Stress Response Direction Determines the Regulation of Cerebral Cortex Neurons Apoptosis in Acute Stroke Brain

Relevance. The development of ischemic stroke (IS) is obligately accompanied by activation of the stress-releasing system. Predominant activation of hypothalamic-pituitary-adrenal axis is associated with a worse IS acute period prognosis. At the same time, the question of the stress-releasing system role in the brain neurons death regulation in IS remains unexplored.

Purpose to study the effect of peripheral blood cortisol concentration on the regulation of apoptosis of cerebral cortex neurons in the acute period of ischemic stroke.

Materials and methods. A prospective clinical and pathomorphological study was carried out. The study included 9 left middle cerebral artery who were admitted to the hospital and died in the acute period of IS in the absence of infectious complications, allergic reactions, oncological diseases, and who did not undergo thrombolysis. Examined the cerebral cortex. On sections, an indirect immunoperoxidase immunohistochemical method revealed neuron specific enolase (NSE), protein p53 (p53), caspase 3, caspase 8, Fas-receptor (CD95), Fas-ligand (CD178), Fas-apoptosis inhibitory molecule 2 (FAIM2). A total of 567 visual fields were processed for the group of patients after IS and 63 visual fields for the control group (3 people). Before the onset of death in the blood, the concentrations of sFas, sFasL, cortisol, adrenocorticotropic hormone, epinephrine, noradrenaline were measured by enzyme immunoassay (the control group consisted of 28 people).

Results. An increase in the proportion of neurons expressing proteins responsible for apoptosis was detected in the cerebral cortex compared to the control group; decrease in the proportion of p53, casp8, casp3-positive cells with distance from the ischemic core.

The proportion of neurons expressing membrane forms of Fas receptors in the 1st zone of the study was the largest, and in the 2nd and 3rd zones it significantly decreased. Expression of membrane Fas ligands was detected on 63.6 (58.3;70)% of NSE positive cells in the 1st zone, which significantly (p < 0.01) differed from control samples (75.5 (66.7;81.5 )%) to a lesser extent, while zones 2 and 3 were characterized by a significant increase in the proportion of neuronal cells expressing FasL, respectively, to 78.1 (71.4;85.7)% (p < 0.05) and 89.1 (81 .4;93)% (р < 0.01). In the 3rd zone, a decrease in the proportion of Fas- and casp8-positive neurons was revealed with an increase in the proportion of FasL-positive non-neuronal cells (r = -0.160, p < 0.05 and r = -0.211, p < 0.01, respectively). The proportion of FAIM2 positive neurons in the 2nd zone was 73 (67.9;78.9)% and did not differ significantly from the indicators of samples in the control group (72.4 (66.1;76.8)%). In the remaining study areas, the differences from the control were significant (p < 0.01), and the values of the indicators were lower. Significant correlations were revealed between the proportion of caspase 3-positive neurons and the concentration of cortisol in peripheral blood in zones 2 (r = 0.263, p < 0.01) and 3 (r = 0.383, p < 0.01). In zone 2, significant negative correlations were noted with the concentrations of sFas (r = -0.177, p < 0.05) and sFasL (r = -0.164, p < 0.05), in zone 3 — significant positive correlations with the ratio of concentrations of sFasL and sFas (r = 0.240, р < 0.01). The proportion of Fas-positive neurons in the cerebral cortex significantly correlated with the concentration of the soluble form of this molecule (for the 1st zone - r = 0.222, for the 2nd zone - r = 0.438, for the 3rd zone - r = 0.289, р < 0.01) and the ratio of concentrations of sFasL and sFas (for zones 1 and 2, respectively: r = 0.231, r = 0.266 and r = 0.281, p < 0.01) in peripheral blood.

Conclusions: The cortisol concentration in peripheral blood has a significant effect on the cerebral cortex neurons apoptosis regulation in the acute IS period.