Effect of JTP-2942, a Novel TRH Analogue, on Cognitive Function and Learning in Rodents
Thyrotropin-releasing hormone (TRH) is a hypothalamic hormone that releases thyrotropin and prolactin from the anterior pituitary, and is widely distributed throughout the central nervous system (CNS).1–5 It has been shown to have various central actions, such as promoting locomotor activity, increasing body temperature in animals, attenuating pentobarbital induced sleep, and promoting recovery from traumatic loss of consciousness in mice.6–10 TRH also increases cholinergic neuronal activity11–14 and improves memory in amnesia models.15 Currently TRH and its analogues are under clinical investigation for treating spinal cord injury, traumatic brain injury, and dementia including Alzheimer’s disease.16–18 However, TRH has some disadvantages for therapeutic use, including a short duration of action and unsuitability for oral administration. Accordingly, we synthesized a novel TRH analogue, Nα-WS, 2R)-2-methyl-4-oxocyclopentanecarbonyl]-L-histidyl-L-prolineamide monohydrate (JTP2942), with a longer duration of action on the CNS and fewer hormonal effects than TRH.19–21 JTP-2942 has been shown to markedly increase CNS cholinergic neuronal activity22 and improve memory in amnesia models and aged animals.23,24 The callosal-neocortical system is implicated in interhemispheric transfer of the engram and the lateralization of information.25–27 The present study investigated whether JTP-2942 could improve cognitive function and learning in rats subjected to a passive avoidance test after transection of the corpus callosum, and investigated the mechanism of action of this drug using the transcallosal response.
KeywordsCorpus Callosum Thyrotropin Release Hormone Acquisition Trial Negative Component Dark Compartment
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