TRH Interactions with Cholinergic Mechanisms and Consequent Therapeutic Implications

[β-Glu2]TRH Is a Functional Antagonist of Thyrotropin-Releasing Hormone (TRH) in the Rodent Brain

“…When [Asp 2 ]TRH (1c, also without innate analeptic effect) was co-injected with TRH at an equimolar dose (10 µmol/kg body weight), a similar modest decrease in TRH's analeptic effect was established compared to what we have seen for [β-hGlu 2 ]TRH (1e); however, the latter exhibited a modest analeptic effect on its own. Altogether, two [Glu 2 ]TRH-like compounds with either Asp or β-Glu central acidic residue (1c and 1d, Figure 1) emerged as non-analeptic tripeptides, but only [β-Glu 2 ]TRH (1d) was able to completely antagonize this prominent central effect of TRH linked to predominantly cholinergic mechanisms [3,4]. Specifically, the sleeping time (78 ± 12 min) was statistically not different from that of the control (80 ± 7 min) when the mice were injected with an equimolar mixture of TRH and 1d.…”

“…TRH exerts its numerous CNS actions most stoutly in the hippocampus through the involvement of cholinergic neurons [3,4]. These actions include the above monitored analeptic and antidepressant-like effects of the peptide [3,4,19].…”

“…TRH exerts its numerous CNS actions most stoutly in the hippocampus through the involvement of cholinergic neurons [3,4]. These actions include the above monitored analeptic and antidepressant-like effects of the peptide [3,4,19]. A plausible confirmation of the functional involvement of central cholinergic neurons in these effects can be achieved through in vivo microdialysis samplings of the extracellular fluid from the target brain region in freely moving animals and, then, measuring the endogenous ACh contents in the collected perfusates [24,31,33].…”

“…The thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH 2 , 1a in Figure 1) is a hypothalamic hormone that has also been recognized as a neuropeptide with profound impacts on the brain [1][2][3]. This peptide's central actions are diverse and they affect central nervous system (CNS) chemistry, physiology, and behavior [4][5][6]. Various neurotransmitters have been implicated in these processes, which prominently include the cholinergic system [3,6].…”