SPAK inhibitor ZT-1a attenuates reactive astrogliosis and oligodendrocyte degeneration in a mouse model of vascular dementia
© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd..
BACKGROUND: Astrogliosis and white matter lesions (WML) are key characteristics of vascular contributions to cognitive impairment and dementia (VCID). However, the molecular mechanisms underlying VCID remain poorly understood. Stimulation of Na-K-Cl cotransport 1 (NKCC1) and its upstream kinases WNK (with no lysine) and SPAK (the STE20/SPS1-related proline/alanine-rich kinase) play a role in astrocytic intracellular Na+ overload, hypertrophy, and swelling. Therefore, in this study, we assessed the effect of SPAK inhibitor ZT-1a on pathogenesis and cognitive function in a mouse model of VCID induced by bilateral carotid artery stenosis (BCAS).
METHODS: Following sham or BCAS surgery, mice were randomly assigned to receive either vehicle (DMSO) or SPAK inhibitor ZT-1a treatment regimen (days 14-35 post-surgery). Mice were then evaluated for cognitive functions by Morris water maze, WML by ex vivo MRI-DTI analysis, and astrogliosis/demyelination by immunofluorescence and immunoblotting.
RESULTS: Compared to sham control mice, BCAS-Veh mice exhibited chronic cerebral hypoperfusion and memory impairments, accompanied by significant MRI DTI-detected WML and oligodendrocyte (OL) death. Increased activation of WNK-SPAK-NKCC1-signaling proteins was detected in white matter tissues and in C3d+ GFAP+ cytotoxic astrocytes but not in S100A10+ GFAP+ homeostatic astrocytes in BCAS-Veh mice. In contrast, ZT-1a-treated BCAS mice displayed reduced expression and phosphorylation of NKCC1, decreased astrogliosis, OL death, and WML, along with improved memory functions.
CONCLUSION: BCAS-induced upregulation of WNK-SPAK-NKCC1 signaling contributes to white matter-reactive astrogliosis, OL death, and memory impairment. Pharmacological inhibition of the SPAK activity has therapeutic potential for alleviating pathogenesis and memory impairment in VCID.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
CNS neuroscience & therapeutics - 30(2024), 3 vom: 04. März, Seite e14654 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bhuiyan, Mohammad Iqbal H [VerfasserIn] |
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| Links: |
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| Themen: |
Astrogliosis |
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| Anmerkungen: |
Date Completed 05.03.2024 Date Revised 09.03.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1111/cns.14654 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369228871 |
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| 100 | 1 | |a Bhuiyan, Mohammad Iqbal H |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a SPAK inhibitor ZT-1a attenuates reactive astrogliosis and oligodendrocyte degeneration in a mouse model of vascular dementia |
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| 500 | |a published: Print | ||
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| 520 | |a © 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd. | ||
| 520 | |a BACKGROUND: Astrogliosis and white matter lesions (WML) are key characteristics of vascular contributions to cognitive impairment and dementia (VCID). However, the molecular mechanisms underlying VCID remain poorly understood. Stimulation of Na-K-Cl cotransport 1 (NKCC1) and its upstream kinases WNK (with no lysine) and SPAK (the STE20/SPS1-related proline/alanine-rich kinase) play a role in astrocytic intracellular Na+ overload, hypertrophy, and swelling. Therefore, in this study, we assessed the effect of SPAK inhibitor ZT-1a on pathogenesis and cognitive function in a mouse model of VCID induced by bilateral carotid artery stenosis (BCAS) | ||
| 520 | |a METHODS: Following sham or BCAS surgery, mice were randomly assigned to receive either vehicle (DMSO) or SPAK inhibitor ZT-1a treatment regimen (days 14-35 post-surgery). Mice were then evaluated for cognitive functions by Morris water maze, WML by ex vivo MRI-DTI analysis, and astrogliosis/demyelination by immunofluorescence and immunoblotting | ||
| 520 | |a RESULTS: Compared to sham control mice, BCAS-Veh mice exhibited chronic cerebral hypoperfusion and memory impairments, accompanied by significant MRI DTI-detected WML and oligodendrocyte (OL) death. Increased activation of WNK-SPAK-NKCC1-signaling proteins was detected in white matter tissues and in C3d+ GFAP+ cytotoxic astrocytes but not in S100A10+ GFAP+ homeostatic astrocytes in BCAS-Veh mice. In contrast, ZT-1a-treated BCAS mice displayed reduced expression and phosphorylation of NKCC1, decreased astrogliosis, OL death, and WML, along with improved memory functions | ||
| 520 | |a CONCLUSION: BCAS-induced upregulation of WNK-SPAK-NKCC1 signaling contributes to white matter-reactive astrogliosis, OL death, and memory impairment. Pharmacological inhibition of the SPAK activity has therapeutic potential for alleviating pathogenesis and memory impairment in VCID | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a BCAS | |
| 650 | 4 | |a NKCC1 | |
| 650 | 4 | |a VCID | |
| 650 | 4 | |a ZT-1a | |
| 650 | 4 | |a astrogliosis | |
| 650 | 4 | |a vascular dementia | |
| 700 | 1 | |a Habib, Khadija |e verfasserin |4 aut | |
| 700 | 1 | |a Sultan, Md Tipu |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Fenghua |e verfasserin |4 aut | |
| 700 | 1 | |a Jahan, Israt |e verfasserin |4 aut | |
| 700 | 1 | |a Weng, Zhongfang |e verfasserin |4 aut | |
| 700 | 1 | |a Rahman, Md Shamim |e verfasserin |4 aut | |
| 700 | 1 | |a Islam, Rabia |e verfasserin |4 aut | |
| 700 | 1 | |a Foley, Lesley M |e verfasserin |4 aut | |
| 700 | 1 | |a Hitchens, T Kevin |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Xianming |e verfasserin |4 aut | |
| 700 | 1 | |a Canna, Scott W |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Dandan |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Guodong |e verfasserin |4 aut | |
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