Abstract
Hypoxic–ischemic encephalopathy (HIE) is a devastating neurological event that contributes to the prolonged neurodevelopmental consequences in infants. Therapeutic strategies focused on attenuating neuronal apoptosis in the penumbra appears to be promising. Given the increasingly recognized neuroprotective roles of adipokines in HIE, we investigated the potential anti-apoptotic roles of a novel member of adipokines, Chemerin, in an experimental model of HIE. In the present study, 10-day-old rat pups underwent right common carotid artery ligation followed by 2.5 h hypoxia. At 1 h post hypoxia, pups were intranasally administered with human recombinant chemerin (rh-chemerin). Here, we showed that rh-chemerin prevented the neuronal apoptosis and degeneration as evidenced by the decreased expression of the pro-apoptotic markers, cleaved caspase 3 and Bax, as well as the numbers of Fluoro-Jade C and TUNEL-positive neurons. Furthermore, rh-Chemerin reversed neurological and morphological impairments induced by hypoxia–ischemia in neonatal rats at 24 h and 4 weeks after HIE. In addition, chemerin-mediated neuronal survival correlated with the elevation of chemerin receptor 23 (chemR23), phosphorylated calmodulin-dependent protein kinase kinase 2 (CAMKK2), as well as phosphorylated adenosine monophosphate-activated protein kinase (AMPK). Specific inhibition of chemR23, CAMKK2, and AMPK abolished the anti-apoptotic effects of rh-chemerin at 24 h after HIE, demonstrating that rh-chemerin ameliorated neuronal apoptosis partially via activating chemR23/CAMKK2/AMPK signaling pathway. Neuronal apoptosis is a well-established contributing factor of pathological changes and the neurological impairment after HIE. These results revealed mechanisms of neuroprotection by rh-chemerin, and indicated that activation of chemR23 might be harnessed to protect from neuronal apoptosis in HIE.
Highlights
Hypoxic–ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in infants, and perinatal brain damage leads to life-long neurodevelopmental consequences, such as cerebral palsy, cognitive deficits, and mental retardation[1,2,3,4]
Double immunofluorescence labeling detected a robust increase in chemerin and chemerin receptor 23 (chemR23) expression in cortical neurons around the peri-infarct area compared to Sham pups and the contralateral control following HIE (Fig. 1a, Supplementary Fig. 1)
Considering chemerin has two other receptors, we evaluated the expression of endogenous G protein-coupled receptor 1 (GPR1) and chemokine receptor-like 2 (CCRL2) following HIE
Summary
Hypoxic–ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in infants, and perinatal brain damage leads to life-long neurodevelopmental consequences, such as cerebral palsy, cognitive deficits, and mental retardation[1,2,3,4]. Several factors have been proposed to be involved in neonates with ischemic brain injury, such as oxidative stress, inflammation, apoptosis. Zhang et al Cell Death and Disease (2019)10:97. Page 2 of 15 97 and necrosis[5] Among these factors, accumulating data suggest that apoptotic mechanisms play a fundamental role in the pathogenesis of ischemic brain injury in neonatal rodents[2,5]. Adipokines, known as adipocyte-derived secretory factors, have been well documented in metabolic diseases[6]. Recent data provided a new sight into the neuroprotective action of adipokines in ischemic stroke. Intrastriatal administration of exogenous adipokines ameliorated neuronal apoptosis and decreased infraction size in rats with cerebral ischemic injury[7], while in vivo knockdown of endogenous adipokines exacerbated the ischemic stroke outcomes[8], indicating that adipokines might be a promising treatment strategy for HIE-induced neuronal apoptosis
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