Circadian Rhythms, Oxidative Stress, and Antioxidative Defense Mechanisms

Endogenous circadian and exogenously driven daily rhythms of antioxidative enzyme activities and of low molecular weight antioxidants (LMWAs) are described in various phylogenetically distant organisms. Substantial amplitudes are detected in several cases, suggesting the significance of rhythmicity in avoiding excessive oxidative stress. Mammalian and/or avian glutathione peroxidase and, as a consequence, glutathione reductase activities follow the rhythm of melatonin. Another hint for an involvement of melatonin in the control of redox processes is seen in its high-affinity binding to cytosolic quinone reductase 2, previously believed to be a melatonin receptor. Although antioxidative protection by pharmacological doses of melatonin is repeatedly reported, explanations of these findings are still insufficient and their physiological and chronobiological relevance is not yet settled. Recent data indicate a role of melatonin in the avoidance of mitochondrial radical formation, a function which may prevail over direct scavenging. Rhythmic changes in oxidative damage of protein and lipid molecules are also reported. Enhanced oxidative protein modification accompanied by a marked increase in the circadian amplitude of this parameter is detected in the Drosophila mutant rosy, which is deficient in the LMWA urate. Preliminary evidence for the significance of circadian rhythmicity in diminishing oxidative stress comes from clock mutants. In Drosophila, moderately enhanced protein damage is described for the arrhythmic and melatonin null mutant per0, but even more elevated, periodic damage is found in the short-period mutant per(s), synchronized to LD 12:12. Remarkably large increases in oxidative protein damage, along with impairment of tissue integrity and--obviously insufficient--compensatory elevations in protective enzymes are observed in a particularly vulnerable organ, the Harderian gland, of another short-period mutant tau, in the Syrian hamster. Mice deficient in the per2 gene homolog are reported to be cancer-prone, a finding which might also relate to oxidative stress. In the dinoflagellate Lingulodinium polyedrum Gonyaulax polyedra, various treatments that cause oxidative stress result in strong suppressions of melatonin and its metabolite 5-methoxytryptamine (5-MT) and to secondary effects on overt rhythmicity. The glow maximum, depending on the presence of elevated 5-MT at the end of subjective night, decreases in a dose-dependent manner already under moderate, non-lethal oxidative stress, but is restored by replenishing melatonin. Therefore, a general effect of oxidative stress may consist in declines of easily oxidizable signaling molecules such as melatonin, and this can have consequences on the circadian intraorganismal organization and expression of overt rhythms. Recent findings on a redox-sensitive input into the core oscillator via modulation of NPAS2/BMAL1 or CLK/BMAL1 heterodimer binding to DNA indicate a direct influence of cellular redox balance, including oxidative stress, on the circadian clock.