Intranasal administration of mesenchymal stem cell secretome reduces hippocampal oxidative stress, neuroinflammation and cell death, improving the behavioral outcome following perinatal asphyxia

Farfan, N.Carril, J.Redel, M.Zamorano, M.Araya, M.Monzón, E.Alvarado, R.Contreras, N.Tapia-Bustos, A.Quintanilla, M.E.Ezquer, F.Valdes, J.L.Israel, Y.Herrera-Marschitz, M.Morales, P.2021-07-182021-07-182020-10International Journal of Molecular SciencesOpen AccessVolume 21, Issue 20, Pages 1 - 272 October 2020 Article number 78001661-6596http://repositorio.unab.cl/xmlui/handle/ria/19423Indexación: Scopus.PerinatalAsphyxia (PA) is a leading cause ofmotor and neuropsychiatric disability associated with sustained oxidative stress, neuroinflammation, and cell death, affecting brain development. Based on a rat model of global PA, we investigated the neuroprotective effect of intranasally administered secretome, derived from human adipose mesenchymal stem cells (MSC-S), preconditioned with either deferoxamine (an hypoxia-mimetic) or TNF-ff+IFN- (pro-inflammatory cytokines). PA was generated by immersing fetus-containing uterine horns in a water bath at 37 ffC for 21 min. Thereafter, 16 ffL of MSC-S (containing 6 ffg of protein derived from 2 ff 105 preconditioned-MSC), or vehicle, were intranasally administered 2 h after birth to asphyxia-exposed and control rats, evaluated at postnatal day (P) 7. Alternatively, pups received a dose of either preconditioned MSC-S or vehicle, both at 2 h and P7, and were evaluated at P14, P30, and P60. The preconditioned MSC-S treatment (i) reversed asphyxia-induced oxidative stress in the hippocampus (oxidized/reduced glutathione); (ii) increased antioxidative Nuclear Erythroid 2-Related Factor 2 (NRF2) translocation; (iii) increased NQO1 antioxidant protein; (iv) reduced neuroinflammation (decreasing nuclearNF-ffB/p65 levels and microglial reactivity); (v) decreased cleaved-caspase-3 cell-death; (vi) improved righting reflex, negative geotaxis, cliff aversion, locomotor activity, anxiety, motor coordination, and recognition memory. Overall, the study demonstrates that intranasal administration of preconditioned MSC-S is a novel therapeutic strategy that prevents the long-term effects of perinatal asphyxia. © 2020 by the authors.enBehavioral developmentCell deathHippocampusIntranasal administrationMemoryMesenchymal stem cell secretome (MSC-S)Neonatal hypoxiaNeuroinflammationNeuroprotectionOxidative stressIntranasal administration of mesenchymal stem cell secretome reduces hippocampal oxidative stress, neuroinflammation and cell death, improving the behavioral outcome following perinatal asphyxiaArtículoAttribution 4.0 International (CC BY 4.0)10.3390/ijms21207800