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Inhibition of Microglial Activation Ameliorates Inflammation, Reduced Neurogenesis in the hippocampus, and Impaired Brain Function in a Rat Model of Bilirubin Encephalopathy

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Abstract

Hyperbilirubinemia is one of the most common occurrence in newborns and is toxic to the brain, resulting in neurological sequelae such as auditory impairment, with potential to evolve to chronic bilirubin encephalopathy and long-term cognitive impairment in adults. In the early postnatal period, neurogenesis is rigorous and neuroinflammation is detrimental to the brain. What are the alterations in neurogenesis and the underlying mechanisms of bilirubin encephalopathy during the early postnatal period? This study found that, there were a reduction in the number of neuronal stem/progenitor cells, an increase in microglia in the dentate gyrus (DG) and an inflammatory state in the hippocampus, characterized by increased levels of IL-6, TNF-α, and IL-1β, as well as a decreased level of IL-10 in a rat model of bilirubin encephalopathy (BE). Furthermore, there was a significant decrease in the number of newborn neurons and the expression of neuronal differentiation-associated genes (NeuroD and Ascl1) in the BE group. Additionally, cognitive impairment was observed in this group. The administration of minocycline, an inhibitor of microglial activation, resulted in a reduction of inflammation in the hippocampus, an enhancement of neurogenesis, an increase in the expression of neuron-related genes (NeuroD and Ascl1), and an improvement in cognitive function in the BE group. These results demonstrate that microglia play a critical role in reduced neurogenesis and impaired brain function resulting from bilirubin encephalopathy model, which could inspire the development of novel pharmaceutical and therapeutic strategies.

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Data Availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Abbreviations

NSPCs:

Neuronal stem and progenitor cells

UCB:

Unconjugated bilirubin

BIND:

Bilirubin-induced neurological dysfunction

NNJ:

Neonatal jaundice

BE:

Bilirubin encephalopathy

DG:

Dentate gyrus

MCP-1:

Monocyte chemoattractant protein-1

CCR2:

C-C chemokine receptor type- 2

BrdU:

Bromodeoxyuridine

SOX2:

SRY-Box Transcription Factor 2

NeuroD1:

Neurogenic differentiation factor 1

ASCL1:

Achaete-scute homolog 1

NEUROG2:

Neurogenin 2

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Funding

This work was supported by grants from National Natural Science Foundation of China [Grant number: 81971426] and Technological Innovation and Applied Development Project of Science and Technology Bureau of Chongqing [Grant number: CSTB2022TIAD-KPX0147].

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Authors and Affiliations

  1. Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Yan Zhang, Siyu Li, Ling Li, Hongmei Huang & Ziyu Hua

  2. Department of Neonatology, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

    Siyu Li, Ling Li, Hongmei Huang & Ziyu Hua

  3. Department of Respiratory Diseases, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

    Zhou Fu

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  1. Yan Zhang
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  2. Siyu Li
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  3. Ling Li
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  5. Zhou Fu
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Contributions

Y.Z. and Z.Y.H. designed the study. Y.Z., S.Y.L., L.L., H.M.H. performed the experiments. Y.Z., S.Y.L., and Z.Y.H. analyzed the data. Z.Y.H. and Z.F. supervised the study. Y.Z., Z.F. and Z.Y.H. wrote the manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Zhou Fu or Ziyu Hua.

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All animal procedures were approved by the Animal Care Professional Committee of Chongqing Medical University (permit number: SYXK2022-0016).

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Zhang, Y., Li, S., Li, L. et al. Inhibition of Microglial Activation Ameliorates Inflammation, Reduced Neurogenesis in the hippocampus, and Impaired Brain Function in a Rat Model of Bilirubin Encephalopathy. J Neuroimmune Pharmacol 19, 23 (2024). https://doi.org/10.1007/s11481-024-10124-y

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