PMID- 29247156 OWN - NLM STAT- MEDLINE DCOM- 20180806 LR - 20190606 IS - 1643-3750 (Electronic) IS - 1234-1010 (Print) IS - 1234-1010 (Linking) VI - 23 DP - 2017 Dec 16 TI - Melatonin Promotes Brain-Derived Neurotrophic Factor (BDNF) Expression and Anti-Apoptotic Effects in Neonatal Hemolytic Hyperbilirubinemia via a Phospholipase (PLC)-Mediated Mechanism. PG - 5951-5959 AB - BACKGROUND Melatonin therapy shows positive effects on neuroprotective factor brain-derived neurotrophic factor (BDNF) expression and neuronal apoptosis in neonatal hemolytic hyperbilirubinemia. We hypothesized that melatonin promotes BDNF expression and anti-apoptotic effects in neonatal hemolytic hyperbilirubinemia through a phospholipase (PLC)-mediated mechanism. MATERIAL AND METHODS A phenylhydrazine hydrochloride (PHZ)-induced neonatal hemolytic hyperbilirubinemia model was constructed in neonatal rats. Four experimental groups - a control group (n=30), a PHZ group (n=30), a PHZ + melatonin group (n=30), and a PHZ + melatonin+U73122 (a PLC inhibitor) group (n=30) - were constructed. Trunk blood was assayed for serum hemoglobin, hematocrit, total and direct bilirubin, BDNF, S100B, and tau protein levels. Brain tissue levels of neuronal apoptosis, BDNF expression, PLC activity, IP3 content, phospho- and total Ca2+/calmodulin-dependent protein kinase type IV (CaMKIV) expression, and phospho- and total cAMP response element binding protein (CREB) expression were also assayed. RESULTS PHZ-induced hemolytic hyperbilirubinemia was validated by significantly decreased serum hemoglobin and hematocrit as well as significantly increased total and direct serum bilirubin (p<0.05). Neonatal bilirubin-induced neurotoxicity was validated by significantly decreased serum BDNF, brain BDNF, and serum S100B, along with significantly increased serum tau protein (p<0.05). PHZ-induced hemolytic hyperbilirubinemia significantly decreased serum BDNF, brain BDNF, and PLC/IP3/Ca2+ pathway activation while increasing neuronal apoptosis levels (p<0.05), all of which were partially rescued by melatonin therapy (p<0.05). Pre-treatment with the PLC inhibitor U73122 largely abolished the positive effects of melatonin on PLC/IP3/Ca2+ pathway activation, downstream BDNF levels, and neuronal apoptosis (p<0.05). CONCLUSIONS Promotion of BDNF expression and anti-apoptotic effects in neonatal hemolytic hyperbilirubinemia by melatonin largely operates via a PLC-mediated mechanism. FAU - Luo, Yong AU - Luo Y AD - Department of Pediatrics, Yongchuan Hospital of Chongqing Medical University, Chongqing, China (mainland). FAU - Peng, Mei AU - Peng M AD - Department of Infectious Diseases, Yongchuan Hospital of Chongqing Medical University, Chongqing, China (mainland). FAU - Wei, Hong AU - Wei H AD - Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, China (mainland). LA - eng PT - Journal Article DEP - 20171216 PL - United States TA - Med Sci Monit JT - Medical science monitor : international medical journal of experimental and clinical research JID - 9609063 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Estrenes) RN - 0 (Phosphodiesterase Inhibitors) RN - 0 (Pyrrolidinones) RN - 112648-68-7 (1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione) RN - EC 3.1.4.- (Type C Phospholipases) RN - JL5DK93RCL (Melatonin) RN - RFM9X3LJ49 (Bilirubin) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Bilirubin/blood MH - Brain-Derived Neurotrophic Factor/*biosynthesis/metabolism MH - Estrenes/pharmacology MH - Hemolysis/drug effects MH - Hyperbilirubinemia, Neonatal/*drug therapy/*metabolism MH - Melatonin/*pharmacology MH - Phosphodiesterase Inhibitors/pharmacology MH - Pyrrolidinones/pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/drug effects MH - Type C Phospholipases/antagonists & inhibitors/*metabolism PMC - PMC5741953 COIS- Conflicts of interest None. EDAT- 2017/12/17 06:00 MHDA- 2018/08/07 06:00 PMCR- 2017/12/16 CRDT- 2017/12/17 06:00 PHST- 2017/12/17 06:00 [entrez] PHST- 2017/12/17 06:00 [pubmed] PHST- 2018/08/07 06:00 [medline] PHST- 2017/12/16 00:00 [pmc-release] AID - 907592 [pii] AID - 10.12659/msm.907592 [doi] PST - epublish SO - Med Sci Monit. 2017 Dec 16;23:5951-5959. doi: 10.12659/msm.907592.