Ac-YVAD-CMK inhibits pyroptosis and improves functional outcome after intracerebral hemorrhage

Xiao Lin, Haotuo Ye, Felix Siaw-Debrah, Sishi Pan, Zibin He, Haoqi Ni, Zhu Xu, Kunlin Jin, Qichuan Zhuge, Lijie Huang

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Intracerebral hemorrhage (ICH) refers to bleeding in the brain and is associated with the release of large amount of inflammasomes, and the activation of different cell death pathways. These cell death pathways lead to removal of inactivated and damaged cells and also result in neuronal cell damage. Pyroptosis is a newly discovered cell death pathway that has gained attention in recent years. This pathway mainly depends on activation of caspase-1-mediated cascades to cause cell death. We tested a well-known selective inhibitor of caspase-1, AC-YVAD-CMK, which has previously been found to have neuroprotective effects in ICH mice model, to ascertain its effects on the activation of inflammasomes mediated pyroptosis. Our results showed that AC-YVAD-CMK could reduce caspase-1 activation and inhibit IL-1β production and maturation, but has no effect on NLRP3 expression, an upstream inflammatory complex. AC-YVAD-CMK administration also resulted in reduction in M1-type microglia polarization around the hematoma, while increasing the number of M2-type cells. Furthermore, AC-YVAD-CMK treated mice showed some recovery of neurological function after hemorrhage especially at the hyperacute and subacute stage resulting in some degree of limb movement. In conclusion, we are of the view that AC-YVAD-CMK could inhibit pyroptosis, decrease the secretion or activation of inflammatory factors, and affect the polarization of microglia resulting in improvement of neurological function after ICH.

Original languageEnglish
Article number3706047
JournalBioMed Research International
Volume2018
DOIs
StatePublished - 1 Jan 2018

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Cerebral Hemorrhage
Cell death
Chemical activation
Cell Death
Inflammasomes
Caspase 1
Microglia
Polarization
Hemorrhage
Recovery of Function
Neuroprotective Agents
Interleukin-1
Hematoma
Cause of Death
Brain
Extremities
Cell Count
Cells
Pyroptosis
N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone

Cite this

Lin, Xiao ; Ye, Haotuo ; Siaw-Debrah, Felix ; Pan, Sishi ; He, Zibin ; Ni, Haoqi ; Xu, Zhu ; Jin, Kunlin ; Zhuge, Qichuan ; Huang, Lijie. / Ac-YVAD-CMK inhibits pyroptosis and improves functional outcome after intracerebral hemorrhage. In: BioMed Research International. 2018 ; Vol. 2018.
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abstract = "Intracerebral hemorrhage (ICH) refers to bleeding in the brain and is associated with the release of large amount of inflammasomes, and the activation of different cell death pathways. These cell death pathways lead to removal of inactivated and damaged cells and also result in neuronal cell damage. Pyroptosis is a newly discovered cell death pathway that has gained attention in recent years. This pathway mainly depends on activation of caspase-1-mediated cascades to cause cell death. We tested a well-known selective inhibitor of caspase-1, AC-YVAD-CMK, which has previously been found to have neuroprotective effects in ICH mice model, to ascertain its effects on the activation of inflammasomes mediated pyroptosis. Our results showed that AC-YVAD-CMK could reduce caspase-1 activation and inhibit IL-1β production and maturation, but has no effect on NLRP3 expression, an upstream inflammatory complex. AC-YVAD-CMK administration also resulted in reduction in M1-type microglia polarization around the hematoma, while increasing the number of M2-type cells. Furthermore, AC-YVAD-CMK treated mice showed some recovery of neurological function after hemorrhage especially at the hyperacute and subacute stage resulting in some degree of limb movement. In conclusion, we are of the view that AC-YVAD-CMK could inhibit pyroptosis, decrease the secretion or activation of inflammatory factors, and affect the polarization of microglia resulting in improvement of neurological function after ICH.",
author = "Xiao Lin and Haotuo Ye and Felix Siaw-Debrah and Sishi Pan and Zibin He and Haoqi Ni and Zhu Xu and Kunlin Jin and Qichuan Zhuge and Lijie Huang",
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Lin, X, Ye, H, Siaw-Debrah, F, Pan, S, He, Z, Ni, H, Xu, Z, Jin, K, Zhuge, Q & Huang, L 2018, 'Ac-YVAD-CMK inhibits pyroptosis and improves functional outcome after intracerebral hemorrhage', BioMed Research International, vol. 2018, 3706047. https://doi.org/10.1155/2018/3706047

Ac-YVAD-CMK inhibits pyroptosis and improves functional outcome after intracerebral hemorrhage. / Lin, Xiao; Ye, Haotuo; Siaw-Debrah, Felix; Pan, Sishi; He, Zibin; Ni, Haoqi; Xu, Zhu; Jin, Kunlin; Zhuge, Qichuan; Huang, Lijie.

In: BioMed Research International, Vol. 2018, 3706047, 01.01.2018.

Research output: Contribution to journalArticle

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T1 - Ac-YVAD-CMK inhibits pyroptosis and improves functional outcome after intracerebral hemorrhage

AU - Lin, Xiao

AU - Ye, Haotuo

AU - Siaw-Debrah, Felix

AU - Pan, Sishi

AU - He, Zibin

AU - Ni, Haoqi

AU - Xu, Zhu

AU - Jin, Kunlin

AU - Zhuge, Qichuan

AU - Huang, Lijie

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Intracerebral hemorrhage (ICH) refers to bleeding in the brain and is associated with the release of large amount of inflammasomes, and the activation of different cell death pathways. These cell death pathways lead to removal of inactivated and damaged cells and also result in neuronal cell damage. Pyroptosis is a newly discovered cell death pathway that has gained attention in recent years. This pathway mainly depends on activation of caspase-1-mediated cascades to cause cell death. We tested a well-known selective inhibitor of caspase-1, AC-YVAD-CMK, which has previously been found to have neuroprotective effects in ICH mice model, to ascertain its effects on the activation of inflammasomes mediated pyroptosis. Our results showed that AC-YVAD-CMK could reduce caspase-1 activation and inhibit IL-1β production and maturation, but has no effect on NLRP3 expression, an upstream inflammatory complex. AC-YVAD-CMK administration also resulted in reduction in M1-type microglia polarization around the hematoma, while increasing the number of M2-type cells. Furthermore, AC-YVAD-CMK treated mice showed some recovery of neurological function after hemorrhage especially at the hyperacute and subacute stage resulting in some degree of limb movement. In conclusion, we are of the view that AC-YVAD-CMK could inhibit pyroptosis, decrease the secretion or activation of inflammatory factors, and affect the polarization of microglia resulting in improvement of neurological function after ICH.

AB - Intracerebral hemorrhage (ICH) refers to bleeding in the brain and is associated with the release of large amount of inflammasomes, and the activation of different cell death pathways. These cell death pathways lead to removal of inactivated and damaged cells and also result in neuronal cell damage. Pyroptosis is a newly discovered cell death pathway that has gained attention in recent years. This pathway mainly depends on activation of caspase-1-mediated cascades to cause cell death. We tested a well-known selective inhibitor of caspase-1, AC-YVAD-CMK, which has previously been found to have neuroprotective effects in ICH mice model, to ascertain its effects on the activation of inflammasomes mediated pyroptosis. Our results showed that AC-YVAD-CMK could reduce caspase-1 activation and inhibit IL-1β production and maturation, but has no effect on NLRP3 expression, an upstream inflammatory complex. AC-YVAD-CMK administration also resulted in reduction in M1-type microglia polarization around the hematoma, while increasing the number of M2-type cells. Furthermore, AC-YVAD-CMK treated mice showed some recovery of neurological function after hemorrhage especially at the hyperacute and subacute stage resulting in some degree of limb movement. In conclusion, we are of the view that AC-YVAD-CMK could inhibit pyroptosis, decrease the secretion or activation of inflammatory factors, and affect the polarization of microglia resulting in improvement of neurological function after ICH.

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DO - 10.1155/2018/3706047

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