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

Journal
International Journal of Molecular Sciences
ISSN
1422-0067
Date Issued
2020
Author(s)
Nancy Farfán
Jaime Carril
Martina Redel
Marta Zamorano
Maureen Araya
Estephania Monzón
Raúl Alvarado
Norton Contreras
Andrea Tapia-Bustos
María Elena Quintanilla
José Luis Valdés
Yedy Israel
Mario Herrera-Marschitz
Paola Morales
Type
Resource Types::text::journal::journal article
Scopus ID
2-s2.0-85094559006
WoS ID
WOS:000585568800001
DOI
URL
URL Institutional Repository
Abstract
<jats:p>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.</jats:p>
Cite this document
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. (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(20), 7800. https://doi.org/10.3390/ijms21207800
Project(s)
Subjects
neonatal hypoxia

; 

mesenchymal stem cell secretome (msc-s)

; 

intranasal administration

; 

oxidative stress

; 

neuroinflammation

; 

cell death

; 

behavioral development

; 

hippocampus

; 

memory

; 

neuroprotection

; 

administration, intranasal

; 

animals

; 

apgar score

; 

asphyxia neonatorum

; 

behavior, animal

; 

cell death

; 

female

; 

hippocampus

; 

humans

; 

inflammation

; 

male

; 

mesenchymal stem cells

; 

neurons

; 

neuroprotective agents

; 

nf-e2-related factor 2

; 

oxidative stress

; 

pregnancy

; 

rats, wistar

; 

caspase 3

; 

deferoxamine

; 

gamma interferon

; 

glutathione

; 

glutathione disulfide

; 

reduced nicotinamide adenine dinucleotide (phosphate) dehydrogenase (quinone)

; 

transcription factor nrf2

; 

transcription factor rela

; 

tumor necrosis factor

; 

neuroprotective agent

; 

nfe2l2 protein, mouse

; 

transcription factor nrf2

; 

adipose derived stem cell

; 

animal behavior

; 

animal cell

; 

animal experiment

; 

animal model

; 

animal tissue

; 

anxiety

; 

article

; 

aversion

; 

cell nucleus

; 

controlled study

; 

cytoplasm

; 

fetus

; 

hippocampus

; 

human

; 

human cell

; 

intranasal drug administration

; 

locomotion

; 

mesenchymal stem cell

; 

mesenchymal stem cell transplantation

; 

microglia

; 

motor coordination

; 

nervous system inflammation

; 

neuroapoptosis

; 

neuroprotection

; 

newborn

; 

nonhuman

; 

oxidative stress

; 

perinatal asphyxia

; 

protein transport

; 

rat

; 

righting reflex

; 

uterus horn

; 

animal

; 

animal behavior

; 

apgar score

; 

cell death

; 

drug effect

; 

female

; 

hippocampus

; 

inflammation

; 

male

; 

metabolism

; 

nerve cell

; 

newborn hypoxia

; 

oxidative stress

; 

pathology

; 

pregnancy

; 

wistar rat