Role of circadian rhythms in pathogenesis of acute CNS injuries: Insights from experimental studies

A wide range of physiological processes show circadian oscillations that are critical for organismal homeostasis. Consequently, disruption of such rhythmicity contributes to the pathogenesis of various chronic diseases. The occurrence, severity, and resolution of acute injuries to the central nervous system may also be modulated by circadian rhythms and/or anti-rhythmic disruptions. Mechanistically, circadian rhythmicity originates from the intrinsic circadian activity of the clock pathway transcription factors that regulate gene expression in a cycle of about 24 h. In addition, their activity is synchronized by external time cues including light, sleep or feeding to produce diurnal rhythms of 24 h. The pathogenic significance of circadian rhythms can be tested experimentally by determining the effects of (i) natural diurnal/circadian time, (ii) time cue manipulations that perturb the rhythmicity, (iii) drugs that target the clock pathway, and (iv) genetic manipulations to inactivate key mediators of the clock pathway. This review summarizes emerging evidence from all those strategies that supports a role of circadian and/or diurnal rhythms in rodent models of stroke, traumatic brain or spinal cord injury, status epilepticus and encephalomyelitis. Potential clinical implications are also considered, including pathogenic effects of the chronodisruptive environment or time of day variability in response to therapeutic interventions. Well-controlled animal studies avoid effects of confounding factors that may complicate interpretation of epidemiological data. They can also help to identify mechanisms that mediate the circadian modulation of a CNS pathology.