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 Oct 21;21(20):7800. doi: 10.3390/ijms21207800.

Abstract

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.

Keywords: Neonatal hypoxia; behavioral development; cell death; hippocampus; intranasal administration; memory; mesenchymal stem cell secretome (MSC-S); neuroinflammation; neuroprotection; oxidative stress.

MeSH terms

  • Administration, Intranasal
  • Animals
  • Apgar Score
  • Asphyxia Neonatorum / pathology
  • Asphyxia Neonatorum / therapy*
  • Behavior, Animal
  • Cell Death / drug effects
  • Female
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Inflammation / pathology
  • Inflammation / therapy
  • Male
  • Mesenchymal Stem Cells / metabolism*
  • NF-E2-Related Factor 2 / metabolism
  • Neurons / drug effects
  • Neurons / pathology
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / pharmacology*
  • Oxidative Stress / drug effects
  • Pregnancy
  • Rats, Wistar

Substances

  • NF-E2-Related Factor 2
  • Neuroprotective Agents
  • Nfe2l2 protein, mouse