Several drugs cause alterations in the 24 hr rhythms of biochemical, physiological and behavioral processes. 6,38,52) The alteration of rhythmicity is sometimes associated with therapeutic eŠects, or may lead to illness and altered homeostatic regulation. Interferons (IFNs) have been widely used as antiviral and antitumor agents; however, IFNs cause adverse neuropsychiatric eŠects such as depression and neurosis and they are reported to sometimes lead to suicide.53,54) When IFNs are administered during the early active phase in diurnally active humans, alterations in the 24 hr rhythm are suggested by the changes in the lymphocyte counts and cortisol levels;55) however, the mechanism has not been clariˆed from the viewpoint of the disruptive eŠect of the drug on the clock genes. Figure 5 shows the disruptive eŠect of interferon-a (IFN-a) on the rhythm of Per genes mRNA expression in the SCN.38) These ˆndings are supported by the inhibitory eŠect of IFN-a on the mRNA expression of Clock and Bmal1, which are important factors in activating the transcription of Pers, vasopressin and the Dbp gene showing speciˆc output function from SCN to the periphery.10,11,13) Also, the rhythmicity of locomotor activity and body temperature are severely blunted by the repetitive administration of IFN-a. Since IFN-a in‰uenced both the SCN and periphery, it is di‹cult to clarify whether the IFN-a eŠects on clock genes are secondarily related to the IFN-a eŠect on locomotor activity. However, IFN-a acts on the SCN as shown in the expression of ISGF38) and the rhythmicity that SCN controls in the periphery.10) The rhythmicity of locomotor activity is severely altered by the continuous administration of corticosterone or a time-restricted feeding schedule while leaving the rhythmic phase of clock genes in the SCN unaŠected.41,46) Thus, the possibility that altered locomotor activity could in turn lead to changed clock gene expression in the SCN is low in the case of IFN-a. The photic induction of the Per1 gene in SCN is also completely disturbed by daily administration of IFN-a at the early active phase, which may have caused a functional disorder in the resetting and entrainment of SCN. Therefore, IFN-a eŠects at the SCN clock gene level may be responsible for some of the adverse behavioral and physiological eŠects. IFN-a sometimes causes ocular adverse eŠects associated with retinal or optic neuropathy,56,57) although the mechanism is not clear at present. Such ocular adverse eŠects caused by IFN-a may decrease the photic information from the retina to SCN and the stimulation of the light responsive element of the per gene.
Interestingly, an inhibitory eŠect of mRNA expression of each clock gene in the SCN is observed by the repetitive administration of IFN-a during the early active phase, but not the early rest phase. Similar dosing schedule-dependent inhibition of Per1 mRNA expression is demonstrated during the repetitive administration of IFN-g, which can be induced by IFN-a or IFN-b in combination with other cytokines.58) The expression of IFN-g receptor in SCN follows a 24 hr rhythm with a peak at the early active phase.59) This may be why the administration of IFN-a during the early rest phase can reduce its side eŠects. The observations for humans described above correspond well to the ˆndings indicating that alteration of the clock genes is induced by IFN-a administration during the early active phase in nocturnally active rodents. Furthermore, the 24 hr dependency of the disruptive eŠect of IFN-a on clock genes in SCN may be applicable to other drugs as shown in the case of IFN-g. Thus, alteration of the clock function, a new concept of adverse eŠects, can be overcome by devising a dosing regimen that minimizes adverse drug eŠects on clock function.
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