Abstract
Recent studies have found that administration of stem cells or extracellular vehicles (EVs) derived from stem cells exert neuroprotective effects after transient global ischemia. However, the underlying mechanisms of this effect remain unclear, especially at the level of synaptic functions. In this study, we compared the suppressive effects on cyclooxygenase-2 (COX-2) upregulation by EVs derived from bone marrow mesenchymal stem cells (BMSC-EV), adipose tissue MSC (AdMSC-EV) and serum (serum-EV). Then we examined whether BMSC-EVs could restore functional integrity of synaptic transmission and plasticity. Mice were randomly assigned to four groups: sham, sham with EV treatment, ischemia and ischemia with EV treatment. EVs were administered by intracerebroventricular injection (ICVI). We examined the consequence of transient global ischemia on pre- and post-synaptic functions of the hippocampal CA3-CA1 synapses at basal level, and long-term potentiation (LTP), an activity-dependent form of synaptic plasticity. Then we tested the therapeutic effects of EVs on these synaptic deficits. Meanwhile, Morris water maze (MWM) test was performed to examine the efficacy of EVs in rescuing ischemia-induced impairments in spatial learning and memory. EV treatment significantly restored impaired basal synaptic transmission and synaptic plasticity, and improved spatial learning and memory compared with the control group. In addition, EVs significantly inhibited ischemia-induced pathogenic expression of COX-2 in the hippocampus. EVs exert ameliorating effects on synaptic functions against transient global cerebral ischemia, which may be partly attributed to suppression of COX-2 pathogenic expression.
Highlights
Global cerebral ischemia is a clinical outcome occurring as a consequence of cerebral infarction, cardiac arrest and severe hypotension, causing deprivation of oxygen and glucose in the brain
One-hundred microgram per ml of serum-extracellular vehicles (EVs) and bone marrow MSCs (BMSCs)-EV both significantly prevented this increase of COX-2 mRNA induced by 0.3 μg/ml LPS treatment, and EVs derived from all three types of resources largely inhibited COX-2 mRNA up-regulation after 1.0 μg/ml LPS treatment
Consistent with changes at mRNA levels (Figure 1A), the increase of COX-2 immunoreactivity was significantly prevented by serum-EV, adipose tissue mesenchymal stem cells (AdMSC)-EV and BMSC-EV (Figure 1B)
Summary
Global cerebral ischemia is a clinical outcome occurring as a consequence of cerebral infarction, cardiac arrest and severe hypotension, causing deprivation of oxygen and glucose in the brain. Studies on functional anatomy of the brain demonstrated that the hippocampus is a central brain region that integrates information to represent memory. Hippocampal CA1 neurons are vulnerable to consequent loss of blood and oxygen supply to the brain in both humans and rodents (Pulsinelli and Brierley, 1979). Cyclooxygenase (COX)-mediated metabolism of arachidonic acid is thought to be the primary sources of reactive oxygen species in the ischemic brain (Nogawa et al, 1998). Mounting evidence showed prolonged up-regulation of cyclooxygenase-2 (COX-2) after cerebral ischemia and the administration of COX-2 selective inhibitors has been shown to reduce brain damage and prostaglandin (PG) accumulation after cerebral ischemia (Candelario-Jalil et al, 2003; Leger et al, 2016), suggesting an important role of COX-2 in neuronal deterioration after the ischemia attack
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