An inhibitory and beneficial effect of chlorpromazine and promethazine (C + P) on hyperglycolysis through HIF-1α regulation in ischemic stroke
Copyright © 2021 Elsevier B.V. All rights reserved..
BACKGROUND: After ischemic stroke, the increased catabolism of glucose (hyperglycolysis) results in the production of reactive oxygen species (ROS) via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). A depressive or hibernation-like effect of C + P on brain activity was reported to induce neuroprotection. The current study assesses the effect of C + P on hyperglycolysis and NOX activation.
METHODS: Adult male Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) followed by 6 or 24 h of reperfusion. At the onset of reperfusion, rats received C + P with or without temperature control, or phloretin [glucose transporter (GLUT)-1 inhibitor], or cytochalasin B (GLUT-3 inhibitor). We detected brain ROS, apoptotic cell death, and ATP levels along with HIF-1α expression. Cerebral hyperglycolysis was measured by glucose, protein expression of GLUT-1/3, and phosphofructokinase-1 (PFK-1), as well as lactate and lactate dehydrogenase (LDH) at 6 and 24 h of reperfusion. The enzymatic activity of NOX and protein expression of its subunits (gp91phox) were detected. Neural SHSY5Y cells were placed under 2 h of oxygen-glucose deprivation (OGD) followed by reoxygenation for 6 and 24 h with C + P treatment. Cell viability and protein levels of HIF-1α, GLUT-1/3, PFK-1, LDH, and gp91phox were measured. A HIF-1α overexpression vector was transfected into the cells, and then protein levels of HIF-1α, GLUT-1/3, PFK-1, and LDH were quantitated. In sham-operated rats and control cells, the protein levels of HIF-1α, GLUT-1/3, PFK-1, LDH, and gp91phox were measured at 6 and 24 h after C + P administration.
RESULTS: C + P reduced the protein elevations after stroke in HIF-1α, glycolytic enzymes, as well as in ROS, cell death, glucose and lactate, but raised ATP levels in the brain. In ischemic rats exposed to GLUT-1/3 inhibitors, ROS, cell death, glucose, and lactate were all decreased, as well as GLUT-1, GLUT-3, LDH, and PFK-1 protein levels. C + P decreased ischemia-induced NOX activation by reducing the enzymatic activity and protein expression of the NOX subunit gp91phox, as was observed in the presence of GLUT-1/3 inhibitors. These markers were significantly decreased following C + P administration with the induced hypothermia, while C + P administration with temperature control at 37 °C induced lesser protection after ischemia stroke. In the OGD/reoxygenation model, C + P treatment increased cell viability and diminished protein levels of HIF-1α, GLUT-1, GLUT-3, PFK-1, LDH, and gp91phox. However, in OGD with HIF-1α overexpression, C + P was unable to effectively reduce the upregulated GLUT-1, GLUT-3, and LDH. In normal conditions, C + P reduced HIF-1α and the levels of key glycolytic enzymes depending on its pharmacological effect.
CONCLUSION: C + P, partially depending on hypothermia, attenuates hyperglycolysis and NOX activation through HIF-1α regulation.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:1763 |
|---|---|
| Enthalten in: |
Brain research - 1763(2021) vom: 15. Juli, Seite 147463 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Guo, Sichao [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 24.01.2022 Date Revised 24.01.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.brainres.2021.147463 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM323673198 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM323673198 | ||
| 003 | DE-627 | ||
| 005 | 20231225184703.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.brainres.2021.147463 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1078.xml |
| 035 | |a (DE-627)NLM323673198 | ||
| 035 | |a (NLM)33811844 | ||
| 035 | |a (PII)S0006-8993(21)00320-6 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Guo, Sichao |e verfasserin |4 aut | |
| 245 | 1 | 3 | |a An inhibitory and beneficial effect of chlorpromazine and promethazine (C + P) on hyperglycolysis through HIF-1α regulation in ischemic stroke |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 24.01.2022 | ||
| 500 | |a Date Revised 24.01.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier B.V. All rights reserved. | ||
| 520 | |a BACKGROUND: After ischemic stroke, the increased catabolism of glucose (hyperglycolysis) results in the production of reactive oxygen species (ROS) via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). A depressive or hibernation-like effect of C + P on brain activity was reported to induce neuroprotection. The current study assesses the effect of C + P on hyperglycolysis and NOX activation | ||
| 520 | |a METHODS: Adult male Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) followed by 6 or 24 h of reperfusion. At the onset of reperfusion, rats received C + P with or without temperature control, or phloretin [glucose transporter (GLUT)-1 inhibitor], or cytochalasin B (GLUT-3 inhibitor). We detected brain ROS, apoptotic cell death, and ATP levels along with HIF-1α expression. Cerebral hyperglycolysis was measured by glucose, protein expression of GLUT-1/3, and phosphofructokinase-1 (PFK-1), as well as lactate and lactate dehydrogenase (LDH) at 6 and 24 h of reperfusion. The enzymatic activity of NOX and protein expression of its subunits (gp91phox) were detected. Neural SHSY5Y cells were placed under 2 h of oxygen-glucose deprivation (OGD) followed by reoxygenation for 6 and 24 h with C + P treatment. Cell viability and protein levels of HIF-1α, GLUT-1/3, PFK-1, LDH, and gp91phox were measured. A HIF-1α overexpression vector was transfected into the cells, and then protein levels of HIF-1α, GLUT-1/3, PFK-1, and LDH were quantitated. In sham-operated rats and control cells, the protein levels of HIF-1α, GLUT-1/3, PFK-1, LDH, and gp91phox were measured at 6 and 24 h after C + P administration | ||
| 520 | |a RESULTS: C + P reduced the protein elevations after stroke in HIF-1α, glycolytic enzymes, as well as in ROS, cell death, glucose and lactate, but raised ATP levels in the brain. In ischemic rats exposed to GLUT-1/3 inhibitors, ROS, cell death, glucose, and lactate were all decreased, as well as GLUT-1, GLUT-3, LDH, and PFK-1 protein levels. C + P decreased ischemia-induced NOX activation by reducing the enzymatic activity and protein expression of the NOX subunit gp91phox, as was observed in the presence of GLUT-1/3 inhibitors. These markers were significantly decreased following C + P administration with the induced hypothermia, while C + P administration with temperature control at 37 °C induced lesser protection after ischemia stroke. In the OGD/reoxygenation model, C + P treatment increased cell viability and diminished protein levels of HIF-1α, GLUT-1, GLUT-3, PFK-1, LDH, and gp91phox. However, in OGD with HIF-1α overexpression, C + P was unable to effectively reduce the upregulated GLUT-1, GLUT-3, and LDH. In normal conditions, C + P reduced HIF-1α and the levels of key glycolytic enzymes depending on its pharmacological effect | ||
| 520 | |a CONCLUSION: C + P, partially depending on hypothermia, attenuates hyperglycolysis and NOX activation through HIF-1α regulation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Chlorpromazine and Promethazine (C+P) | |
| 650 | 4 | |a Hypoxia-induced factor-1α (HIF-1α) | |
| 650 | 4 | |a Ischemia/reperfusion | |
| 650 | 4 | |a Pharmacological hypothermia | |
| 650 | 4 | |a Phenothiazines | |
| 650 | 4 | |a Stroke | |
| 650 | 7 | |a Glucose Transporter Type 1 |2 NLM | |
| 650 | 7 | |a Glucose Transporter Type 3 |2 NLM | |
| 650 | 7 | |a Hif1a protein, rat |2 NLM | |
| 650 | 7 | |a Hypoxia-Inducible Factor 1, alpha Subunit |2 NLM | |
| 650 | 7 | |a L-Lactate Dehydrogenase |2 NLM | |
| 650 | 7 | |a EC 1.1.1.27 |2 NLM | |
| 650 | 7 | |a Cybb protein, rat |2 NLM | |
| 650 | 7 | |a EC 1.6.3.- |2 NLM | |
| 650 | 7 | |a NADPH Oxidase 2 |2 NLM | |
| 650 | 7 | |a EC 1.6.3.- |2 NLM | |
| 650 | 7 | |a Phosphofructokinase-1 |2 NLM | |
| 650 | 7 | |a EC 2.7.1.11 |2 NLM | |
| 650 | 7 | |a Promethazine |2 NLM | |
| 650 | 7 | |a FF28EJQ494 |2 NLM | |
| 650 | 7 | |a Glucose |2 NLM | |
| 650 | 7 | |a IY9XDZ35W2 |2 NLM | |
| 650 | 7 | |a Chlorpromazine |2 NLM | |
| 650 | 7 | |a U42B7VYA4P |2 NLM | |
| 700 | 1 | |a Cosky, Eric |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Fengwu |e verfasserin |4 aut | |
| 700 | 1 | |a Guan, Longfei |e verfasserin |4 aut | |
| 700 | 1 | |a Ji, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Wenjing |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Changya |e verfasserin |4 aut | |
| 700 | 1 | |a Geng, Xiaokun |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Yuchuan |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Brain research |d 1966 |g 1763(2021) vom: 15. Juli, Seite 147463 |w (DE-627)NLM000001538 |x 1872-6240 |7 nnns |
| 773 | 1 | 8 | |g volume:1763 |g year:2021 |g day:15 |g month:07 |g pages:147463 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.brainres.2021.147463 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 1763 |j 2021 |b 15 |c 07 |h 147463 | ||