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.