Tryptophan Hydroxylase as Novel Target for the Treatment of Depressive Disorders

Abstract

Serotonin (5-HT) is a monoamine implicated in a variety of physiological processes that functions either as a neurotransmitter or as a peripheral hormone. Pharmacological and genetic studies in humans and experimental animals have shown that 5-HT is important for the pathophysiology of depressive disorders. The 5-HT system is thus already a main target for the therapy of these diseases. The peripheral and cerebral biosynthesis of 5-HT is initiated by two distinct tryptophan hydroxylases: TPH1 and TPH2. This duality of the serotonergic system and the existence of a brain-specific TPH isoform provide a promising new target for pharmacological intervention with higher selectivity and specificity and, therefore, possibly with reduced side effects and increased efficiency. This paper summarizes the data which support TPH2 as novel drug target and discusses strategies for its pharmacological exploitation.

Effect of fluoxetine on the expression of tryptophan hydroxylase and 14-3-3 protein in the dorsal raphe nucleus and hippocampus of rat

“…TPH is a rate-limiting enzyme that plays a vital role in the biosynthesis of 5-HT (Matthes et al, 2010). In the present study, we showed that TPH-positive cells were mainly localized to the dorsal raphe nucleus, the largest serotonergic nucleus, in rats.…”

Physical Weight Loading Induces Expression of Tryptophan Hydroxylase 2 in the Brain Stem

“…Although not shown in the present study, insufficient tph2 or lack of serotonin has been shown to lead to mood disorders such as depression [30], schizophrenia [31] and neurodegeneration such as Alzheimer’s dementia [32], [33]. Our mRNA expression study clearly demonstrated that unloading-induced tph2 deficiency is prevented by pre-application of knee loading.…”

Targeting tryptophan hydroxylase 2 in affective disorder

“…However, currently the attempts of manipulation with dietary tryptophan for therapeutic effect were not impressive and the clinical value of TPH2 as a target for psychotropic drugs is lower compared with SERT or MAOA. However, in perspective, TPH2's value as a target for psychotropic drugs may be increased, when selective TPH2-activating drugs are created [149]. We hope that further study of the TPH2 genetics in humans, mice and other species will increase clinical value of this enzyme as a predictor of affective disorder risk and efficacy of antidepressant drugs.…”