Abstract
The heightened vulnerability of premyelinating oligodendrocytes (PreOLs) in response to hypoxia–ischemia may contribute to perinatal white matter injury and subsequent neurobehavioral dysfunction. Intracellular Ca2+ overload is considered a crucial mechanism predisposing PreOLs to ischemic injury. We previously reported that catalpol, an iridoid glycoside extracted from Rehmannia root, inhibits intracellular Ca2+ overload of PreOLs in an in vitro ischemia model. However, the exact underlying mechanisms remain elusive. In the present study, we aimed to investigate the protective effects of catalpol on PreOLs and to explore the underlying mechanisms involved in the modulation of intracellular Ca2+ homeostasis. Postnatal day 2 (P2) Sprague-Dawley (SD) rats subjected to bilateral common carotid artery ligation followed by exposure to 8% oxygen for 10 min were used as a rat model of neonatal hypoxia–ischemia. We found that catalpol significantly improved behavioral functions and prevented PreOL loss and myelination deficit after hypoxia–ischemia. Our in vitro studies also confirmed the direct effects of catalpol on oxygen-glucose deprivation (OGD)-induced cell death and arrested maturation of PreOLs. Moreover, we demonstrated that catalpol significantly inhibited intracellular Ca2+ overload and promoted the expression of Na+/Ca2+ exchanger 3 (NCX3). Finally, we found that catalpol significantly reduced mitochondrial damage and subsequent extracellular signal-regulated kinase 1/2 (ERK1/2) and poly-ADP-ribose polymerase-1 (PARP-1) activation. Treatment with NCX3-preferring inhibitor 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R7943) significantly reversed the protective effects of catalpol on PreOLs under OGD. Overall, our data suggest that catalpol protects PreOLs from ischemic injury through regulation of intercellular Ca2+ homeostasis via upregulation of NCX3 activity.
Highlights
Periventricular white matter injury is a predominant form of perinatal brain injury and hypoxia–ischemia is thought to be the leading cause [1]
The results of Rotarod test showed that the average latency time that the vehicle-treated (Veh) group remained on the cylinder was decreased to 48.47% of that of the sham-control (Sha) group (p < 0.01), demonstrating the motor dysfunction caused by hypoxia–ischemia
We found that catalpol remarkably improved both behavioral functions and myelination by preventing premyelinating oligodendrocytes (PreOLs) loss in a neonatal hypoxia-ischemia rat model
Summary
Periventricular white matter injury is a predominant form of perinatal brain injury and hypoxia–ischemia is thought to be the leading cause [1]. When intracellular Ca2+ homeostasis is perturbed by ischemia, an elevation in cytosolic Ca2+ concentration occurs, which is attributable to Ca2+ influx through the plasma membrane and intracellular stores [7]. This massive Ca2+ influx causes excessive activation of Ca2+-dependent signaling pathways, leading to the damage or death of OL lineage cells [7,8]. Recent evidence has suggested that dysfunction of plasma membrane Ca2+ extrusion systems may contribute to sustained intracellular Ca2+ overload following ischemic brain damage by blocking the extrusion of excess cytosolic Ca2+ [9,10]
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