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Inducing Neurophysiological Recovery of the Post-mortem Mammalian Brain

Review of “Restoration of brain circulation and cellular functions hours post-mortem” from Nature by Stuart P. Atkinson

The loss of the oxygenated blood supply to the mammalian brain initiates a progressive cascade of cell death mechanisms and axonal damage; however, recent studies have suggested that neural cell death shortly following the causative event may not represent an inevitable occurrence. Evidence for this claim includes the maintenance of electrophysiological activity and mitochondrial function in the brain hours after death [1, 2], full neurological recovery from prolonged cardiac arrest in humans with hypothermia [3], and favorable patient outcomes following blood clot removal up to 16 hours after an ischemic event [4].

This suggested to researchers led by Nenad Sestan (Yale School of Medicine, New Haven, CT, USA) that a widened temporal window may exist for the application of therapeutics aiming to halt the progression of the damaging cellular programs initiated by the ischaemic insult and perhaps even to restore brain function. To this end, Vrselja et al. now report on the development of a novel approach that restored and maintained microcirculation and cellular viability in the brain of a large animal model after a prolonged post-mortem interval. Excitingly, this study may represent the first step towards the development of a therapy that promotes neurophysiological recovery of the brain following the loss of the blood supply [5].

The authors christened their novel approach “BrainEx”, which included the development of a precise surgical procedure, the formulation of a hemoglobin-based, acellular, and non-coagulative cytoprotective fluid for brain perfusion, and the construction of an extracorporeal pulsatile-perfusion device. The team then aimed to restore and support microcirculation and cellular viability in the brains of 6–8-month-old pigs at four hours post-mortem.

Fascinatingly, the authors reported that BrainEx reduced reperfusion injury, prevented edema, and provided metabolically support for the energetic requirements of the brain while also reducing levels of neuronal death and preserving anatomical and neural cell integrity. Furthermore, BrainEx restored specific cellular functions, as evidenced by the restoration of vascular dilatory and glial inflammatory responses, the induction of spontaneous synaptic activity, and the detection of active cerebral metabolism. While the authors underlined the complete absence of global brain activity associated with awareness, perception, or other higher-order brain functions, the consequences of more extended perfusion studies remain unknown.

Through the development of BrainEx, the authors now establish that the brain displays robust metabolic and neurophysiological resilience and that any deterioration occurs over a more extended period than previously surmised. Furthermore, they anticipate that this new technology will allow researchers to move past static histological, biochemical, or structural investigations and conduct prospective, functional ex vivo studies in intact brains.

For more on his fascinating subject, see the related Nature News and Nature Comment articles that discuss the “slew of ethical and legal questions about the nature of death and consciousness”, and, as always, stay tuned to the Stem Cells Portal!

References

  1. Charpak S and Audinat E, Cardiac arrest in rodents: maximal duration compatible with a recovery of neuronal activity. Proceedings of the National Academy of Sciences of the United States of America 1998;95:4748-53.
  2. Barksdale KA, Perez-Costas E, Gandy JC, et al., Mitochondrial viability in mouse and human postmortem brain. FASEB Journal 2010;24:3590-9.
  3. Hughes A, Riou P, and Day C, Full neurological recovery from profound (18.0 degrees C) acute accidental hypothermia: successful resuscitation using active invasive rewarming techniques. Emergency Medicine Journal 2007;24:511-2.
  4. Albers GW, Marks MP, Kemp S, et al., Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. New England Journal of Medicine 2018;378:708-718.
  5. Vrselja Z, Daniele SG, Silbereis J, et al., Restoration of brain circulation and cellular functions hours post-mortem. Nature 2019;568:336-343.