Effects of a Novel TRH Analog, JTP-2942, on Cholinergic and Monoaminergic Neurons in the Brain

Abstract

Thyrotropin-releasing hormone (TRH) is a hypothalamic hormone that releases thyrotropin and prolactin from the anterior pituitary gland. TRH and its receptor are widely distributed throughout the brain, including the amygdala, medulla, cerebral cortex, septal region, and hippocampus,^1–4 suggesting that TRH may play an important role as a neurotransmitter as well as a neuromodulator regulating the functions of cholinergic^5–7 and monoaminergic neurons.^8,9 At present, several TRH analogues designed to reduce the hormonal actions and to increase the potency and duration of the central actions of TRH are under clinical investigation for the treatment of spinal cord injury, traumatic brain injury, and Alzheimer’s disease.^10,11 A novel TRH analogue, Nα-[(1S, 2R)-2-methyl-4-oxocyclopentanecarbonyl]-L-histidyl-L-prolineamide (JTP-2942), with a cyclopentanone structure substituted for the pyroglutamyl moiety of TRH, has recently been demonstrated to have an increased therapeutic potency compared with the parent compound.¹² JTP-2942 has been shown to cause reversal of experimental amnesia¹³ and to enhance both learning and memory in rodents in a Morris water maze study. The present study was performed to clarify the effects of JTP-2942 on cholinergic and monoaminergic neurons.