Mild stimulation improves neuronal survival in an in-vitro model of the ischemic penumbra

Lorenzo Muzzi, Gerco Hassink, Marloes Rianne Levers, M.M.T. Jansman, Monica Frega, Jeannette Hofmeijer, Michel J.A.M. van Putten, Joost le Feber*

*Corresponding author for this work

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Abstract

OBJECTIVE: In the core of a brain infarct, characterized by severely reduced blood supply, loss of neuronal function is rapidly followed by neuronal death. In peripheral areas of the infarct, the penumbra, damage is initially reversible, and neuronal activity is typically reduced due to ischemia-induced synaptic failure. There is limited understanding of factors governing neuronal recovery or the transition to irreversible damage. Neuronal activity has been shown to be crucial for survival. Consequently, hypoxia induced neuronal inactivity may contribute to cell death, and activation of penumbral neurons possibly improves survival. Adversely, activation increases ATP demand, and a balance should be found between the available energy and sufficient activity. APPROACH: We monitored activity and viability of neurons in an in vitro model of the penumbra, consisting of (rat) neuronal networks on micro electrode arrays (MEAs) under controlled hypoxic conditions. We tested effects of optogenetic and electrical activation during hypoxia. MAIN RESULTS: Mild stimulation yielded significantly better recovery of activity immediately after re-oxygenation, compared with no stimulation, and a 60%-70% higher survival rate after 5 d. Stronger stimulation was not associated with better recovery than no stimulation, suggesting that beneficial effects depend on a delicate balance between sufficient activity and available energy. SIGNIFICANCE: We show that mild activation during hypoxia/ischemia is beneficial for cell survival in an in vitro model of the penumbra. This finding opposes the current common belief that suppression of neuronal activity is the cornerstone of neuroprotection during cerebral ischemia, and may open new possibilities for the treatment of secondary brain damage after stroke.

Original languageEnglish
Article number016001
Number of pages1
JournalJournal of neural engineering
Volume17
Issue number1
DOIs
Publication statusPublished - 5 Dec 2019

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Chemical activation
Ischemia
Optogenetics
Recovery
Neurons
Brain
Brain Ischemia
Oxygenation
Adenosinetriphosphate
Cell Survival
Electrodes
Cell Death
Cell death
Survival Rate
Adenosine Triphosphate
Stroke
Rats
Blood
Cells
In Vitro Techniques

Cite this

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title = "Mild stimulation improves neuronal survival in an in-vitro model of the ischemic penumbra",
abstract = "OBJECTIVE: In the core of a brain infarct, characterized by severely reduced blood supply, loss of neuronal function is rapidly followed by neuronal death. In peripheral areas of the infarct, the penumbra, damage is initially reversible, and neuronal activity is typically reduced due to ischemia-induced synaptic failure. There is limited understanding of factors governing neuronal recovery or the transition to irreversible damage. Neuronal activity has been shown to be crucial for survival. Consequently, hypoxia induced neuronal inactivity may contribute to cell death, and activation of penumbral neurons possibly improves survival. Adversely, activation increases ATP demand, and a balance should be found between the available energy and sufficient activity. APPROACH: We monitored activity and viability of neurons in an in vitro model of the penumbra, consisting of (rat) neuronal networks on micro electrode arrays (MEAs) under controlled hypoxic conditions. We tested effects of optogenetic and electrical activation during hypoxia. MAIN RESULTS: Mild stimulation yielded significantly better recovery of activity immediately after re-oxygenation, compared with no stimulation, and a 60{\%}-70{\%} higher survival rate after 5 d. Stronger stimulation was not associated with better recovery than no stimulation, suggesting that beneficial effects depend on a delicate balance between sufficient activity and available energy. SIGNIFICANCE: We show that mild activation during hypoxia/ischemia is beneficial for cell survival in an in vitro model of the penumbra. This finding opposes the current common belief that suppression of neuronal activity is the cornerstone of neuroprotection during cerebral ischemia, and may open new possibilities for the treatment of secondary brain damage after stroke.",
author = "Lorenzo Muzzi and Gerco Hassink and Levers, {Marloes Rianne} and M.M.T. Jansman and Monica Frega and Jeannette Hofmeijer and {van Putten}, {Michel J.A.M.} and {le Feber}, Joost",
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language = "English",
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journal = "Journal of neural engineering",
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Mild stimulation improves neuronal survival in an in-vitro model of the ischemic penumbra. / Muzzi, Lorenzo ; Hassink, Gerco; Levers, Marloes Rianne; Jansman, M.M.T.; Frega, Monica ; Hofmeijer, Jeannette ; van Putten, Michel J.A.M.; le Feber, Joost.

In: Journal of neural engineering, Vol. 17, No. 1, 016001, 05.12.2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Mild stimulation improves neuronal survival in an in-vitro model of the ischemic penumbra

AU - Muzzi, Lorenzo

AU - Hassink, Gerco

AU - Levers, Marloes Rianne

AU - Jansman, M.M.T.

AU - Frega, Monica

AU - Hofmeijer, Jeannette

AU - van Putten, Michel J.A.M.

AU - le Feber, Joost

PY - 2019/12/5

Y1 - 2019/12/5

N2 - OBJECTIVE: In the core of a brain infarct, characterized by severely reduced blood supply, loss of neuronal function is rapidly followed by neuronal death. In peripheral areas of the infarct, the penumbra, damage is initially reversible, and neuronal activity is typically reduced due to ischemia-induced synaptic failure. There is limited understanding of factors governing neuronal recovery or the transition to irreversible damage. Neuronal activity has been shown to be crucial for survival. Consequently, hypoxia induced neuronal inactivity may contribute to cell death, and activation of penumbral neurons possibly improves survival. Adversely, activation increases ATP demand, and a balance should be found between the available energy and sufficient activity. APPROACH: We monitored activity and viability of neurons in an in vitro model of the penumbra, consisting of (rat) neuronal networks on micro electrode arrays (MEAs) under controlled hypoxic conditions. We tested effects of optogenetic and electrical activation during hypoxia. MAIN RESULTS: Mild stimulation yielded significantly better recovery of activity immediately after re-oxygenation, compared with no stimulation, and a 60%-70% higher survival rate after 5 d. Stronger stimulation was not associated with better recovery than no stimulation, suggesting that beneficial effects depend on a delicate balance between sufficient activity and available energy. SIGNIFICANCE: We show that mild activation during hypoxia/ischemia is beneficial for cell survival in an in vitro model of the penumbra. This finding opposes the current common belief that suppression of neuronal activity is the cornerstone of neuroprotection during cerebral ischemia, and may open new possibilities for the treatment of secondary brain damage after stroke.

AB - OBJECTIVE: In the core of a brain infarct, characterized by severely reduced blood supply, loss of neuronal function is rapidly followed by neuronal death. In peripheral areas of the infarct, the penumbra, damage is initially reversible, and neuronal activity is typically reduced due to ischemia-induced synaptic failure. There is limited understanding of factors governing neuronal recovery or the transition to irreversible damage. Neuronal activity has been shown to be crucial for survival. Consequently, hypoxia induced neuronal inactivity may contribute to cell death, and activation of penumbral neurons possibly improves survival. Adversely, activation increases ATP demand, and a balance should be found between the available energy and sufficient activity. APPROACH: We monitored activity and viability of neurons in an in vitro model of the penumbra, consisting of (rat) neuronal networks on micro electrode arrays (MEAs) under controlled hypoxic conditions. We tested effects of optogenetic and electrical activation during hypoxia. MAIN RESULTS: Mild stimulation yielded significantly better recovery of activity immediately after re-oxygenation, compared with no stimulation, and a 60%-70% higher survival rate after 5 d. Stronger stimulation was not associated with better recovery than no stimulation, suggesting that beneficial effects depend on a delicate balance between sufficient activity and available energy. SIGNIFICANCE: We show that mild activation during hypoxia/ischemia is beneficial for cell survival in an in vitro model of the penumbra. This finding opposes the current common belief that suppression of neuronal activity is the cornerstone of neuroprotection during cerebral ischemia, and may open new possibilities for the treatment of secondary brain damage after stroke.

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U2 - 10.1088/1741-2552/ab51d4

DO - 10.1088/1741-2552/ab51d4

M3 - Article

VL - 17

JO - Journal of neural engineering

JF - Journal of neural engineering

SN - 1741-2560

IS - 1

M1 - 016001

ER -