N-acetylserotonin: neuroprotection, neurogenesis, and the sleepy brain

Abstract

N-Acetylserotonin (NAS) is a naturally occurring chemical intermediate in biosynthesis of melatonin. Previous studies have shown that NAS has different brain distribution patterns from those of serotonin and melatonin, suggesting that NAS might have functions other than as a precursor or metabolite of melatonin. Indeed, several studies have now shown that NAS may play an important role in mood regulation and may have antidepressant activity. Additional studies have shown that NAS stimulates proliferation of neuroprogenitor cells and prevents some of the negative effects of sleep deprivation. It is believed that the antidepressant and neurotrophic actions of NAS are due at least in part to the capability on this molecule to activate the TrkB receptor in a brain-derived neurotrophic factor-independent manner. Emerging evidence also indicates that NAS and its derivatives have neuroprotective properties and protect retinal photoreceptor cells from light-induced degeneration. In this review, the authors discuss the literature about this exciting and underappreciated molecule.

Figure 1

The levels of N-Acetylserotonin are high during the night and low during the day and the rhythm is controlled by circadian clocks. The circadian clock controls the transcription of the Aanat gene and thus the enzymatic activity of AANAT and NAS levels (see text for details).

Figure 2

Regulation of NAS biosynthesis and its suppression by light. At night in darkness cAMP levels are elevated, activating PKA, which induces Aanat gene transcription and phosphorylates AANAT protein. Phosphylated AANAT (pAANAT) associates with 14-3-3 proteins, which activate and stabilize the enzyme resulting in increased conversion of serotonin to N-acetylserotonin. Light exposure decreases cAMP levels resulting in dephosphorylation of AANAT and its subsequent degradation by proteasomal degradation.

Figure 3

The current model for sleep regulation involves two processes: a sleep-dependent process (Process S, blue line) and a circadian process (Process C, red line). Sleep propensity (Process S) increases during the wake time and rapidly decrease during sleep. The circadian clock (Process C) opposes sleep propensity by sending an alerting signal that begins to rise before the awakening and continues to increase into the late part of the wake period. Therefore, the sleep and wake cycle is determined by the coincident and opposing actions of these two processes (adapted from Borbely and Ackermann, 1999).

Figure 4

BDNF interacts with TrkB receptors activating pathways that promote neuronal survival and neurogenesis. NAS also activates TrkB and its downstream signaling pathways, but it is unclear whether NAS directly interacts with the TrkB receptor to promote its activation or triggers activation through unknown molecular effectors.