Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.
Division of Immune-Neuropsychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.
Pediatr Res. 2022 Feb;91(3):556-564. doi: 10.1038/s41390-021-01446-1. Epub 2021 Mar 31.
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.
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.
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.
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.
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.
严重的新生儿高胆红素血症已被证实会导致脑核性黄疸的临床综合征，以及较轻的胆红素诱导的神经功能障碍（BIND）综合征。BIND 在新生儿期后表现为发育迟缓、认知障碍以及相关的行为和精神障碍。BIND 的全貌尚不清楚。
Gunn 大鼠是 Wistar 大鼠的突变株，具有 BIND 表型，表现出异常行为。我们通过药理学分析和离体神经化学分析研究 Gunn 大鼠的 5-羟色胺能功能障碍。
5-HT2AR 拮抗剂酮色林使 Gunn 大鼠的过度活跃正常化。Gunn 大鼠前额皮质中的 5-羟色胺及其代谢物浓度均高于对照组 Wistar 大鼠。Gunn 大鼠前额皮质中 5-HT2AR mRNA 表达下调，而蛋白丰度没有改变。Gunn 大鼠中缝核区域的 TPH2 蛋白水平明显高于 Wistar 大鼠。
如果能够假设 BIND 障碍的治疗策略是将受 5-羟色胺能功能障碍影响的脑区恢复正常运作，以预防或在 BIND 表现出现后使脑区恢复正常，这将具有重要意义。
我们证明了 Gunn 大鼠过度活跃与 5-羟色胺能调节异常有关。这一发现表明，针对胆红素诱导的神经功能障碍（BIND）的治疗策略可能是恢复受 5-羟色胺能功能障碍影响的脑区的正常运作，以预防 BIND 表现出现前或使其在出现后恢复正常。酮色林使 Gunn 大鼠的过度活跃正常化。据我们所知，这是第一项证明 Gunn 大鼠过度活跃与 5-羟色胺能调节异常有关的研究。
