Ece OdabaşıY. , Elif DuymazE.
The permanent loss of circulatory, respiratory, or cerebral activity is defined as death of peripheral human organs. Tissues of the central nervous system, except for many peripheral human organs, swiftly lose their viability when circulation is stopped. Using the retina as a model of the central nervous system (CNS), this study investigates the dynamics of death and neural regeneration. Ischemic events in the central nervous system that result in circulatory arrest have long been known to induce irreparable brain damage. During these situations, electrical activity increases, but the impression of bright light just after death – the “near-death experience” – disappears within minutes of cardiac arrest, as does awareness and brain function. This work, which used the retina as a CNS model, explored the notion that light-evoked spherical electrical activity arising from simultaneous activation of neuronal populations can be recovered after death. Previous research has found similarities and variations in light transmission and gene expression in mouse retinas. In vivo electroretinography (ERG), a technology that gives information about the retina, was used to evaluate cell responses in mice before and after death. Previous research has shown that a few minutes after death, in vivo light-evoked retinal responses were drastically diminished.
The goal of Abbas et al. in the investigation was to see if retinal neuron activity could be triggered ex vivo by restoring normal pH and oxygenation levels. Consequently, photoreceptor-driven ERG-wave and ON bipolar cell-driven ERG b-wave light responses recovered significantly between 15 and 3 hours after death. Ex vivo restoration recovered light-evoked photoreceptor responses even after the evoked neuronal activity had stopped following death.
Activated caspase-3 protein was examined in slices from eyes with varied enucleation delays from death to see if partial loss of responsiveness is related to apoptosis in photoreceptor and ON bipolar cells. The limited recovery of responses during the 3-hour postmortem period was not caused by apoptotic cell death, suggesting that photoreceptor and bipolar cell function may be fully recovered. It is theorized that prolonged hypoxia and/or acidification of retinal tissue diminishes light-induced responses recovered ex vivo and inhibits signal transmission from the body. Because the loss of circulatory and respiratory activity after death results in a reduction in oxygen content and pH. The findings suggest that postmortem hypoxia plays a significant role in the development of cancer.
The kinetics of light-evoked b-wave amplitude loss under low pH conditions, then, the researchers studied. Since the pH of postmortem eyes lowers to 6, b-wave responses were examined under physiological (7.4) and low (6.8) pH by altering the bicarbonate (HCO3-) concentration of the medium while keeping the CO2 level at 5%. After death, in vivo light responses was degraded somewhat faster than ex vivo low O2 or low pH responses. Hypoxia and acidosis, on the other hand, are major contributors to the loss of retinal light signal after death. Even after a recovery time under normal perfusion circumstances, prolonged hypoxia incubation has been shown to irrevocably diminish b-wave amplitudes. These findings show that chronic hypoxia prevents Aretinal function from fully recovering. In contrast, even after bipolar cell activity has halted, b-waves produced by ON bipolar cells may be fully restored under low pH circumstances by returning the retinas’ environment to normal pH. Shortly, postmortem hypoxia is a rate-limiting factor that results in partial retinal light response restoration.
Ex vivo modifications might affect the quantities of chemicals like glutamate and GABA which could explain why postmortem retinal tissues have poor signal transduction. Both glutamine and glutamate levels were shown to be lower in all cells 45 minutes after death result of computational molecules phenotyping (CMP). This might explain why ON bipolar cell light responses fade quickly after death.
The human retina is physically distinct, having a central macula and fovea, as well as a greater cone density and metabolic rate. As a result, restoring light signals in human retinal photoreceptors after death is predicted to be more challenging. Explants from donor human eyes obtained 2-5 hours after death were used in this investigation to improve macular photoreceptor light responses. The use of human donor eyes involves a lot of unknown variables. This discrepancy might be due to human cone density being higher, mouse rod density being higher, or other distinctions between species. Older eyes may have pre-death exposure to preconditioning events due to a decreased metabolic rate or hypoxia. The findings demonstrate that increasing donor age has no negative impact on physiological measurements, and the reason for death is an essential factor to consider when setting donor criteria. In studies, however, b-waves were not consistently recovered. To examine if hypoxia is the major cause of the disorder, b-waves were regularly recorded in the eyes of organ donors who had a postmortem hypoxic duration of fewer than 20 minutes. The explanation for the lack of recovery of b-waves in donors with an enucleation delay of 45 minutes to 5 hours is the extension of the postmortem hypoxic period.
Furthermore, the findings reveal that deactivation of phosphodiesterases and visual pigments in human macular cones is substantially faster than in rods, contributing to human cone-mediated high-acuity colour vision’s lower light sensitivity and faster kinetics. According to the research, the typical length of human macular rods is 10 times that of macular cones. Macular rods and peripheral rods from healthy donors were found to be identical. Finally, light responses in the macular and peripheral cones of humans and macaques were compared. The amplitudes of the cone response in human peripheral samples are about five times less than in macular samples. The sensitivity of macular and peripheral cones, on the other hand, did not differ considerably.
As summary, the purpose of the article is to investigate death kinetics by using the retina as a central nervous system model. By defining neuronal signaling, a new perspective has been given to the human central nervous system by investigating how much postmortem light signaling is reversible in mouse and human retinas.
Reference
Abbas, F., Becker, S., Jones, B. W., Mure, L. S., Panda, S., Hanneken, A., & Vinberg, F. (2022). Revival of light signalling in the postmortem mouse and human retina. Nature |, 606, 351. https://doi.org/10.1038/s41586-022-04709-x
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