Catalpol Inhibits Ischemia-Induced Premyelinating Oligodendrocyte Damage through Regulation of Intercellular Calcium Homeostasis via Na⁺/Ca Exchanger 3.

The heightened vulnerability of premyelinating oligodendrocytes (PreOLs) in response to hypoxia⁻ischemia may contribute to perinatal white matter injury and subsequent neurobehavioral dysfunction. Intracellular Ca 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 Ca 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 Ca 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 Ca overload and promoted the expression of Na⁺/Ca 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 Ca homeostasis via upregulation of NCX3 activity.