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Article

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

1
Molecular & Clinical Pharmacology Program, ICBM, Faculty of Medicine University of Chile, Santiago 8380453, Chile
2
Department of Neuroscience, Faculty of Medicine, University of Chile, Santiago 8380453, Chile
3
School of Pharmacy, Faculty of Medicine, Universidad Andres Bello, Santiago 8370149, Chile
4
Center for Regenerative Medicine, Faculty of Medicine-Clínica Alemana, Universidad del Desarrollo, Santiago 7710162, Chile
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(20), 7800; https://doi.org/10.3390/ijms21207800
Received: 31 August 2020 / Revised: 11 October 2020 / Accepted: 14 October 2020 / Published: 21 October 2020
(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)
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-α+IFN-γ (pro-inflammatory cytokines). PA was generated by immersing fetus-containing uterine horns in a water bath at 37 °C for 21 min. Thereafter, 16 μL of MSC-S (containing 6 μg of protein derived from 2 × 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-κB/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. View Full-Text
Keywords: Neonatal hypoxia; mesenchymal stem cell secretome (MSC-S); intranasal administration; oxidative stress; neuroinflammation; cell death; behavioral development; hippocampus; memory; neuroprotection Neonatal hypoxia; mesenchymal stem cell secretome (MSC-S); intranasal administration; oxidative stress; neuroinflammation; cell death; behavioral development; hippocampus; memory; neuroprotection
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MDPI and ACS Style

Farfán, N.; Carril, J.; Redel, M.; Zamorano, M.; Araya, M.; Monzón, E.; Alvarado, R.; Contreras, N.; Tapia-Bustos, A.; Quintanilla, M.E.; Ezquer, F.; Valdés, J.L.; Israel, Y.; Herrera-Marschitz, M.; Morales, P. Intranasal Administration of Mesenchymal Stem Cell Secretome Reduces Hippocampal Oxidative Stress, Neuroinflammation and Cell Death, Improving the Behavioral Outcome Following Perinatal Asphyxia. Int. J. Mol. Sci. 2020, 21, 7800. https://doi.org/10.3390/ijms21207800

AMA Style

Farfán N, Carril J, Redel M, Zamorano M, Araya M, Monzón E, Alvarado R, Contreras N, Tapia-Bustos A, Quintanilla ME, Ezquer F, Valdés JL, Israel Y, Herrera-Marschitz M, Morales P. Intranasal Administration of Mesenchymal Stem Cell Secretome Reduces Hippocampal Oxidative Stress, Neuroinflammation and Cell Death, Improving the Behavioral Outcome Following Perinatal Asphyxia. International Journal of Molecular Sciences. 2020; 21(20):7800. https://doi.org/10.3390/ijms21207800

Chicago/Turabian Style

Farfán, Nancy, Jaime Carril, Martina Redel, Marta Zamorano, Maureen Araya, Estephania Monzón, Raúl Alvarado, Norton Contreras, Andrea Tapia-Bustos, María E. Quintanilla, Fernando Ezquer, José L. Valdés, Yedy Israel, Mario Herrera-Marschitz, and Paola Morales. 2020. "Intranasal Administration of Mesenchymal Stem Cell Secretome Reduces Hippocampal Oxidative Stress, Neuroinflammation and Cell Death, Improving the Behavioral Outcome Following Perinatal Asphyxia" International Journal of Molecular Sciences 21, no. 20: 7800. https://doi.org/10.3390/ijms21207800

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