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

Abstract

BackgroundMelatonin 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/MethodsA 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.ResultsPHZ-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).ConclusionsPromotion of BDNF expression and anti-apoptotic effects in neonatal hemolytic hyperbilirubinemia by melatonin largely operates via a PLC-mediated mechanism.

Pharmacological evidence for transactivation within melatonin MT 2 and serotonin 5‐HT 2C receptor heteromers in mouse brain

“…[48][49][50] Furthermore, the positive effect of melatonin on the expression of the brain-derived neurotrophic factor (BDNF) under neonatal hemolytic hyperbilirubinemic conditions is largely driven by increased PLC activity. 51 For these studies and future ones, transactivation of 5-HT 2C receptors by melatonin should be considered. Given the possibility of MT 2 /5-HT 2C heteromer formation, it might be also of interest to test the effect of melatonin on well-known 5-HT 2C receptorassociated functions, namely body weight regulation, satiety, and addiction.…”

“…For example, the PLC/protein kinase C signaling pathway is important for the phase‐shift of the peak of neuronal firing in the SCN by MT 2 receptors 48‐50 . Furthermore, the positive effect of melatonin on the expression of the brain‐derived neurotrophic factor (BDNF) under neonatal hemolytic hyperbilirubinemic conditions is largely driven by increased PLC activity 51 . For these studies and future ones, transactivation of 5‐HT 2C receptors by melatonin should be considered.…”

Investigation of the Neuroprotective Effect of Melatonin on Hippocampal Neuron Injury Developing Due to the Neurotoxic Effect of Cisplatin

“…Melatonin, which has antioxidant and positive effects in brain metabolism against stress, is an appropriate candidate molecule for this combination (Fernandez A et al, 2015p.292, Dong Y et al, 2016. It is known that melatonin increases neuronal regeneration as well as having antiapoptotic efficiency (Luo Y et al, 2017p.5951, Ali T et al, 2015.…”

Melatonin and Regulation of Immune Function: Impact on Numerous Diseases

“…The binding of melatonin to the G-protein coupled membrane-bound melatonin receptors MT1/MT2, can modulate the activity of several transcription factors, either by way of a GTPase pathway or by phospholipase C (Fig. 1) [126]. Melatonin is clearly involved with the signaling of the nuclear orphan receptor, ROR [119,127].…”