Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin

Abstract

Sleep is an essential component of overall human health but is so tightly regulated that when disrupted can cause or worsen certain ailments. An important part of this process is the presence of the well-known hormone, melatonin. This compound assists in the governing of sleep and circadian rhythms. Previous studies have postulated that dysregulation of melatonin rhythms is the driving force behind sleep and circadian disorders. A computer-aided search spanning the years of 2015-2020 using the search terms melatonin, circadian rhythm, disorder yielded 52 full text articles that were analyzed. We explored the mechanisms behind melatonin dysregulation and how it affects various disorders. Additionally, we examined associated therapeutic treatments including bright light therapy (BLT) and exogenous forms of melatonin. We found that over the past 5 years, melatonin has not been widely investigated in clinical studies thus there remains large gaps in its potential utilization as a therapy.

Keywords: bright light therapy; circadian rhythm; delayed sleep phase disorder; melatonin; sleep.

Figure 1

Literature selection flow chart. All steps of the literature search are represented within the flow chart, resulting in 52 full-text articles included in this analysis.

Figure 2

Neuroanatomical pathway of light stimulus to the pineal gland. Light strikes the retina, which results in a neuronal signaling cascade from retina to retinohypothalamic tract (RHT) to suprachiasmatic nucleus (SCN) to paraventricular nucleus (PVN) to the brainstem to the spinal cord (levels T1-T3) to the superior cervical ganglion (SCG) to the pineal gland.

Figure 3

Melatonin metabolic pathway. Melatonin is synthesized from tryptophan and serotonin by a series of enzymes. * AA-NAT enzyme is the rate-limiting enzyme of this pathway. Melatonin is catabolized by cytochrome P450 enzymes (like CYP1A2) into 6-hydroxymelatonin. ** 6-hydroxymelatonin can be excreted or sulfated and then excreted.

Figure 4

Transcription pathway for melatonin biosynthetic enzymes. The axon terminal of the neuron originating from the superior cervical ganglion releases norepinephrine (NE) into the synapse when stimulated. NE binds to beta-1 (β1) and alpha-1 (α1) receptors on the cell membrane of pineal gland cells (pinealocytes). β1 receptor stimulation leads to activation of downstream signaling of Gαs, adenylate cyclase (AC), and phosphorylated protein kinase A (PKA-P) to stimulate the transcription of AA-NAT RNA which will be transcribed into biosynthetic enzymes to synthesize melatonin.