Abstract
We have recently found that the temperature variability (TV) in the day–night cycle may predict the mean intracranial pressure in the following 24 h (ICP24) in subarachnoid hemorrhage (SAH) patients under multimodality monitoring, sedation, and hypothermia (<35°C). Specifically, we found that ICP24 = 6 (4 − TV) mmHg. TV is the ratio between the coefficient of variation of temperature during the nocturnal and the preceding diurnal periods. This result suggests that the circadian clock reflects brain plasticity mechanisms and its malfunctioning leads to deterioration of the neurologic status. The sleep–wake cycle is absent in these patients and their circadian clock can function properly only by environment light-independent mechanisms. One mechanism involves the circadian clock proteins named cryptochromes (CRYs). CRYs are highly preserved and widespread in the evolutionary tree, are expressed in different cell types in humans [type II CRYs, in two forms: human cryptochrome 1 and 2 (hCRY1 and hCRY2)], and in certain species, respond to blue light and play role in magnetoreception. Interestingly, SAH outcome seems to correlate with inflammation, and CRYs decrease inflammatory activity. Our hypothesis derived from these observations is that CRYs modulate the circadian oscillation of temperature even during therapeutic hypothermia and improve outcome in SAH through decrease in inflammation. A strategy to test this hypothesis is to measure periodically during the acute phase of high-grade SAH the level of CRYs in cerebrospinal fluid (CSF) and circulating white blood cells, and to correlate these levels with outcome, TV, ICP24, and pro- and anti-inflammatory markers in CSF and blood. If this hypothesis is true, the development of therapies targeting inflammation in SAH could take advantage of cryptochrome properties. It has been shown that blue light phototherapy increases the expression of CRYs in blood mononuclear cells in jaundiced neonates. Likewise, visual stimulus with flashing light improves Alzheimer’s disease features in experimental model and there is a prominent expression of CRYs in the retina. Remarkably, recent evidence showed that hCRY2 responds to electromagnetic fields, which could be one elusive mechanism of action of transcranial magnetic stimulation and a reason for its use in SAH.
Highlights
Our previous work indicates that circadian rhythms are a primary factor to predict brain injury [1,2,3,4,5,6]
If CRYn/d or WBCCn/d correlates with temperature variability (TV) and ICP24 and transcranial magnetic stimulation and blue light interfere in the level of hCRYs, the endpoint of these therapies in high-grade subarachnoid hemorrhage (SAH) could be the value of CRYn/d or WBCCn/d that leads to a TV higher than 0.666 and to a predicted ICP24 lower than 20 mmHg (Figure 2)
We are currently testing whether ICP24 can be predicted by TV during non-hypothermia periods using variables derived from the mean coefficient of variation of harmonics of 12 h obtained during day or night, similar to the formula to predict ICP24 already described (Figure 3)
Summary
Our previous work indicates that circadian rhythms are a primary factor to predict brain injury [1,2,3,4,5,6]. The circadian pattern of temperature oscillation correlates with further neurologic signs (i.e., seizure in epileptic patients and intracranial hypertension in high-grade SAH) [1,2,3], and an elusive mechanism of this finding is that a normal circadian rhythm reflects normal hypothalamic neurogenesis (Figure 1) [1,2,3,4,5,6] Another potential marker of circadian rhythm, which could theoretically form a loop involving hCRYs and neurogenesis is blue light emission by the body. Neurogenesis could close the loop by decreasing ROS formation, blue light emission, and CRY stimulation These observations raise the possibility that the circadian pattern of CRY expression correlates with circadian patterns of markers of inflammation and neurogenesis, neurologic signs in the following day–night cycle, and outcome in high-grade SAH. The presence of mast cells in circumventricular organs, action of histamine to increase blood–brain barrier permeability, decrease inflammation, protect neurons from secondary injury, and stimulate neurogenesis suggest that mast cells may play a role in endogenous mechanisms of neuroprotection and neuroregeneration
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