotective effects within the central nervous system (CNS) are facilitated by the blood-brain barrier (BBB). Research findings have indicated that MINO possess a safeguarding influence on central nervous system (CNS) disorders, namely depression [ 7 ], ischemic stroke [ 8 ], AD [ 9 ], and PD [ 10 ]. Thus far, evidence has demonstrated that MINO mitigates cognitive dysfunction by diminishing inflammation and apoptosis [ 11 , 12 ].…”