Menyhárt, Ákos and Frank, Rita and Farkas, Elek Attila and Süle, Zoltán and Varga, Viktória Éva and Nyúl-Tóth, Ádám and Ivánkovitsné Kiss, Orsolya and Szabó, Írisz and Zölei-Szénási, Dániel and Krizbai, István Adorján and Bari, Ferenc and Farkas, Eszter (2022) Malignant astrocyte swelling and impaired glutamate clearance drive the expansion of injurious spreading depolarization foci. JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 42 (4). pp. 584-599. ISSN 0271-678X
|
Text
2022jcbfmmenyhartfrank.pdf Available under License Creative Commons Attribution. Download (2MB) | Preview |
Abstract
Spreading depolarizations (SDs) indicate injury progression and predict worse clinical outcome in acute brain injury. We demonstrate in rodents that acute brain swelling upon cerebral ischemia impairs astroglial glutamate clearance and increases the tissue area invaded by SD. The cytotoxic extracellular glutamate accumulation (>15 mu M) predisposes an extensive bulk of tissue (4-5 mm(2)) for a yet undescribed simultaneous depolarization (SiD). We confirm in rat brain slices exposed to osmotic stress that SiD is the pathological expansion of prior punctual SD foci (0.5-1 mm(2)), is associated with astrocyte swelling, and triggers oncotic neuron death. The blockade of astrocytic aquaporin-4 channels and Na+/K+/Cl- co-transporters, or volume-regulated anion channels mitigated slice edema, extracellular glutamate accumulation (<10 mu M) and SiD occurrence. Reversal of slice swelling by hyperosmotic mannitol counteracted glutamate accumulation and prevented SiD. In contrast, inhibition of glial metabolism or inhibition of astrocyte glutamate transporters reproduced the SiD phenotype. Finally, we show in the rodent water intoxication model of cytotoxic edema that astrocyte swelling and altered astrocyte calcium waves are central in the evolution of SiD. We discuss our results in the light of evidence for SiD in the human cortex. Our results emphasize the need of preventive osmotherapy in acute brain injury.
| Item Type: | Article |
|---|---|
| Additional Information: | Funding Agency and Grant Number: National Research, Development and Innovation Office of HungaryNational Research, Development & Innovation Office (NRDIO) - Hungary [PD128821, K134377, K120358, K135425, FK132638]; Ministry of Human Capacities of Hungary [UNKP-20-3 -SZTE-110]; Economic Development and Innovation Operational Programme in Hungary - European Union; European Regional Development FundEuropean Commission [GINOP-2.3.2-15-2016-00048, GINOP2.3.2-15-2016-0034]; EU-funded Hungarian [EFOP-3.6.1-16-2016-00008]; EU's Horizon 2020 research and innovation program [739593]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [DFG DR 323/5-1, DFG DR 323/10-1, 602150 CENTER-TBI]; BMBFFederal Ministry of Education & Research (BMBF) [0101EW2004]; Fondation Les Gueules Cassees Sourire Quand Meme [FGC 34-2018, FGC 49-2016] Funding text: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the National Research, Development and Innovation Office of Hungary (No. PD128821 to ~ AM, K134377 to EF, K120358 to FB, K135425 to IAK, FK132638 to AEF); the Ministry of Human Capacities of Hungary (~ UNKP-20-3 -SZTE-110 to RF); the Economic Development and Innovation Operational Programme in Hungary co-financed by the European Union and the European Regional Development Fund (No. GINOP-2.3.2-15-2016-00048 to EF and GINOP2.3.2-15-2016-0034 to IAK); the EU-funded Hungarian grant No. EFOP-3.6.1-16-2016-00008 to EF; the EU's Horizon 2020 research and innovation program under grant agreement No. 739593; the Deutsche Forschungsgemeinschaft (DFG DR 323/5-1 and DFG DR 323/10-1 to JPD), FP7 No. 602150 CENTER-TBI to JPD and Era-Net Neuron EBio2, with funds from BMBF (0101EW2004) to JPD; Inserm U1028 and CNRS UMR 5292 to AM and SM; grants from Fondation Les Gueules Cass~ees Sourire Quand Me<^> me (No. FGC 34-2018, FGC 49-2016 to AM and SM). |
| Uncontrolled Keywords: | Brain; IN-VIVO; GLUTAMATE; SYNAPTIC-TRANSMISSION; ISCHEMIA; CEREBRAL-BLOOD-FLOW; DEPRESSION; Hematology; stroke; Cerebral ischemia; ASTROCYTE; ANOXIC DEPOLARIZATION; Endocrinology & Metabolism; Cerebral edema; dendritic injury; |
| Subjects: | R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 25 Jul 2022 08:08 |
| Last Modified: | 25 Jul 2022 08:08 |
| URI: | http://real.mtak.hu/id/eprint/145139 |
Actions (login required)
 |
Edit Item |
