| dc.description.abstract | Background Perinatal hypoxia-ischemia (HI) is the leading cause of morbidity and mortality among infants worldwide. Currently, the only approved treatment for infants suffering from HI injury is hypothermia, which has a lot of limitations. Hence, there is a pressing need for new therapies. One promising option in the treatment of perinatal HI is mesenchymal stem cell (MSC) therapy, which is effective in reducing lesion size and improving motor and cognitive impairment. However, there is still room to optimise this MSC therapy. Nutritional interventions might be a viable new option, as they can be rapidly implemented in the clinic and are generally considered safe. One such nutritional intervention is the omega-3 fatty acid docosahexaenoic acid (DHA), which has neuroprotective effects by acting anti-apoptotic, anti-inflammatory, and pro-regenerative. DHA bound to lysophosphatidylcholine (LPC) seems to lead to targeted enrichment of brain DHA and corresponding functional improvement. Therefore, this study combined LPC-DHA with MSC therapy to increase the treatment effect in a mouse model of perinatal HI. Besides, in vitro neuronal cell culture experiments were performed to unravel the mechanisms behind (LPC-)DHA treatment.
Methods C57Bl/6 mice were subjected to HI injury at postnatal day 9 (P9) followed by a daily oral gavage of LPC-DHA between P9 and P15. At P12, MSCs were administered intranasally to the HI injured mice. At P37, brains were collected and used for immunohistological analysis. Coronal sections at bregma level -1.34 were stained for microtubule-associated protein 2 (MAP2), myelin basic protein (MBP), and chicken ovalbumin upstream promoter transcription factor-interacting protein 2 (CTIP2) to examine the grey matter, white matter, and cortical organization, respectively. In vitro, the anti-inflammatory effects of DHA were examined in primary microglia cultures. Besides, the neuroprotective effects of both DHA and LPC-DHA were examined in H2O2, etoposide and oxygen glucose deprivation (OGD) hit models using the neuronal SH-SY5Y cell line.
Results A combined treatment of LPC-DHA with MSCs can decrease grey matter loss and restore the balance of deeper layer pyramidal neuron density within the somatosensory cortex of HI injured mice, whereas separate treatments with LPC-DHA or MSCs could not. Moreover, our in vitro studies show DHA has anti-inflammatory effects and increases cell viability after an H2O2 and OGD hit, but not after an etoposide hit. LPC-DHA also increases cell viability after an H2O2 hit, but decreases cell viability after an etoposide or OGD hit.
Conclusion Our study indicates a combined treatment with LPC-DHA and MSCs aids in brain recovery after perinatal HI in mice. The action of LPC-DHA is possibly exhibited by anti-oxidant, anti-inflammatory and proliferative action. Future research should further optimize and unravel the mechanism behind a treatment combining LPC-DHA and MSCs to take the next step towards improved treatment for infants suffering from perinatal HI.
Keywords: Perinatal hypoxia-ischemia; Mesenchymal stem cells; Lysophosphatidylcholine; Docosahexaenoic acid. | |
