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Kernicterus is a leading cause of neonatal death throughout the world, especially in low-middle-income countries. It is developed by an unconjugated hyperbilirubinemia in the blood and brain tissue, triggering pathological processes that spawn neurotoxicity and neurodegeneration. However, the biological mechanism (s) of bilirubin-induced neurotoxicity and Kernicterus development remain to be well elucidated. Likewise, a practical therapeutic approach for human Kernicterus has yet to be found. Undoubtedly, animal models of Kernicterus can be helpful in the identification of underlying biological processes of hyperbilirubinemia evolution to Kernicterus, as well as the evaluation of various treatments efficacy in preclinical studies. More importantly, establishing an animal model that can mimic the Kernicterus and its behavioral, neuro-histological, and hematological manifestations is a severe priority in preclinical studies. So far, several Kernicterus animal models have been established that could partially mimic one or more clinical and paraclinical signs of human Kernicterus. The present study aimed to review all methods modeling Kernicterus with a focus on their potentials and shortcomings and subsequently provide the optimal methods for an ideal Kernicterus animal model., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: Hemolytic kernicterus, an indirect bilirubin-induced brain dysfunction, is associated with hyper-bilirubinemia in mammalian neonates. In this study, a new model of kernicterus has been developed using intra-peritoneal injections of phenyl hydrazine and subcutaneous injections of sulfisoxazole. These drugs can potentially induce kernicterus in neonatal through changes in hemolysis and hypo-albumin., Methods: For this purpose, 7-day-old male Wistar rats (n=72; mean weight 11±1g) were used. The animals have been divided into six different groups which received the drugs alone and their combination, and the drugs' solvents and their combination. Biochemical parameters, brain iron and bilirubin, behavioural performance, auditory function and apoptosis were measured using auto-analyser instruments; atomic absorption spectroscopy, Sawasaki, footprint, auditory brainstem response (ABR) and TUNEL test, respectively., Result: The drug-injected groups showed a significant reduction in serum haematocrit and an increase in the concentration of brain bilirubin, total and indirect bilirubin as well as TUNEL positive cells in basal ganglia. In addition, the obtained results showed that there was a significant increase in behavioural disturbance and auditory dysfunction in the group injected with the combination of two drugs., Conclusion: This kernicterus-induced rat model could perfectly mimic the common conditions of the hyperbilirubinemia in human neonates. This study offers an easy technique to develop more stable models for follow-up studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Kernicterus is a neurological syndrome associated with indirect bilirubin accumulation and damages to the basal ganglia, cerebellum and brain stem nuclei particularly the cochlear nucleus. To mimic haemolysis in a rat model such that it was similar to what is observed in a preterm human, we injected phenylhydrazine in 7-day-old rats to induce haemolysis and then infused sulfisoxazole into the same rats at day 9 to block bilirubin binding sites in the albumin. We have investigated the effectiveness of human adiposity-derived stem cells as a therapeutic paradigm for perinatal neuronal repair in a kernicterus animal model. The level of total bilirubin, indirect bilirubin, brain bilirubin and brain iron was significantly increased in the modelling group. There was a significant decreased in all severity levels of the auditory brainstem response test in the two modelling group. Akinesia, bradykinesia and slip were significantly declined in the experience group. Apoptosis in basal ganglia and cerebellum were significantly decreased in the stem cell-treated group in comparison to the vehicle group. All severity levels of the auditory brainstem response tests were significantly decreased in 2-month-old rats. Transplantation results in the substantial alleviation of walking impairment, apoptosis and auditory dysfunction. This study provides important information for the development of therapeutic strategies using human adiposity-derived stem cells in prenatal brain damage to reduce potential sensori motor deficit.