Central thyrotropin-releasing hormone stimulates hepatic DNA synthesis in rats

Central neuropeptides play a role as physiological regulators in the autonomic nervous system. One of these neuropeptides, thyrotropin-releasing hormone (TRH), is distributed throughout the central nervous system (CNS) and acts as a neurotransmitter to regulate gastric functions through the vagus nerve. However, the autonomic nervous system is also involved in hepatic regeneration, but the effect of TRH is unknown. Therefore, the CNS's effect of TRH on hepatic DNA synthesis was studied in rats. Hepatic DNA synthesis was assessed by [Methyl-3H]thymidine incorporation 6, 12, 24, 48, and 72 hours after intracisternal injection of the TRH analog, RX 77368 (1, 5, 10, and 100 ng), and by 5-bromo-2'-deoxyuridine (BrdU) labeling of the liver section. Hepatic DNA synthesis was stimulated by intracisternal TRH analog (10 ng), with a peak response at 24 hours after peptide injection, and returned to baseline by 72 hours. This stimulatory effect by central TRH analog on hepatic DNA synthesis was dose-related, ranging from 1 ng to 10 ng (dpm/microg DNA at 24 hours [mean +/- SE]: saline, 95 +/- 6; 1 ng, 114 +/- 14; 5 ng, 318 +/- 57; 10 ng, 693 +/- 78; 100 ng, 710 +/- 135). Hepatocytes were randomly labeled by BrdU 24 hours after intracisternal TRH analog (10 ng). Intravenous TRH analog (10 ng) did not influence hepatic DNA synthesis. The stimulatory effect of TRH analog was blocked by hepatic branch vagotomy and atropine, but not by hepatic sympathectomy, 6-hydroxydopamine, insulin antibody, or hypophysectomy. These results indicate that TRH acts in the CNS to stimulate hepatic DNA synthesis through vagal and cholinergic mechanisms, and that TRH may be the chemical messenger involved in brain regulation of hepatic proliferation.