All pre-term newborns and a high proportion of term newborns develop
neonatal jaundice.
Neonatal jaundice is usually a benign condition and self-resolves within few days after birth. However, a combination of unfavorable complications may lead to acute
hyperbilirubinemia. Excessive
hyperbilirubinemia may be toxic for the developing nervous system leading to severe neurological damage and death by
kernicterus. Survivors show irreversible neurological deficits such as motor, sensitive and cognitive abnormalities. Current
therapies rely on the use of
phototherapy and, in unresponsive cases, exchange transfusion, which is performed only in specialized centers. During
bilirubin-induced neurotoxicity different molecular pathways are activated, ranging from oxidative stress to endoplasmic reticulum (ER) stress response and
inflammation, but the contribution of each pathway in the development of the disease still requires further investigation. Thus, to increase our understanding of the pathophysiology of
bilirubin neurotoxicity,
encephalopathy and
kernicterus, we pharmacologically modulated neurodegeneration and
neuroinflammation in a lethal mouse model of
neonatal hyperbilirubinemia. Treatment of mutant mice with
minocycline, a second-generation
tetracycline with anti-inflammatory and neuroprotective properties, resulted in a dose-dependent rescue of lethality, due to reduction of neurodegeneration and
neuroinflammation, without affecting plasma
bilirubin levels. In particular, rescued mice showed normal motor-coordination capabilities and behavior, as determined by the accelerating rotarod and open field tests, respectively. From the molecular point of view, rescued mice showed a dose-dependent reduction in apoptosis of cerebellar neurons and improvement of dendritic arborization of Purkinje cells. Moreover, we observed a decrease of
bilirubin-induced M1 microglia activation at the sites of damage with a reduction in oxidative and ER stress markers in these cells. Collectively, these data indicate that neurodegeneration and neuro-
inflammation are key factors of
bilirubin-induced neonatal lethality and neuro-behavioral abnormalities. We propose that the application of pharmacological treatments having anti-inflammatory and
neuroprotective effects, to be used in combination with the current treatments, may significantly improve the management of acute
neonatal hyperbilirubinemia, protecting from
bilirubin-induced neurological damage and death.