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Normalizing hyperactivity of the Gunn rat with bilirubin-induced neurological disorders via ketanserin

Abstract

Background

Severe neonatal hyperbilirubinemia has been known to cause the clinical syndrome of kernicterus and a milder one the syndrome of bilirubin-induced neurologic dysfunction (BIND). BIND clinically manifests itself after the neonatal period as developmental delay, cognitive impairment, and related behavioral and psychiatric disorders. The complete picture of BIND is not clear.

Methods

The Gunn rat is a mutant strain of the Wistar rat with the BIND phenotype, and it demonstrates abnormal behavior. We investigated serotonergic dysfunction in Gunn rats by pharmacological analyses and ex vivo neurochemical analyses.

Results

Ketanserin, the 5-HT2AR antagonist, normalizes hyperlocomotion of Gunn rats. Both serotonin and its metabolites in the frontal cortex of Gunn rats were higher in concentrations than in control Wistar rats. The 5-HT2AR mRNA expression was downregulated without alteration of the protein abundance in the Gunn rat frontal cortex. The TPH2 protein level in the Gunn rat raphe region was significantly higher than that in the Wistar rat.

Conclusions

It would be of value to be able to postulate that a therapeutic strategy for BIND disorders would be the restoration of brain regions affected by the serotonergic dysfunction to normal operation to prevent before or to normalize after onset of BIND manifestations.

Impact

  • We demonstrated serotonergic dysregulation underlying hyperlocomotion in Gunn rats. This finding suggests that a therapeutic strategy for bilirubin-induced neurologic dysfunction (BIND) would be the restoration of brain regions affected by the serotonergic dysfunction to normal operation to prevent before or to normalize after the onset of the BIND manifestations.

  • Ketanserin normalizes hyperlocomotion of Gunn rats.

  • To our knowledge, this is the first study to demonstrate a hyperlocomotion link to serotonergic dysregulation in Gunn rats.

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Fig. 1: Ketanserin treatment normalized abnormal locomotor activity in Gunn rats.
Fig. 2: Increased concentrations of 5-HT and 5HIAA in the Gunn rat frontal cortex.
Fig. 3: Reduction of 5-HT2AR mRNA expression in the Gunn rat frontal cortex.
Fig. 4: Immunohistochemistry and western blotting for TPH2 in the raphe region.

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Acknowledgements

We are grateful to Professor emeritus Tadakazu Maeda (Kitasato Univ.) and Dr. Nobuyuki Suzuki (neuroscientist) for giving us advice and to Riho Murai (Shimane Univ.), Kohei Ueda (Shimane Univ.), and Ayumi Fujiwara (Shimane Univ.) for research assistances. Funding came from KAKENHI 19K17363 (to S.M.), from the Ministry of Education, Culture, Sports, Science and Technology (MEXT).

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Authors and Affiliations

Authors

Contributions

Conceived and designed the experiments: S.M. and A.O.-N. Performed the experiments: S.M., K.T., M.F., R.A., T.T., and A.O.-N. Discussed the data: T.T., K.O., M.H., S.H., R.W., T.M., and M.I. Wrote the paper: all authors contributed. A.O.-N. supervised this study.

Corresponding author

Correspondence to Arata Oh-Nishi.

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Competing interests

Shimane University has submitted a patent application (PCT/JP2020/017552) for the use of the compound described in this paper. M.I. has received grants from Research for Promotion of Cancer Control Programs during the conduct of the study. He has received lecture fees from Technomics, Fuji Keizai, Novartis, Yoshitomiyakuhin, Pfizer, MSD, Meiji Seika Pharma, Eisai, Otsuka, Sumitomo Dainippon Pharma, Mochida, Janssen, Takeda, and Eli Lilly. The institution of M.I. received grants or research support from Otsuka, Eisai, Daiichi-Sankyo, Pfizer, Astellas, MSD, Takeda, Fujifilm, Shionogi, and Mochida. A.O.-N. is listed as an inventor of this patent. A.O.-N. is CEO & CTO of RESVO Inc. and has >5% of RESVO Inc. shares but had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to Pediatric Research publication policy. Other authors have no competing interests to declare.

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Miura, S., Tsuchie, K., Fukushima, M. et al. Normalizing hyperactivity of the Gunn rat with bilirubin-induced neurological disorders via ketanserin. Pediatr Res 91, 556–564 (2022). https://doi.org/10.1038/s41390-021-01446-1

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