Hypothesis on the Role of Cryptochromes in Inflammation and Subarachnoid Hemorrhage Outcome

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.

Keywords: circadian rhythm; cryptochromes; inflammation; intracranial pressure prediction; neurogenesis; subarachnoid hemorrhage; targeted temperature management; therapeutic hypothermia.

Figure 1

Elusive mechanism of the correlation between cryptochrome expression, temperature variability (TV), and further intracranial pressure (ICP). The potential neurogenic system that we described recently may be a background mechanism of brain plasticity whose core is located in the hypothalamus. This system may be modulated by the redox state of brain cells, which is remarkably altered in brain injury. An effective injury-induced neurogenesis would restore hypothalamus-related functions such as circadian rhythms and next autonomic functions related to cerebral autoregulation, contributing to ICP control. TV seems to be a marker of circadian rhythm even in comatose and sedated patients undergoing hypothermia. This condition implies the role of a light-independent mechanism of circadian rhythm control, which may be played by hCRY expression.

Figure 2

Key temperature variability (TV) values and corresponding predicted mean intracranial pressure in the following 24 h (ICP₂₄). This figure is a schematic representation of key TV values and their corresponding predicted ICP₂₄ [for detailed explanation, please see Ref. (2)]. Numbers between parentheses correspond to 80% prediction interval. These values could guide a further circadian rhythm modulation by stimulation of hCRY expression through transcranial magnetic and blue light stimulations.

Figure 3

Caveat on intracranial pressure (ICP) prediction via temperature variability (TV) analysis. This panel illustrates that TV can predict ICP (in millimeter of mercury) only when mean daily T < 35°C and points to possible factor that contributes for this feature. (A,D) Show temperature in the same scale to visualize that absolute values were practically the same only during intravascular-induced hypothermia, which implicates that night–day ratio of coefficient of variation and night–day ratio of SD of temperature are practically the same only during hypothermia. In (B,E), the temperature curves were zoomed in to show that temperature range is larger during normothermia. Note that the baseline changes in the second part of the day during normothermia [day is represented at the left side of vertical line of (A,B,D,E)], which reflects in the SD found; on the other hand, SD during hypothermia reflects principally temperature variation on a constant baseline. We are calculating the coefficient of variation of shorter periods (harmonics of 12 h) to see if the mean of these values can be used to derive a formula to predict ICP₂₄. (C,F) shows the ICP curves of the next day. The predicted ICP (pICP₂₄) matches ICP₂₄ only during hypothermia. For details regarding calculation, please see Ref. (2), from which (A–C) were adapted; (D–F) have not been published previously.