Hypoxic-ischemic (HI) injury is one of the initial factors contributing to neonatal brain injury. Src family kinases (SFKs) are considered to act as molecular hubs for N-methyl-d-aspartate receptor (NMDAR) regulation and participate in the HI injury process. The objectives of this study were to evaluate the levels of phospho-Src (p-Src), the relationship between NMDARs and SFKs, and the effects of SFK inhibition on an immature rat HI brain injury model. The model was induced in 3-day-old Sprague–Dawley rats using the Rice-Vannucci model operation. The level of p-Src was evaluated using Western blotting. The association of NMDARs with SFKs was detected using Western blotting and coimmunoprecipitation. After intraperitoneal injection of 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine (PP2), an SFK-selective inhibitor, neuropathological changes were observed by performing H&E and immunofluorescence staining, and the neurological functions were assessed using the following behavioral tests: modified neurological severity score, open field test, and Morris water maze test. The levels of p-Src first decreased at 0 h after injury, increased at 2 h after injury, and continuously decreased from 6 h to 3 days. Along with the increased p-Src levels observed at 2 h after injury, the phosphorylation of NMDAR subunit NR2B at tyrosine 1472 was increased. Following the administration of PP2, the increased p-Src and NMDAR-2B levels detected at 2 h after injury were decreased, and tissue injury and myelin basic protein expression were improved at 7 days after injury. The PP2 intervention improved the performance of injured rats on behavioral tests. In conclusion, we determined the patterns of p-Src expression after HI brain injury in immature rats and showed a relationship with the activated NMDA receptor. The inhibition of p-Src ameliorates neuropathological changes and damages neurological functions induced by HI injury.
Preterm birth is a global public health problem. A large number of preterm infants survive with preterm white matter injury (PWMI), which leads to neurological deficits, and has multifaceted etiology, clinical course, monitoring, and outcomes. The principal upstream insults leading to PWMI initiation are hypoxia‐ischemia and infection and/or inflammation and the key target cells are late oligodendrocyte precursor cells. Current PWMI treatments are mainly supportive, and thus have little effect in terms of protecting the immature brain or repairing injury to improve long‐term outcomes. Umbilical cord blood (UCB) cells comprise abundant immunomodulatory and stem cells, which have the potential to reduce brain injury, mainly due to anti‐inflammatory and immunomodulatory mechanisms, and also through their release of neurotrophic or growth factors to promote endogenous neurogenesis. In this review, we briefly summarize PWMI pathogenesis and pathophysiology, and the specific properties of different cell types in UCB. We further explore the potential mechanism by which UCB can be used to treat PWMI, and discuss the advantages of and potential issues related to UCB cell therapy. Finally, we suggest potential future studies of UCB cell therapy in preterm infants.
Hypoxic-ischemic (HI) induced perinatal white matter injury (PWMI) is a major cause of neurologic disabilities characterized by selective oligodendroglial death and myelin disruption. Galectin-3 (Gal-3) modulates postnatal subventricular zone gliogenesis and attenuates ischemic injury. However, the association between Gal-3 and myelin formation still remains unclear. In this study, we first perform Gal-3 knockdown (KD) to identify the importance of Gal-3 on myelin formation. Our results show impeded myelin formation, manifested by Olig2/CC1 (+) mature oligodendrocytes number, expression of oligodendroglial maturation-associated markers (MBP and CNPase), and myelin thickness and integrity. Then we perform recombinant Gal-3 (rGal-3) administration by intracerebroventricular injection. Notably, although rGal-3 administration shows no beneficial effect on oligodendrogenesis and myelin formation under normal condition, our results show that rGal-3 administration attenuates cognitive deficits and drives remyelination after PWMI, which are coupled to signs of enhanced myelin resiliency and cognition. Also, our results indicates that the significant increases in substrates for remyelination of rGal-3 administration are accompanied by enhanced Iba-1 (microglia marker)/ Mrc1 (M2 marker) (+) microglia and decreased Iba-1/ iNOS (M1 marker) (+) microglia. Altogether, our data in this research confirm the association between Gal-3 and myelin formation, underscore its position for the capacity for remyelination and restoration of function, and unveils the efficacy of rGal-3 administration with anti-inflammatory phenotype microglia (M2 microglia) activation. Thus, the findings suggest that Gal-3 plays a significant role in myelin formation and remyelination restoration.
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