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COMMENTARY
Year : 2019  |  Volume : 5  |  Issue : 2  |  Page : 94-96

Restoring cerebral circulation and function postmortem: A multidimensional analysis


1 Interdisciplinary Program in Neuroscience, George Mason University, Fairfax, VA, USA
2 Department of Environmental Health Sciences, University of Massachusetts, Amherst, MA, USA
3 Departments of Neurology and Biochemistry; Neuroethics Studies Program, Georgetown University Medical Center, Washington, DC, USA

Date of Submission02-May-2019
Date of Decision03-May-2019
Date of Acceptance03-May-2019
Date of Web Publication27-Jun-2019

Correspondence Address:
Dr. James Giordano
Departments of Neurology and Biochemistry; Neuroethics Studies Program, Georgetown University Medical Center, Washington, DC
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bc.bc_10_19

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How to cite this article:
DeFranco J, Calabrese E, Giordano J. Restoring cerebral circulation and function postmortem: A multidimensional analysis. Brain Circ 2019;5:94-6

How to cite this URL:
DeFranco J, Calabrese E, Giordano J. Restoring cerebral circulation and function postmortem: A multidimensional analysis. Brain Circ [serial online] 2019 [cited 2019 Nov 19];5:94-6. Available from: http://www.braincirculation.org/text.asp?2019/5/2/94/261589



While many types of mammalian cells have been shown to remain viable after the cessation of blood flow and/or deprivation of oxygen, neurons have not been known to recover well after substantial insult, thus making the brain susceptible to irreversible damage. However, recent studies have demonstrated that neuronal apoptosis and necrosis may be delayed for several hours if the brain is kept under certain conditions postmortem. Vrselja et al.[1] isolated the brain of a pig (Sus scrofa domesticus) 4-h postmortem and showed that with specific intervention, cerebral blood vessel perfusion and glial function could be restored and sustained, and neuroanatomical structure and neuronal vitality maintained. Employing a system of their own design called BrainEx (BEx), the carotid arteries were connected and perfused following isolation of the brain just superior (i.e., rostral) to the medulla oblongata. The perfusate was primarily composed of Hemopure, a bovine hemoglobin-based solution previously employed as a medium for tissue delivery of oxygen.[2] At 4-h postmortem, porcine brains were perfused for 6-h ex vivo using the BEx device (i.e., for a total postmortem interval [PMI] of 10 h). The effects of BEx perfusion on neural integrity and function were evaluated against three control brain groups: (1) a 1-h PMI, (2) a 10-h PMI, which had been left in crania at room temperature, and (3) BEx perfusion using a control liquid.

To be sure, many of the reported results were indubitably important, if not “landmark.” First, it was found that the BEx system enabled successful circulation of the perfusate throughout the brain. Second, administration of nimodipine increased perfusion, thereby demonstrating that the BEx system sustained cerebrovascular responsivity postmortem. Third, it was found that Hemopure perfusion using the BEx system significantly reduced postmortem deterioration of both gray matter and white matter, with neuroanatomical (i.e., morphologic and histologic) integrity preserved in the hippocampus, neocortex, and cerebellum.

When compared to the 1-h PMI (and the other two control groups), hippocampi perfused with the BEx system showed considerably less swelling and significantly preserved neural circuitry. As well, it was found that BEx perfusion resulted in increased levels of cerebral interleukin (viz., a glial-derived immunomodulatory peptide in the brain), thereby suggesting that glia remained viable 4-h postmortem. Finally, perhaps of most significant media interest, perfusion using the BEx system enabled spontaneous excitatory postsynaptic currents in hippocampal pyramidal neurons, thus possibly demonstrating postmortem neuronal viability.

These findings could and should foster further research on the viability of this system, and other technologies and techniques of cerebral perfusion that could be instrumental to developing improved interventions for neurological trauma and disorders. For example, such approaches could be developed and employed for retaining and/or restoring certain brain functions after traumatic brain injuries, stroke, and/or loss of network activity as a consequence of progressive insult of neurodegenerative diseases.

Of particular note is that the use of the BEx system can reestablish, if not completely restore, cerebral blood flow and thereby mitigate loss of cerebral perfusion and the effects of anoxia even after a substantial PMI. This is of interest in light of our ongoing work examining the effects of acute and chronic metabolic stress on neural biochemistry, function, and integrity.[3] In almost every instance, the integrity or disruption of oxygen-dependent neuronal and/or glial metabolic pathways involves hormetic mechanisms and responses.[4],[5]

Hormesis is a highly conserved and generally adaptive process that is manifested as a biphasic dose response, with specific quantitative features (i.e., 30%–60% stimulatory amplitude, typically 5–20-fold stimulatory range).[6],[7] It occurs as a consequence of either direct stimulation or within pre- or postconditioning contexts in a variety of species and in several organ systems, including the brain (i.e., in both neuronal and glial cell types).[8] Hormetic agents upregulate a number of adaptive mechanisms that can be activated within hours to days following hormetic induction to protect neural cells against numerous types of insult, including anoxia and oxidative stress (which can subsequently induce apoptosis and/or necrosis).[9] We believe that further understanding these mechanisms – and their dosimetric properties – may be important to developing improved methods of postinsult (and/or postmortem) cerebral protection, perfusion, and possible sustenance or recovery of function.[10]

However, keeping in mind the maxim that “small doses can exert a profound effect,” it is equally important to address the media – and some academic – handling of, and reactions to Vrselja et al.'s work. On one hand, the media response(s) can be seen as viable promotion, if not advocacy for “brave new advances” in the brain sciences.[11] Yet, the nature of the findings led to ampliative claims and debates about the ethical improbity of “reviving brain cells”[12] and bringing “a dead pig brain back to life outside its corpse.”[13] Importantly, Vrselja et al. explicitly stated that their results do not demonstrate or prove the recovery of brain functions after 4-h PMI. Hence, reactive assertions of both fantastical scientific interventions and abrogation of ethical probity were exaggerated at least, and wholly misrepresentational, at worst.

Both science fiction tales and nonfictional speculations about the (outer) limits of restorative biomedicine often center upon goals and/or unrealistic hopes and claims of extending the life – or “consciousness – span;” sometimes with view saecula saeculorum (viz., for ever and ever).[14] However, any ethical analyses of emergent capabilities in science and technology must be based on, proceed from, and adhere to the fact(s). While it may be tempting – and not without some merit – to extrapolate future possibilities and potentialities, and/or allude to science fictional accounts, both should be explicitly stated as such. The former, as based on realistic models that forecast trajectories of scientific and technological developments, and their uses in practices in varied socioeconomic, cultural, and political environments.[15] The latter as means to communicate what might be possible or potentially viable, in explicitly defined scenarios of near – or far – term futures, given certain directions and valences of what is currently probable (or at least imaginable).[16] Nevertheless, we have argued that here too, perhaps even more than ever, there is an ethical importance (if not responsibility) to adhere to fact, while entertaining creative license, so as to create depictions of “what might be” given distinct manifestations of science, and effects and manifestations of its use (or misuse) given certain pushing and pulling forces in the social milieu.[16]

It is likely that the efforts of Vrselja et al. will prompt future research using BEx and related and/or derived technologies. Although there are existing regulations that govern research and its clinical applications, there is an increasing concern that not every nation state or culture is willing to comply with those ethical guidelines.[17] Thus, what may need to be “resuscitated” and “kept alive” are genuine efforts to sustain more accurate media (and academic) representation of science and technology and methods and opportunities for cosmopolitan ethical discourse and address of the real issues, problems, and solutions that such science fosters on the global stage.

Acknowledgment

EJC acknowledges long time support from the US Air Force (AFOSR FA9550-13-1-0047) and ExxonMobil Foundation (S18200000000256). The US Government is authorized to reproduce and distribute for governmental purposes notwithstanding any copyright notation thereon. JG is supported by federal funds UL1TR001409 from the National Center for Advancing Translational Sciences, National Institutes of Health, through the Clinical and Translational Science Awards Program, a trademark of the Department of Health and Human Services, part of the Roadmap Initiative, “Re-Engineering the Clinical Research Enterprise.” The views and conclusions contained herein are those of the author and should not be interpreted as necessarily representing policies or endorsement, either expressed or implied. Sponsors had no involvement in study design, collection, analysis, interpretation, writing, and decision to and where to submit for publication consideration.



 
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Vrselja Z, Daniele SG, Silbereis J, Talpo F, Morozov YM, Sousa AM, et al. Restoration of brain circulation and cellular functions hours post-mortem. Nature 2019;568:336-43.  Back to cited text no. 1
    
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Sprung J, Kindscher JD, Wahr JA, Levy JH, Monk TG, Moritz MW, et al. The use of bovine hemoglobin glutamer-250 (Hemopure) in surgical patients: Results of a multicenter, randomized, single-blinded trial. Anesth Analg 2002;94:799-808.  Back to cited text no. 2
    
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Calabrese V, Santoro A, Trovato Salinaro A, Modafferi S, Scuto M, Albouchi F, et al. Hormetic approaches to the treatment of Parkinson's disease: Perspectives and possibilities. J Neurosci Res 2018;96:1641-62.  Back to cited text no. 3
    
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Calabrese EJ, Calabrese V, Giordano J. The role of hormesis in the functional performance and protection of neural systems. Brain Circ 2017;3:1-13.  Back to cited text no. 4
[PUBMED]  [Full text]  
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Calabrese V, Giordano J, Crupi R, Di Paola R, Ruggieri M, Bianchini R, et al. Hormesis, cellular stress response and neuroinflammation in schizophrenia: Early onset versus late onset state. J Neurosci Res 2017;95:1182-93.  Back to cited text no. 7
    
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Calabrese V, Giordano J, Signorile A, Laura Ontario M, Castorina S, De Pasquale C, et al. Major pathogenic mechanisms in vascular dementia: Roles of cellular stress response and hormesis in neuroprotection. J Neurosci Res 2016;94:1588-603.  Back to cited text no. 8
    
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Calabrese V, Giordano J, Ruggieri M, Berritta D, Trovato A, Ontario ML, et al. Hormesis, cellular stress response, and redox homeostasis in autism spectrum disorders. J Neurosci Res 2016;94:1488-98.  Back to cited text no. 9
    
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Zhang C, Chen S, Bao J, Zhang Y, Huang B, Jia X, et al. Low doses of camptothecin induced hormetic and neuroprotective effects in PC12 cells. Dose Response 2015;13:1559325815592606.  Back to cited text no. 10
    
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Agius C. Reanimated Pig Brain Cells Raise Ethical Concerns. ABC News; 18 April, 2019 Available from: https://www.abc.net.au/radio/programs/worldtoday/reanimated-pig-brain-cells-raise-ethical-concerns/11028652. [Last accessed 2019 Apr 30].  Back to cited text no. 11
    
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Vox F. How Reviving Cells in a Pig's Brain Could Change Medicine. CNN; 20 April, 2019. Available from: https://www.cnn.com/2019/04/20/opinions/pig-brain-experiment-medicine-vox/index.html. [Last retrieved on 2019 Apr 30].  Back to cited text no. 12
    
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Burns C. Pig Brain Lives Outside Corpse after Beheading. Slash Gear; 23 April, 2019. Available from: https://www.slashgear.com/pig-brain-lives- outside- corpse-after-beheading-23574468/. [Last retrieved on 2019 Apr 30].  Back to cited text no. 13
    
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Fitzpatrick C, Giordano J. In saecula saeculorum? Bioscience, biotechnology and the construct of death. In: Tandy C. editor. Death and Anti-Death: Ten Years after Donald Davidson. Vol. 11. MO: RIA Press; 2014.  Back to cited text no. 14
    
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DeFranco J, Bremseth LR, Giordano J. The Importance of Integrative Science/Technology Intelligence (InS/TINT) to the Prediction of Future Vistas of Emerging Threats. Mad Scientist Laboratory Post #125; 13 March, 2019. Available from: https://madsciblog.tradoc.army.mil/125-the-importance-of-integrative-science-technology-intelligence-ins-tint-to-the-prediction-of-future-vistas-of-emerging-threats/. [Last accessed 2019 Apr 30].  Back to cited text no. 15
    
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Shook JR, Giordano J. Ethics transplants? Addressing the risks and benefits of guiding international biomedicine. AJOB Neurosci 2017;8:230-2.  Back to cited text no. 17
    




 

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