Cargando…

Therapeutic Effect of Mitochondrial Division Inhibitor-1 (Mdivi-1) on Hyperglycemia-Exacerbated Early and Delayed Brain Injuries after Experimental Subarachnoid Hemorrhage

Background: Neurological deficits following subarachnoid hemorrhage (SAH) are caused by early or delayed brain injuries. Our previous studies have demonstrated that hyperglycemia induces profound neuronal apoptosis of the cerebral cortex. Morphologically, we found that hyperglycemia exacerbated late...

Descripción completa

Detalles Bibliográficos
Autores principales: Chung, Chia-Li, Huang, Yu-Hua, Lin, Chien-Ju, Chong, Yoon-Bin, Wu, Shu-Chuan, Chai, Chee-Yin, Tsai, Hung-Pei, Kwan, Aij-Lie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9267000/
https://www.ncbi.nlm.nih.gov/pubmed/35805932
http://dx.doi.org/10.3390/ijms23136924
_version_ 1784743607858626560
author Chung, Chia-Li
Huang, Yu-Hua
Lin, Chien-Ju
Chong, Yoon-Bin
Wu, Shu-Chuan
Chai, Chee-Yin
Tsai, Hung-Pei
Kwan, Aij-Lie
author_facet Chung, Chia-Li
Huang, Yu-Hua
Lin, Chien-Ju
Chong, Yoon-Bin
Wu, Shu-Chuan
Chai, Chee-Yin
Tsai, Hung-Pei
Kwan, Aij-Lie
author_sort Chung, Chia-Li
collection PubMed
description Background: Neurological deficits following subarachnoid hemorrhage (SAH) are caused by early or delayed brain injuries. Our previous studies have demonstrated that hyperglycemia induces profound neuronal apoptosis of the cerebral cortex. Morphologically, we found that hyperglycemia exacerbated late vasospasm following SAH. Thus, our previous studies strongly suggest that post-SAH hyperglycemia is not only a response to primary insult, but also an aggravating factor for brain injuries. In addition, mitochondrial fusion and fission are vital to maintaining cellular functions. Current evidence also shows that the suppression of mitochondrial fission alleviates brain injuries after experimental SAH. Hence, this study aimed to determine the effects of mitochondrial dynamic modulation in hyperglycemia-related worse SAH neurological prognosis. Materials and methods: In vitro, we employed an enzyme-linked immunosorbent assay (ELISA) to detect the effect of mitochondrial division inhibitor-1 (Mdivi-1) on lipopolysaccharide (LPS)-induced BV-2 cells releasing inflammatory factors. In vivo, we produced hyperglycemic rats via intraperitoneal streptozotocin (STZ) injections. Hyperglycemia was confirmed using blood-glucose measurements (>300 mg/dL) 7 days after the STZ injection. The rodent model of SAH, in which fresh blood was instilled into the craniocervical junction, was used 7 days after STZ administration. We investigated the mechanism and effect of Mdivi-1, a selective inhibitor of dynamin-related protein (Drp1) to downregulate mitochondrial fission, on SAH-induced apoptosis in a hyperglycemic state, and evaluated the results in a dose–response manner. The rats were divided into the following five groups: (1) control, (2) SAH only, (3) Diabetes mellitus (DM) + SAH, (4) Mdivi-1 (0.24 mg/kg) + DM + SAH, and (5) Mdivi-1 (1.2 mg/kg) + DM + SAH. Results: In vitro, ELISA revealed that Mdivi-1 inhibited microglia from releasing inflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. In vivo, neurological outcomes in the high-dose (1.2 mg/kg) Mdivi-1 treatment group were significantly reduced compared with the SAH and DM + SAH groups. Furthermore, immunofluorescence staining and ELISA revealed that a high dose of Mdivi-1 had attenuated inflammation and neuron cell apoptosis by inhibiting Hyperglycemia-aggravated activation, as well as microglia and astrocyte proliferation, following SAH. Conclusion: Mdivi-1, a Drp-1 inhibitor, attenuates cerebral vasospasm, poor neurological outcomes, inflammation, and neuron cell apoptosis following SAH + hyperglycemia.
format Online
Article
Text
id pubmed-9267000
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-92670002022-07-09 Therapeutic Effect of Mitochondrial Division Inhibitor-1 (Mdivi-1) on Hyperglycemia-Exacerbated Early and Delayed Brain Injuries after Experimental Subarachnoid Hemorrhage Chung, Chia-Li Huang, Yu-Hua Lin, Chien-Ju Chong, Yoon-Bin Wu, Shu-Chuan Chai, Chee-Yin Tsai, Hung-Pei Kwan, Aij-Lie Int J Mol Sci Article Background: Neurological deficits following subarachnoid hemorrhage (SAH) are caused by early or delayed brain injuries. Our previous studies have demonstrated that hyperglycemia induces profound neuronal apoptosis of the cerebral cortex. Morphologically, we found that hyperglycemia exacerbated late vasospasm following SAH. Thus, our previous studies strongly suggest that post-SAH hyperglycemia is not only a response to primary insult, but also an aggravating factor for brain injuries. In addition, mitochondrial fusion and fission are vital to maintaining cellular functions. Current evidence also shows that the suppression of mitochondrial fission alleviates brain injuries after experimental SAH. Hence, this study aimed to determine the effects of mitochondrial dynamic modulation in hyperglycemia-related worse SAH neurological prognosis. Materials and methods: In vitro, we employed an enzyme-linked immunosorbent assay (ELISA) to detect the effect of mitochondrial division inhibitor-1 (Mdivi-1) on lipopolysaccharide (LPS)-induced BV-2 cells releasing inflammatory factors. In vivo, we produced hyperglycemic rats via intraperitoneal streptozotocin (STZ) injections. Hyperglycemia was confirmed using blood-glucose measurements (>300 mg/dL) 7 days after the STZ injection. The rodent model of SAH, in which fresh blood was instilled into the craniocervical junction, was used 7 days after STZ administration. We investigated the mechanism and effect of Mdivi-1, a selective inhibitor of dynamin-related protein (Drp1) to downregulate mitochondrial fission, on SAH-induced apoptosis in a hyperglycemic state, and evaluated the results in a dose–response manner. The rats were divided into the following five groups: (1) control, (2) SAH only, (3) Diabetes mellitus (DM) + SAH, (4) Mdivi-1 (0.24 mg/kg) + DM + SAH, and (5) Mdivi-1 (1.2 mg/kg) + DM + SAH. Results: In vitro, ELISA revealed that Mdivi-1 inhibited microglia from releasing inflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. In vivo, neurological outcomes in the high-dose (1.2 mg/kg) Mdivi-1 treatment group were significantly reduced compared with the SAH and DM + SAH groups. Furthermore, immunofluorescence staining and ELISA revealed that a high dose of Mdivi-1 had attenuated inflammation and neuron cell apoptosis by inhibiting Hyperglycemia-aggravated activation, as well as microglia and astrocyte proliferation, following SAH. Conclusion: Mdivi-1, a Drp-1 inhibitor, attenuates cerebral vasospasm, poor neurological outcomes, inflammation, and neuron cell apoptosis following SAH + hyperglycemia. MDPI 2022-06-22 /pmc/articles/PMC9267000/ /pubmed/35805932 http://dx.doi.org/10.3390/ijms23136924 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chung, Chia-Li
Huang, Yu-Hua
Lin, Chien-Ju
Chong, Yoon-Bin
Wu, Shu-Chuan
Chai, Chee-Yin
Tsai, Hung-Pei
Kwan, Aij-Lie
Therapeutic Effect of Mitochondrial Division Inhibitor-1 (Mdivi-1) on Hyperglycemia-Exacerbated Early and Delayed Brain Injuries after Experimental Subarachnoid Hemorrhage
title Therapeutic Effect of Mitochondrial Division Inhibitor-1 (Mdivi-1) on Hyperglycemia-Exacerbated Early and Delayed Brain Injuries after Experimental Subarachnoid Hemorrhage
title_full Therapeutic Effect of Mitochondrial Division Inhibitor-1 (Mdivi-1) on Hyperglycemia-Exacerbated Early and Delayed Brain Injuries after Experimental Subarachnoid Hemorrhage
title_fullStr Therapeutic Effect of Mitochondrial Division Inhibitor-1 (Mdivi-1) on Hyperglycemia-Exacerbated Early and Delayed Brain Injuries after Experimental Subarachnoid Hemorrhage
title_full_unstemmed Therapeutic Effect of Mitochondrial Division Inhibitor-1 (Mdivi-1) on Hyperglycemia-Exacerbated Early and Delayed Brain Injuries after Experimental Subarachnoid Hemorrhage
title_short Therapeutic Effect of Mitochondrial Division Inhibitor-1 (Mdivi-1) on Hyperglycemia-Exacerbated Early and Delayed Brain Injuries after Experimental Subarachnoid Hemorrhage
title_sort therapeutic effect of mitochondrial division inhibitor-1 (mdivi-1) on hyperglycemia-exacerbated early and delayed brain injuries after experimental subarachnoid hemorrhage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9267000/
https://www.ncbi.nlm.nih.gov/pubmed/35805932
http://dx.doi.org/10.3390/ijms23136924
work_keys_str_mv AT chungchiali therapeuticeffectofmitochondrialdivisioninhibitor1mdivi1onhyperglycemiaexacerbatedearlyanddelayedbraininjuriesafterexperimentalsubarachnoidhemorrhage
AT huangyuhua therapeuticeffectofmitochondrialdivisioninhibitor1mdivi1onhyperglycemiaexacerbatedearlyanddelayedbraininjuriesafterexperimentalsubarachnoidhemorrhage
AT linchienju therapeuticeffectofmitochondrialdivisioninhibitor1mdivi1onhyperglycemiaexacerbatedearlyanddelayedbraininjuriesafterexperimentalsubarachnoidhemorrhage
AT chongyoonbin therapeuticeffectofmitochondrialdivisioninhibitor1mdivi1onhyperglycemiaexacerbatedearlyanddelayedbraininjuriesafterexperimentalsubarachnoidhemorrhage
AT wushuchuan therapeuticeffectofmitochondrialdivisioninhibitor1mdivi1onhyperglycemiaexacerbatedearlyanddelayedbraininjuriesafterexperimentalsubarachnoidhemorrhage
AT chaicheeyin therapeuticeffectofmitochondrialdivisioninhibitor1mdivi1onhyperglycemiaexacerbatedearlyanddelayedbraininjuriesafterexperimentalsubarachnoidhemorrhage
AT tsaihungpei therapeuticeffectofmitochondrialdivisioninhibitor1mdivi1onhyperglycemiaexacerbatedearlyanddelayedbraininjuriesafterexperimentalsubarachnoidhemorrhage
AT kwanaijlie therapeuticeffectofmitochondrialdivisioninhibitor1mdivi1onhyperglycemiaexacerbatedearlyanddelayedbraininjuriesafterexperimentalsubarachnoidhemorrhage