Circadian rhythm as a therapeutic target

Abstract

The circadian clock evolved in diverse organisms to integrate external environmental changes and internal physiology. The clock endows the host with temporal precision and robust adaptation to the surrounding environment. When circadian rhythms are perturbed or misaligned, as a result of jet lag, shiftwork or other lifestyle factors, adverse health consequences arise, and the risks of diseases such as cancer, cardiovascular diseases or metabolic disorders increase. Although the negative impact of circadian rhythm disruption is now well established, it remains underappreciated how to take advantage of biological timing, or correct it, for health benefits. In this Review, we provide an updated account of the circadian system and highlight several key disease areas with altered circadian signalling. We discuss environmental and lifestyle modifications of circadian rhythm and clock-based therapeutic strategies, including chronotherapy, in which dosing time is deliberately optimized for maximum therapeutic index, and pharmacological agents that target core clock components and proximal regulators. Promising progress in research, disease models and clinical applications should encourage a concerted effort towards a new era of circadian medicine.

Fig. 1 |. Hierarchical organization of the mammalian clock system.

The central pacemaker is located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. In the input pathway to the SCN, light is received by the intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing melanopsin, which sends electric signals to the SCN through the retinohypothalamic tract (RHT). Neurotransmitters released by ipRGCs, such as excitatory glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP), cause membrane depolarization in postsynaptic SCN neurons. Changes in Ca²⁺ and cAMP levels, in turn, induce phosphorylation of cAMP-response element (CRE)-binding protein (CREB) and expression of immediate early genes including the core clock genes, PER1 and PER2, thereby resetting SCN cellular oscillators. Meanwhile, the inhibitory neurotransmitter γ-aminobutyric acid (GABA) decreases the sensitivity of non-image-forming behaviours at low light levels. The SCN neurons are tightly coupled and control peripheral clocks in other brain regions and throughout the body via neuronal and hormonal signals.

Fig. 2 |. The cell-autonomous core components of the circadian oscillator govern the ~24-hour cycle of gene expression.

The oscillator consists of positive-feedback and negative-feedback loops that intersect via transcriptional and post-transcriptional regulatory mechanisms. In the core loop, circadian locomotor output cycles kaput (CLOCK) and aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1, encoded by ARNTL) heterodimerize to drive expression of period circadian protein homologue (PER) and cryptochrome (CRY) genes via the E-box elements in the morning. PER and CRY proteins subsequently form a repressive complex to inhibit CLOCK and BMAL1 transactivation. The stability of the PER and CRY proteins is regulated by parallel E3 ubiquitin ligase pathways^–. In the secondary, or stabilization, loop two subfamilies of nuclear receptors, REV-ERBα and REV-ERBβ (encoded by NR1D1 and NR1D2, respectively) as repressors and RAR-related orphan receptors (RORs) α, β and γ as activators, antagonistically regulate BMAL1 and other target genes at the ROR/REV-ERB-response element (RORE) promoter elements at night-time. Another key circadian promoter element is the D-box, activated by the proline and acidic amino acid-rich basic leucine zipper (PAR-bZIP) proteins (such as D-box binding PAR bZIP transcription factor; DBP) and repressed by E4 promoter-binding protein 4 (E4BP4; also known as NFIL3). Together, clock-controlled genes (CCGs) are transcriptionally regulated by the three loops via activation of the E-box, RORE and D-box elements in their gene promoter regions. Various ligands (PER/CRY, ROR and REV-ERB ligands) and small molecules (casein kinase 1 (CK1) inhibitors) have been found to regulate core clock components and circadian functions.

Fig. 3 |. Melatonin and orexin signalling in circadian rhythm.

a | Melatonin promotes sleep at night: the nightly release of noradrenaline (NE; in orange) stimulated by the suprachiasmatic nucleus (SCN) induces melatonin synthesis in the pineal gland (blue circle). Melatonin functions through activation of two G-protein-coupled receptors, melatonin receptor 1 (MT₁) and melatonin receptor 2 (MT₂) mainly in the SCN^,. By interacting with pertussis toxin-sensitive Gα_i, MT₁ receptor can inhibit cAMP-response element-binding protein (CREB) phosphorylation, thus is crucial for the suppression (minus symbols) of neuronal firing, whereas MT₂ receptor exerts a phase-shifting effect^,, and shortens the circadian period of bioluminescence in SCN explant cultures from Clock/+ mutant mice. b | Orexin promotes wakefulness during daytime. The SCN receives signals from light through the retinohypothalamic tract (RHT) and activates orexinergic neurons (purple circle) in the lateral hypothalamic area. Activated orexinergic neurons release orexin A and orexin B and project signals by binding to orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R) in various neurons located throughout the central nervous system (CNS): (1) the locus coeruleus; (2) the tuberomammillary nucleus; (3) the dorsal raphe and median raphe nuclei; (4) the laterodorsal tegmental nucleus; and (5) the pedunculopontine tegmental nucleus. Together, these activating neurons constitute the ascending reticular activating system (ARAS) and directly activate (plus symbols) the cortex, thus promoting wakefulness. Furthermore, OX2R has a major role in stabilization of wakefulness and suppression of sleep. NREM sleep, non-rapid-eye-movement sleep; REM sleep, rapid eye movement sleep.

Fig. 4 |. Pharmacological interventions for insomnia and jet lag.

a | Changes in lifestyle, the environment and health conditions and abnormal action of orexin or/and melatonin could all trigger insomnia. According to its sleep-promoting effect, melatonin and its agonists have therapeutic potential to treat insomnia. Circadin, a commercially available prolonged-release form of melatonin (PRM) has been licensed on the basis of improved nightly sleep quality for treating insomnia disorder in adults older than 55 years in Europe^,. Circadin has a similar affinity for melatonin receptors. Conversely, ramelteon is a melatonin receptor agonist and its affinity for melatonin receptor 1 (MT1 receptor) is eight times higher than that for melatonin receptor 2 (MT₂ receptor), thus exerting a stronger inhibition of the neuronal firing in the suprachiasmatic nucleus to facilitate bedtime sleep onset^,. Finally, suvorexant, which is a dual orexin receptor antagonist, attenuates orexin receptor 2 (OX2R)-mediated cortical arousal and enhances sleep maintenance and onset associated with orexin receptor 1 (OX1R), respectively. b | Melatonin and its receptor agonists can be used in the treatment of jet lag disorder. The key to treating jet lag is the phase response of melatonin. Therefore, tasimelteon, a melatonin agonist with higher affinity for the phase-shifting MT₂ receptor, has been shown to result not only in a significant shift in endogenous circadian rhythms but also an improvement in sleep initiation and maintenance. The timing of melatonin administration is of the essence. Melatonin can phase-advance the physiological and behavioural circadian rhythm when administered in the late biological afternoon. Conversely, when administered in the early biological morning, melatonin delays the circadian clock^,,,. Circadian status can be approximately predicted by habitual sleep timing in the adapted departure time zone, and the plasma melatonin level (blue curve) can be used to define circadian phase for the timing of melatonin administration. The adaptation to the destination time zone before transmeridian travel could be achieved as follows: for eastward travel across six time zones, administration of melatonin (blue hexagon) in the afternoon at departure can advance circadian phase (left-shifted plasma melatonin level, red curve); for westward travel across six time zones, administration of melatonin (blue hexagon) in the early morning can delay circadian phase (right-shifted plasma melatonin level, red curve).