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

• Published in: Pediatric research Vol. 91; no. 3; pp. 556 - 564
• Main Authors: Miura, Shoko, Tsuchie, Keiko, Fukushima, Michiyo, Arauchi, Ryosuke, Tsumori, Toshiko, Otsuki, Koji, Hayashida, Maiko, Hashioka, Sadayuki, Wake, Rei, Miyaoka, Tsuyoshi, Inagaki, Masatoshi, Oh-Nishi, Arata
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2022; Nature Publishing Group
• Subjects: Animal cognition; Animals; Basic Science Article; Behavior; Bilirubin; Brain research; Cognitive ability; Dopamine; Drug dosages; Enzymes; Field study; Hemoglobin; Histopathology; Humans; Hyperactivity; Hyperbilirubinemia - complications; Kernicterus - prevention & control; Ketanserin - pharmacology; Liver; Medical research; Medicine; Medicine & Public Health; Mental disorders; Neurological disorders; Neurotoxicity; Newborn babies; Pediatric Surgery; Pediatrics; Proteins; Rats; Rats, Gunn; Rats, Wistar; Rodents; Serotonin
• ISSN: 0031-3998; 1530-0447
• DOI: 10.1038/s41390-021-01446-1

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.