Mesenchymal stem cell (MSC)
transplantation has been shown to be beneficial in treating
cerebral ischemia. However, such benefit is limited by the low survival of transplanted MSCs in an ischemic microenvironment. Previous studies showed that
melatonin pretreatment can increase MSC survival in the ischemic kidney. However, whether it will improve MSC survival in
cerebral ischemia is unknown. Our study examined the effect of
melatonin pretreatment on MSCs under
ischemia-related conditions in vitro and after
transplantation into ischemic rat brain. Results showed that
melatonin pretreatment greatly increased survival of MSCs in vitro and reduced their apoptosis after
transplantation into ischemic brain.
Melatonin-treated MSCs (MT-MSCs) further reduced
brain infarction and improved neurobehavioral outcomes. Angiogenesis, neurogenesis, and the expression of
vascular endothelial growth factor (
VEGF) were greatly increased in the MT-MSC-treated rats.
Melatonin treatment increased the level of p-ERK1/2 in MSCs, which can be blocked by the
melatonin receptor antagonist
luzindole. ERK phosphorylation inhibitor
U0126 completely reversed the protective effects of
melatonin, suggesting that
melatonin improves MSC survival and function through activating the ERK1/2 signaling pathway. Thus, stem cells pretreated by
melatonin may represent a feasible approach for improving the beneficial effects of stem cell therapy for
cerebral ischemia.