Abstract
Neonatal hypoxic-ischemic (HI) brain injury is a devastating disease that often leads to death and detrimental neurological deficits. The present study was designed to evaluate the ability of metformin to provide neuroprotection in a model of neonatal hypoxic-ischemic brain injury and to study the associated molecular mechanisms behind these protective effects. Here, we found that metformin treatment remarkably attenuated brain infarct volumes and brain edema at 24 h after HI injury, and the neuroprotection of metformin was associated with inhibition of neuronal apoptosis, suppression of the neuroinflammation and amelioration of the blood brain barrier breakdown. Additionally, metformin treatment conferred long-term protective against brain damage at 7 d after HI injury. Our study indicates that metformin treatment protects against neonatal hypoxic-ischemic brain injury and thus has potential as a therapy for this disease.
Highlights
Neonatal hypoxic-ischemic (HI) brain injury remains a major contributor to high mortality and lifelong morbidity in neonates, along with a reported incidence of 1-8 per 1000 live births in developed countries and 26 per 1000 live births in developing countries [1]
We found that metformin treatment remarkably attenuated brain infarct volumes and brain edema at 24 h after HI injury, and the neuroprotection of metformin was associated with inhibition of neuronal apoptosis, suppression of the neuroinflammation and amelioration of the blood brain barrier breakdown
Metformin treatment reduces infarct volume and ameliorates brain edema To make sure whether treatment of metformin was able to exert a protective effect on neonatal rats following hypoxia-ischemia, metformin was administered immediately after HI, the infarct volume was measured to evaluate the extent of brain damage at 24 h post HI via TTC staining
Summary
Neonatal hypoxic-ischemic (HI) brain injury remains a major contributor to high mortality and lifelong morbidity in neonates, along with a reported incidence of 1-8 per 1000 live births in developed countries and 26 per 1000 live births in developing countries [1]. 10% to 20% of affected infants will die during the postnatal period, and up to 25% of the survivors will develop longterm and irreversible neurological deficits, including neurodevelopmental impairment, epilepsy, learning difficulties and cerebral palsy [2]. Toll-like receptors (TLRs) are first-line molecules for initiating innate immune responses. Among all TLRs, Toll-like receptor (TLR4) has been shown to widely express on microglia, and mediates neuroinflammatory diseases www.impactjournals.com/oncotarget through activation of innate immunity [8]. Recent studies have shown that the expression of TLR4 is up-regulated in a neonatal rat model of hypoxic-ischemic brain injury [9] and in microglia exposed to hypoxic treatment in vitro [10]. TLR4/NFκB signaling pathway provides the potential therapeutic target for neonatal hypoxic-ischemic brain damage
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