Modulation of the Circadian Rhythm and Oxidative Stress as Molecular Targets to Improve Vascular Dementia: A Pharmacological Perspective

Abstract

The circadian rhythms generated by the master biological clock located in the brain's hypothalamus influence central physiological processes. At the molecular level, a core set of clock genes interact to form transcription-translation feedback loops that provide the molecular basis of the circadian rhythm. In animal models of disease, a desynchronization of clock genes in peripheral tissues with the central master clock has been detected. Interestingly, patients with vascular dementia have sleep disorders and irregular sleep patterns. These alterations in circadian rhythms impact hormonal levels, cardiovascular health (including blood pressure regulation and blood vessel function), and the pattern of expression and activity of antioxidant enzymes. Additionally, oxidative stress in vascular dementia can arise from ischemia-reperfusion injury, amyloid-beta production, the abnormal phosphorylation of tau protein, and alterations in neurotransmitters, among others. Several signaling pathways are involved in the pathogenesis of vascular dementia. While the precise mechanisms linking circadian rhythms and vascular dementia are still being studied, there is evidence to suggest that maintaining healthy sleep patterns and supporting proper circadian rhythm function may be important for reducing the risk of vascular dementia. Here, we reviewed the main mechanisms of action of molecular targets related to the circadian cycle and oxidative stress in vascular dementia.

Keywords: circadian rhythm; oxidative stress; pharmacology; vascular dementia.

Figure 1

Molecular circadian clock. Black lines: main negative loop; molecularly, we have four main genes that regulate the cycle through negative feedback; the CLOCK and BMAL1 proteins form a heterodimer, acting as a transcriptional activator of PER and CRY; the PER and CRY proteins are translocated to the cytoplasm and, in turn, they form a heterodimer that negatively inhibits CLOCK and BMAL1. During the day, the PER/CRY heterodimer is elevated, inhibiting CLOCK/BMAL1; at night, it is ubiquitinated, degraded, and allows the cycle to begin. Gray lines: another mechanism that CLOCK/BMAL induces is the transcription of orphan nuclear receptors Rev-Erb and ROR-α. Rev-Erb, in turn, is an inhibitor of BMAL1, and ROR-α is a stimulator; also, the CRY/PER heterodimer inhibits ROR-α.

Figure 2

Relationship between oxidative stress and molecular clock. The schematic shows the cycle of the transcriptional cog and metabolic cog. In the TTFL mechanism, the CLOCK/BMAL1 heterodimer binds to promoters (E-BOX), initiating the transcription of PER and CRY genes. Following transcription, messenger RNA moves to the cytoplasm, facilitating the translation and formation of PER and CRY proteins. These proteins, in a phosphorylated heterodimer form, inhibit their own transcription and that of other CCGs through negative feedback. Over the course of a 24 h day, they degrade, enabling the re-binding of the BMAL1/CLOCK heterodimer. The second loop involves the activation and inhibition of the orphan nuclear receptors related to Rev-Erb and ROR-α, which competitively bind to retinoic acid response elements. Dotted lines represent transcription, while lines with arrows on both sides signify binding and heterodimer formation. Promoters are denoted by green arrows; inhibition is represented by a red line. It is noteworthy that the CRE promoter also drives the transcription of the PER2 gene. The activation of CRE elements is associated with the binding of proteins such as CREB (cyclic AMP response element-binding protein). FOXOs are involved in the regulation of the gene expression of circadian rhythms. The molecules NADP and NADPH participate in redox processes and energy balance, which can impact the activity of genes and proteins in the TTFL. The NAMPT is involved in the synthesis of NAD+ and may affect the activity of sirtuins, such as SIRT1, which modulate protein acetylation, and may have effects on the activity of components of the TTFL, thereby influencing circadian rhythms. SIRT1 plays a role in circadian regulation and is NAD+-dependent. Changes in NAD+ levels caused by the presence of ROS could affect the activity of sirtuins and, therefore, the regulation of circadian rhythms. SIRT1 plays a role in oxidative stress through the initiation of several downstream effectors, including FOXO transcription factors, as well as the generation of O2, through the donation of electrons from NADPH in a reaction catalyzed by NADPH oxidase. Thus, the initiation of oxidative stress and the general redox state of the cell affects the availability of NAD+ and consequent activity of SIRT1. Finally, both NADH and NADPH have been shown to enhance the DNA binding of the CLOCK/BMAL1 and NPAS2/BMAL1 heterodimers to their transcriptional targets, whereas NAD+ and NADP+ inhibit this activity. Thus, there is a direct link between the redox state of NAD+/NADH and NADP+/NADPH and circadian rhythms’ ROS signaling and it is important for this NAD + NADP+ activation. Abbreviations: COG: clusters of orthologous genes; TTFL: transcription–translation feedback loop; CCG: clock-controlled genes; RORs: retinoic acid-related orphan receptors; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4750502/ (accessed on 3 March 2024). FOXOs: forkhead box-O; NADP: nicotinamide adenine nucleotide phosphate; NADPH: nicotinamide adenine dinucleotide phosphate; NAMPT: nicotinamide phosphoribosyltransferase; ROS: reactive oxygen species; PRX: peroxiredoxins; SIRT 1: sirtuin 1; CAT: catalase; SOD: superoxide dismutase; GPX: glutathione peroxidase.

Figure 3

Time-dependent fluctuating levels of some circadian rhythms and oxidative stress markers. In healthy patients, melatonin levels (blue line)begin to rise around 20 h, reach their highest concentration in plasma at 24 h, and then start to decrease; cortisol, on the contrary, begins to rise in the morning and its lowest levels are at night (yellow line), as with the antioxidant enzymes superoxide dismutase (green line) and glutathione peroxidase (red line). Regarding the clock genes, the PER:CRY heterodimer is in higher concentrations during the night and is degraded in the morning, and the CLOCK:BMAL heterodimer is elevated during the morning and is degraded during the night. Abbreviations: SOD: superoxide dismutase; GPX: glutathione peroxidase.