Intranasal Administration of Mesenchymal Stem Cell Secretome Reduces Hippocampal Oxidative Stress, Neuroinflammation and Cell Death, Improving the Behavioral Outcome Following Perinatal Asphyxia

Perinatal Asphyxia (PA) is a leading cause of motor 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-&alpha
+IFN-&gamma
(pro-inflammatory cytokines). PA was generated by immersing fetus-containing uterine horns in a water bath at 37 &deg
C for 21 min. Thereafter, 16 &mu
L of MSC-S (containing 6 &mu
g of protein derived from 2 &times
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-&kappa
B/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.