New Efforts to Demonstrate the Successful Use of TRH as a Therapeutic Agent

Abstract

Thyrotropin-releasing hormone (TRH) is a tripeptide that regulates the neuroendocrine thyroid axis. Moreover, its widespread brain distribution has indicated that it is a relevant neuromodulator of behaviors such as feeding, arousal, anxiety, and locomotion. Importantly, it is also a neurotrophic peptide, and thus may halt the development of neurodegenerative diseases and improve mood-related disorders. Its neuroprotective actions on those pathologies and behaviors have been limited due to its poor intestinal and blood-brain barrier permeability, and because it is rapidly degraded by a serum enzyme. As new strategies such as TRH intranasal delivery emerge, a renewed interest in the peptide has arisen. TRH analogs have proven to be safe in animals and humans, while not inducing alterations in thyroid hormones' levels. In this review, we integrate research from different approaches, aiming to demonstrate the therapeutic effects of TRH, and to summarize new efforts to prolong and facilitate the peptide's actions to improve symptoms and the progression of several pathologies.

Keywords: TRH analogs; neuromodulator; therapeutic factor; thyrotropin-releasing hormone.

Figure 1

Summary of the different mechanisms of action of TRH in the central nervous system (CNS) and their relationship with the treatment of some pathologies. The myriad of TRH actions in the CNS is paralleled by a complex set of neuronal changes that depend on the region and type of cell analyzed. Importantly, responses are also influenced by the internal state of the animal and are directed by TRH’s role in homeostasis maintenance. It is noteworthy that more than one pathway may be involved in mediating TRH’s actions in the same illness. At the presynaptic neuron, TRH may inhibit glutamate release, acting as a neuroprotective agent and preventing cellular death (1); at the postsynaptic cell, TRH is able to stimulate the release of different NTs (2), thus promoting several effects such as hyperthermia, breathing stimulation, neuroprotection, arousal, analepsia and improved locomotion. TRH’s neuroprotective action may be mediated by GSK3 β inhibition (3), or by the inhibition of NMDA receptors (4). However, when acting as a respiratory activator, it stimulates this receptor. As a neurotrophic factor, TRH may act though BDNF expression (5). In blue squares are the specific conditions that can benefit from TRH administration acting in each pathway. Solid arrows represent well-studied pathways, while dashed lines depict signaling cascades that remain speculative. Ach: acetylcholine; Akt: serine/threonine protein kinase; BDNF: brain-derived neurotrophic factor; β-arr2: β-arrestin 2; CamK: calcium/calmodulin-dependent protein kinase; CREB: cAMP responsive element-binding protein; ER: endoplasmic reticulum; Glu: glutamate; GSK3β: glycogen synthase kinase-3β; Hist: histamine; IP3: inositol 1,4,5-triphosphate; NE: norepinephrine; NMDA: N-Methyl-D-aspartic acid; NT: neurotransmitter; PKC: protein kinase C; SMN: survival motor neuron protein.