Novel GLP-1/GIP Dual Receptor Agonist Alleviates Neonatal Hypoxic-Ischemic Encephalopathy by Inhibiting TLR2/NF-κB/NLRP3 Mediated-Neuroinflammation

Abstract

Hypoxic-ischemic encephalopathy (HIE) is an irreversible brain injury attributable to impaired blood oxygen delivery in the brain after perinatal asphyxia. The pathogeny of HIE is very complex, and there is still shortage of effective treatment. DA5-CH is a novel dual receptor agonist of glucose dependent insulin stimulating polypeptide (GIP) and glucagon like peptide-1 (GLP-1). However, the function and mechanism of DA5-CH in HIE remain unclear. In this paper, cultured cortical neurons were exposed to oxygen-glucose deprivation (OGD) and neonatal rats were subjected to hypoxic-ischemic damage to explore the protective effects of DA5-CH. Our work revealed that DA5-CH markedly increased cell viability, reduced intracellular ROS levels and DNA damage, and decreased cell apoptosis in OGD-treated cultured cortical neurons. In vivo, DA5-CH treatment significantly improved cognitive dysfunction and neuronal damage, decreased the infarct volume and neuronal death of hypoxic-ischemic (HI) neonatal rats. In addition, DA5-CH decreased TNFα, IL-1β and IL-6 levels in cortical tissue of HI neonatal rats and in microglia cells subjected to OGD. Moreover, DA5-CH treated microglia medium increased the cell viability, but decreased apoptosis of cortical neurons. DA5-CH suppressed NLRP3 inflammasome activation through inactivation of the TLR2/NF-κB signalling pathway. Furthermore, the protective effects of DA5-CH on the hypoxic-ischemic brain injury were antagonized by nigericin (an NLRP3 agonist). Taken together, our findings revealed that DA5-CH alleviates neonatal hypoxic-ischemic encephalopathy by inhibiting TLR2/NF-κB/NLRP3 mediated-neuroinflammation.