Disruption of the light/dark cycle and outcome after experimental stroke

Circadian rhythms optimise health by ensuring that the internal rhythms of metabolism and cardiovascular physiology are synchronised to daily variations in the light/dark cycle and other recurrent environmental challenges. Disruption in in the light/dark cycle (photoperiod disruption; PD) which occurs during shift work has been associated with changes in metabolism or physiology, (e.g. hypertension, hyperglycaemia) that may influence outcome after stroke. Evidence from pre-clinical studies indicates that hyperglycaemia and hypertension are associated with increased lesion growth and final infarct after focal cerebral ischaemia. Therefore, it was hypothesised that PD would impact on physiological parameters and increase sensitivity to focal cerebral ischaemia. Investigating the effect of chronic photoperiod disruption on outcome following permanent focal cerebral ischaemia For this purpose, a PD protocol was employed to simulate shift work patterns of light/dark (LD) exposure. Male Wistar rats were exposed to either a 12:12 LD cycle or a 6-hour phase advance protocol for 9 weeks. This was done by switching the lights on 6 hours earlier than the previous photoperiod every 3 days. T2-weighted MRI was performed at 48 hours after permanent middle cerebral artery occlusion. Chronic PD for 9 weeks did not significantly affect food intake, body weight and key physiological parameters such as blood glucose and blood pressure and did not increase sensitivity to ischaemic damage in young, normotensive rats. This suggests that light alone is not a single factor to induce circadian disruption. The potentially adverse impact of shift work on stroke outcome may require additional factors such as high fat/high sugar diet or pre-existing co-morbidities. Characterisation and optimisation of animal model for transient focal cerebral ischaemia Results from the previous study of permanent ischaemia raised the question as to on how PD impacts on stroke outcome in the presence of reperfusion. In addition, since the majority of stroke patients present with co-morbid factors, subsequent studies aimed to determine the impact of PD in the presence of pre-existing hypertension following transient focal ischaemia. Prior to this a pilot study was conducted to optimise the time of middle cerebral artery (MCA) occlusion and to characterise the associated neurological and functional outcomes. The following information was used to inform the subsequent studies; 1) the optimal MCA occlusion time in spontaneously hypertensive rats (SHR) was 30 min and 2) transient MCA occlusion resulted in reproducible functional impairments in both neurological score and the adhesive label test assessed at 7-days. Impact of photoperiod disruption on sensitivity to focal cerebral ischaemia and microglia activation in spontaneously hypertensive rats Adult male SHR underwent 30 min transient MCAO following the 9-week PD protocol. Reperfusion resulted in significant tissue salvage. However, PD in the presence of pre-existing hypertension did not exacerbate ischaemic lesion evolution assessed by diffusion-weighted MRI, and by measuring the final infarct volume. Furthermore, PD alone did not induce significant changes in microglia activation in the brains of SHR that were not subjected to ischaemia. Poor collaterals and pre-existing hypertension in SHR may explained to lesser effect of PD on lesion evolution, as there may have been less penumbral tissue available for PD to exert its detrimental effect. Conclusion The studies presented in this thesis demonstrated that PD did not increase sensitivity to focal cerebral ischaemia in normotensive rats. Similarly, PD in the context of major stroke co-morbidity/risk factor did not exacerbate ischaemic damage. This suggest that the primary mechanism of cardiometabolic disturbances among shift workers may not primarily mediated by shifting in the light/dark cycle.