Bilateral transcranial direct-current stimulation confers neuroprotection through suppression of PKM2 after mouse cerebral ischemia injury
[Display omitted] •The level of PKM2 tetramers and the activity of PKM2 are increased after cerebral ischemia injury.•Ischemia-induced increase of PKM2 activity promotes neuronal death via the suppression of PPP-dependent antioxidant capacity.•We have established a newly direct-current stimulation a...
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| Veröffentlicht in: | Brain research 2025-02, Vol.1849, p.149353, Article 149353 |
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| creator | Ren, Jinyang Gao, Jingchen Yao, Xujin Wang, Xiyuran Kong, Xiangyi Lin, Tao Wang, Hui Ma, Wenlong Glebov, Oleg O. Wan, Qi |
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•The level of PKM2 tetramers and the activity of PKM2 are increased after cerebral ischemia injury.•Ischemia-induced increase of PKM2 activity promotes neuronal death via the suppression of PPP-dependent antioxidant capacity.•We have established a newly direct-current stimulation approach, Bilateral transcranial direct-current stimulation (BtDCS).•BtDCS confers neuroprotection through regulating PKM2-mediated metabolic reprogramming.
In its tetrameric form, pyruvate kinase M2 isoform (PKM2) catalyzes the last step of glycolysis and plays a key role in the metabolic reprogramming via regulating the signaling of pentose phosphate pathway (PPP). But the role of PKM2 in cerebral ischemia–reperfusion (I/R) injury remains unknown.
Mice model of middle cerebral artery occlusion (MCAO) and model of oxygen-glucose deprivation (OGD) injury in cultured neurons were established. PKM2 activator or inhibitor were used to test the effects of PKM2 in wild-type and PKM2 (−/-) mice after I/R injury. Biochemical and molecular approach were used to detect the level of PKM2 tetramers and PPP metabolites.
We showed for the first time that ischemia-induced increase of PKM2 activity promoted neuronal death via the suppression of PPP-dependent antioxidant capacity. To identify therapeutic approach that suppresses ischemia-induced increase of PKM2 activity, we tested the effect of bilateral transcranial direct-current stimulation (BtDCS), a newly established BtDCS approach by us, on PKM2 activity after mouse I/R. Our data demonstrated that BtDCS inhibited PKM2 activity in the ischemic neurons. BtDCS also reduced the cerebral infarct volume and the neurological deficits in stroke mice. We found that BtDCS-induced neuroprotection was mediated through the suppression of PKM2 activity after I/R.
Together, this study provided novel evidence that supported PKM2 as a crucial regulator of neuronal metabolism after cerebral I/R injury, and revealed the molecular mechanism by which BtDCS protects against mouse cerebral I/R injury through regulating PKM2-mediated metabolic reprogramming. |
| doi_str_mv | 10.1016/j.brainres.2024.149353 |
| format | Article |
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•The level of PKM2 tetramers and the activity of PKM2 are increased after cerebral ischemia injury.•Ischemia-induced increase of PKM2 activity promotes neuronal death via the suppression of PPP-dependent antioxidant capacity.•We have established a newly direct-current stimulation approach, Bilateral transcranial direct-current stimulation (BtDCS).•BtDCS confers neuroprotection through regulating PKM2-mediated metabolic reprogramming.
In its tetrameric form, pyruvate kinase M2 isoform (PKM2) catalyzes the last step of glycolysis and plays a key role in the metabolic reprogramming via regulating the signaling of pentose phosphate pathway (PPP). But the role of PKM2 in cerebral ischemia–reperfusion (I/R) injury remains unknown.
Mice model of middle cerebral artery occlusion (MCAO) and model of oxygen-glucose deprivation (OGD) injury in cultured neurons were established. PKM2 activator or inhibitor were used to test the effects of PKM2 in wild-type and PKM2 (−/-) mice after I/R injury. Biochemical and molecular approach were used to detect the level of PKM2 tetramers and PPP metabolites.
We showed for the first time that ischemia-induced increase of PKM2 activity promoted neuronal death via the suppression of PPP-dependent antioxidant capacity. To identify therapeutic approach that suppresses ischemia-induced increase of PKM2 activity, we tested the effect of bilateral transcranial direct-current stimulation (BtDCS), a newly established BtDCS approach by us, on PKM2 activity after mouse I/R. Our data demonstrated that BtDCS inhibited PKM2 activity in the ischemic neurons. BtDCS also reduced the cerebral infarct volume and the neurological deficits in stroke mice. We found that BtDCS-induced neuroprotection was mediated through the suppression of PKM2 activity after I/R.
Together, this study provided novel evidence that supported PKM2 as a crucial regulator of neuronal metabolism after cerebral I/R injury, and revealed the molecular mechanism by which BtDCS protects against mouse cerebral I/R injury through regulating PKM2-mediated metabolic reprogramming.</description><identifier>ISSN: 0006-8993</identifier><identifier>ISSN: 1872-6240</identifier><identifier>EISSN: 1872-6240</identifier><identifier>DOI: 10.1016/j.brainres.2024.149353</identifier><identifier>PMID: 39603317</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Bilateral transcranial direct current stimulation (BtDCS) ; Ischemic stroke ; Metabolic reprogramming ; Neuroprotection ; Pyruvate kinase isoform M2 (PKM2)</subject><ispartof>Brain research, 2025-02, Vol.1849, p.149353, Article 149353</ispartof><rights>2024 Elsevier B.V.</rights><rights>Copyright © 2024 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c245t-9157f83dafa1dc1bbf79c5edd9f91bbde850db8dae1c7b2d4ab26e35d72377c53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.brainres.2024.149353$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39603317$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ren, Jinyang</creatorcontrib><creatorcontrib>Gao, Jingchen</creatorcontrib><creatorcontrib>Yao, Xujin</creatorcontrib><creatorcontrib>Wang, Xiyuran</creatorcontrib><creatorcontrib>Kong, Xiangyi</creatorcontrib><creatorcontrib>Lin, Tao</creatorcontrib><creatorcontrib>Wang, Hui</creatorcontrib><creatorcontrib>Ma, Wenlong</creatorcontrib><creatorcontrib>Glebov, Oleg O.</creatorcontrib><creatorcontrib>Wan, Qi</creatorcontrib><title>Bilateral transcranial direct-current stimulation confers neuroprotection through suppression of PKM2 after mouse cerebral ischemia injury</title><title>Brain research</title><addtitle>Brain Res</addtitle><description>[Display omitted]
•The level of PKM2 tetramers and the activity of PKM2 are increased after cerebral ischemia injury.•Ischemia-induced increase of PKM2 activity promotes neuronal death via the suppression of PPP-dependent antioxidant capacity.•We have established a newly direct-current stimulation approach, Bilateral transcranial direct-current stimulation (BtDCS).•BtDCS confers neuroprotection through regulating PKM2-mediated metabolic reprogramming.
In its tetrameric form, pyruvate kinase M2 isoform (PKM2) catalyzes the last step of glycolysis and plays a key role in the metabolic reprogramming via regulating the signaling of pentose phosphate pathway (PPP). But the role of PKM2 in cerebral ischemia–reperfusion (I/R) injury remains unknown.
Mice model of middle cerebral artery occlusion (MCAO) and model of oxygen-glucose deprivation (OGD) injury in cultured neurons were established. PKM2 activator or inhibitor were used to test the effects of PKM2 in wild-type and PKM2 (−/-) mice after I/R injury. Biochemical and molecular approach were used to detect the level of PKM2 tetramers and PPP metabolites.
We showed for the first time that ischemia-induced increase of PKM2 activity promoted neuronal death via the suppression of PPP-dependent antioxidant capacity. To identify therapeutic approach that suppresses ischemia-induced increase of PKM2 activity, we tested the effect of bilateral transcranial direct-current stimulation (BtDCS), a newly established BtDCS approach by us, on PKM2 activity after mouse I/R. Our data demonstrated that BtDCS inhibited PKM2 activity in the ischemic neurons. BtDCS also reduced the cerebral infarct volume and the neurological deficits in stroke mice. We found that BtDCS-induced neuroprotection was mediated through the suppression of PKM2 activity after I/R.
Together, this study provided novel evidence that supported PKM2 as a crucial regulator of neuronal metabolism after cerebral I/R injury, and revealed the molecular mechanism by which BtDCS protects against mouse cerebral I/R injury through regulating PKM2-mediated metabolic reprogramming.</description><subject>Bilateral transcranial direct current stimulation (BtDCS)</subject><subject>Ischemic stroke</subject><subject>Metabolic reprogramming</subject><subject>Neuroprotection</subject><subject>Pyruvate kinase isoform M2 (PKM2)</subject><issn>0006-8993</issn><issn>1872-6240</issn><issn>1872-6240</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><recordid>eNqFUU1v1DAUtBAV3Rb-QuUjlyz-SOL4BlS0VBSVA5wtx35mvUrsxY6R-hf41ThKy5WL7Xma92b8BqErSvaU0P7dcT8m7UOCvGeEtXvaSt7xF2hHB8GanrXkJdoRQvpmkJKfo4ucjxVyLskrdM5lX59U7NCfj37SCyQ94SXpkE09fAXWJzBLY0pKEBacFz-XSvQxYBODg5RxgJLiKcWlEtf6ckix_DzgXE6n6iuvtejwty9fGdauauA5lgzYQIJxFfTZHGD2GvtwLOnxNTpzesrw5um-RD9uPn2__tzcP9zeXX-4bwxru6WRtBNu4FY7Ta2h4-iENB1YK52syMLQETsOVgM1YmS21SPrgXdWMC6E6fglervNrd5_FciLmqsTmCYdoBpUnHIu6qL6tlL7jWpSzDmBU6fkZ50eFSVqzUEd1XMOas1BbTnUxqsnjTLOYP-1PS--Et5vBKg__e0hqWw8BAPb4pWN_n8afwH5U6J5</recordid><startdate>20250215</startdate><enddate>20250215</enddate><creator>Ren, Jinyang</creator><creator>Gao, Jingchen</creator><creator>Yao, Xujin</creator><creator>Wang, Xiyuran</creator><creator>Kong, Xiangyi</creator><creator>Lin, Tao</creator><creator>Wang, Hui</creator><creator>Ma, Wenlong</creator><creator>Glebov, Oleg O.</creator><creator>Wan, Qi</creator><general>Elsevier B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20250215</creationdate><title>Bilateral transcranial direct-current stimulation confers neuroprotection through suppression of PKM2 after mouse cerebral ischemia injury</title><author>Ren, Jinyang ; Gao, Jingchen ; Yao, Xujin ; Wang, Xiyuran ; Kong, Xiangyi ; Lin, Tao ; Wang, Hui ; Ma, Wenlong ; Glebov, Oleg O. ; Wan, Qi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c245t-9157f83dafa1dc1bbf79c5edd9f91bbde850db8dae1c7b2d4ab26e35d72377c53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Bilateral transcranial direct current stimulation (BtDCS)</topic><topic>Ischemic stroke</topic><topic>Metabolic reprogramming</topic><topic>Neuroprotection</topic><topic>Pyruvate kinase isoform M2 (PKM2)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ren, Jinyang</creatorcontrib><creatorcontrib>Gao, Jingchen</creatorcontrib><creatorcontrib>Yao, Xujin</creatorcontrib><creatorcontrib>Wang, Xiyuran</creatorcontrib><creatorcontrib>Kong, Xiangyi</creatorcontrib><creatorcontrib>Lin, Tao</creatorcontrib><creatorcontrib>Wang, Hui</creatorcontrib><creatorcontrib>Ma, Wenlong</creatorcontrib><creatorcontrib>Glebov, Oleg O.</creatorcontrib><creatorcontrib>Wan, Qi</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Brain research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ren, Jinyang</au><au>Gao, Jingchen</au><au>Yao, Xujin</au><au>Wang, Xiyuran</au><au>Kong, Xiangyi</au><au>Lin, Tao</au><au>Wang, Hui</au><au>Ma, Wenlong</au><au>Glebov, Oleg O.</au><au>Wan, Qi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bilateral transcranial direct-current stimulation confers neuroprotection through suppression of PKM2 after mouse cerebral ischemia injury</atitle><jtitle>Brain research</jtitle><addtitle>Brain Res</addtitle><date>2025-02-15</date><risdate>2025</risdate><volume>1849</volume><spage>149353</spage><pages>149353-</pages><artnum>149353</artnum><issn>0006-8993</issn><issn>1872-6240</issn><eissn>1872-6240</eissn><abstract>[Display omitted]
•The level of PKM2 tetramers and the activity of PKM2 are increased after cerebral ischemia injury.•Ischemia-induced increase of PKM2 activity promotes neuronal death via the suppression of PPP-dependent antioxidant capacity.•We have established a newly direct-current stimulation approach, Bilateral transcranial direct-current stimulation (BtDCS).•BtDCS confers neuroprotection through regulating PKM2-mediated metabolic reprogramming.
In its tetrameric form, pyruvate kinase M2 isoform (PKM2) catalyzes the last step of glycolysis and plays a key role in the metabolic reprogramming via regulating the signaling of pentose phosphate pathway (PPP). But the role of PKM2 in cerebral ischemia–reperfusion (I/R) injury remains unknown.
Mice model of middle cerebral artery occlusion (MCAO) and model of oxygen-glucose deprivation (OGD) injury in cultured neurons were established. PKM2 activator or inhibitor were used to test the effects of PKM2 in wild-type and PKM2 (−/-) mice after I/R injury. Biochemical and molecular approach were used to detect the level of PKM2 tetramers and PPP metabolites.
We showed for the first time that ischemia-induced increase of PKM2 activity promoted neuronal death via the suppression of PPP-dependent antioxidant capacity. To identify therapeutic approach that suppresses ischemia-induced increase of PKM2 activity, we tested the effect of bilateral transcranial direct-current stimulation (BtDCS), a newly established BtDCS approach by us, on PKM2 activity after mouse I/R. Our data demonstrated that BtDCS inhibited PKM2 activity in the ischemic neurons. BtDCS also reduced the cerebral infarct volume and the neurological deficits in stroke mice. We found that BtDCS-induced neuroprotection was mediated through the suppression of PKM2 activity after I/R.
Together, this study provided novel evidence that supported PKM2 as a crucial regulator of neuronal metabolism after cerebral I/R injury, and revealed the molecular mechanism by which BtDCS protects against mouse cerebral I/R injury through regulating PKM2-mediated metabolic reprogramming.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>39603317</pmid><doi>10.1016/j.brainres.2024.149353</doi></addata></record> |
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| subjects | Bilateral transcranial direct current stimulation (BtDCS) Ischemic stroke Metabolic reprogramming Neuroprotection Pyruvate kinase isoform M2 (PKM2) |
| title | Bilateral transcranial direct-current stimulation confers neuroprotection through suppression of PKM2 after mouse cerebral ischemia injury |
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