Melatonin antagonizes interleukin‐18‐mediated inhibition on neural stem cell proliferation and differentiation

Abstract

Neural stem cells (NSCs) are self‐renewing, pluripotent and undifferentiated cells which have the potential to differentiate into neurons, oligodendrocytes and astrocytes. NSC therapy for tissue regeneration, thus, gains popularity. However, the low survivals rate of the transplanted cell impedes its utilities. In this study, we tested whether melatonin, a potent antioxidant, could promote the NSC proliferation and neuronal differentiation, especially, in the presence of the pro‐inflammatory cytokine interleukin‐18 (IL‐18). Our results showed that melatonin per se indeed exhibited beneficial effects on NSCs and IL‐18 inhibited NSC proliferation, neurosphere formation and their differentiation into neurons. All inhibitory effects of IL‐18 on NSCs were significantly reduced by melatonin treatment. Moreover, melatonin application increased the production of both brain‐derived and glial cell‐derived neurotrophic factors (BDNF, GDNF) in IL‐18‐stimulated NSCs. It was observed that inhibition of BDNF or GDNF hindered the protective effects of melatonin on NSCs. A potentially protective mechanism of melatonin on the inhibition of NSC's differentiation caused IL‐18 may attribute to the up‐regulation of these two major neurotrophic factors, BNDF and GNDF. The findings indicate that melatonin may play an important role promoting the survival of NSCs in neuroinflammatory diseases.

Melatonin Promotes Brain-Derived Neurotrophic Factor (BDNF) Expression and Anti-Apoptotic Effects in Neonatal Hemolytic Hyperbilirubinemia via a Phospholipase (PLC)-Mediated Mechanism

“…Here, through application of the PLC inhibitor U73122, we showed that the positive effect of melatonin on brain BDNF expression under neonatal hemolytic hyperbilirubinemic conditions is largely driven through upregulated PLC activity. These findings are consistent with previous in vitro research showing that the G protein-coupled melatonin receptors MT1 and MT2/5-HT2C heteromer both couple to the PLC/IP3/Ca 2+ pathway [ 10 , 31 ] and that the MT1/MT2 antagonist luzindole significantly suppresses protective effects of melatonin in neural stem cells [ 32 ]. Our findings also agree with reports of melatonin’s in vivo reversal of sleep deprivation-induced brain BDNF downregulation and calcium-calmodulin-dependent kinase II (CaMKII) downregulation in the rat cerebral cortex and hippocampus [ 33 ], as well as the efficacy of the MT2 agonist agomelatine in increasing serum BDNF levels in patients with severe clinical depression [ 31 , 34 ].…”

Extended Combined Neonatal Treatment With Erythropoietin Plus Melatonin Prevents Posthemorrhagic Hydrocephalus of Prematurity in Rats

“…EPO and MLT also have numerous overlapping complementary mechanisms of action on neural cells that result in repair ( Brines et al, 2000 ; Carloni et al, 2008 ). Receptors for both EPO and MLT are present on neural cells ( Mazur et al, 2010 ; Bahna and Niles, 2017 ; Ng et al, 2017 ; Osier et al, 2017 ; Tsai et al, 2017 ), and both EPO and MLT enhance the genesis, survival and maturation of multiple neural cell types ( Iwai et al, 2010 ; Mazur et al, 2010 ; Jantzie et al, 2013 ; Li et al, 2017 ; Zhang et al, 2018 ). EPO and MLT reduce neuroinflammation and oxidative stress ( Carloni et al, 2016 ; Ramirez-Jirano et al, 2016 ; Dominguez Rubio et al, 2017 ; McDougall et al, 2017 ; Wang et al, 2017 ; Wei et al, 2017 ; Zhou et al, 2017 ).…”

“…The pluripotent cytokines, erythropoietin (EPO) and melatonin (MLT), are leading candidates for neurorepair in neonates with central nervous system (CNS) injury due to their safety profile ( Robertson et al, 2012 ), and multiple and complementary, mechanisms of action on developing neural cells ( Brines et al, 2000 ; Carloni et al, 2008 ; Mazur et al, 2010 ; Jantzie et al, 2018 ). Both EPO and MLT support the genesis, survival and maturation of neural cells ( Iwai et al, 2010 ; Mazur et al, 2010 ; Jantzie et al, 2013 ; Li et al, 2017 ; Zhang et al, 2018 ), reduce excess calpain degradation ( Samantaray et al, 2008 ; Jantzie et al, 2014b , 2016 ; Robinson et al, 2016 ), limit neuroinflammation and oxidative damage ( Carloni et al, 2016 ; Ramirez-Jirano et al, 2016 ; Dominguez Rubio et al, 2017 ; McDougall et al, 2017 ; Wang et al, 2017 ; Wei et al, 2017 ; Zhou et al, 2017 ), and suppress endoplasmic reticulum stress and mitochondrial dysfunction ( Hong et al, 2012 ; Das et al, 2013 ; Carloni et al, 2014 ; Fernandez et al, 2015 ; Hadj Ayed Tka et al, 2015 ; Zhao et al, 2015 ; Hu et al, 2016 ; Hardeland, 2017 ; Mendivil-Perez et al, 2017 ; Tang et al, 2017 ; Xue et al, 2017 ). Individually, EPO and MLT are in clinical trials to ameliorate CNS injury from extremely preterm birth, demonstrating their clinical viability as therapeutics in preterm infants ( Juul et al, 2008 ; Ohls et al, 2014 , 2016 ; Fauchere et al, 2015 ; Wu et al, 2016 ; Carloni et al, 2017 ).…”

Protective Effects of Melatonin on Neurogenesis Impairment in Neurological Disorders and Its Relevant Molecular Mechanisms

“…IL-18 is a cytokine that is detrimental to the NSCs. Melatonin, moreover, could promote the production of BDNF and GDNF in the IL-18-stimulated NSCs and suppressed the IL18-induced inhibition of proliferation, neurosphere formation, and neuronal differentiation of the NSCs [ 93 ] ( Table 9 ).…”