SPAK inhibitor ZT-1a attenuates reactive astrogliosis and oligodendrocyte degeneration in a mouse model of vascular dementia.

Autor: Bhuiyan MIH; Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, Texas, USA.; Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Veterans Affairs Pittsburgh Health Care System Pittsburgh Healthcare System, Geriatric Research Education and Clinical Center, Pittsburgh, Pennsylvania, USA., Habib K; Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, Texas, USA., Sultan MT; Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, Texas, USA., Chen F; Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Jahan I; Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, Texas, USA.; Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Weng Z; Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Rahman MS; Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, Texas, USA., Islam R; Nostrum Hospital, Dhaka, Bangladesh., Foley LM; Animal Imaging Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Hitchens TK; Animal Imaging Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Deng X; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China., Canna SW; Department of Pediatric Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Sun D; Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Veterans Affairs Pittsburgh Health Care System Pittsburgh Healthcare System, Geriatric Research Education and Clinical Center, Pittsburgh, Pennsylvania, USA., Cao G; Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Veterans Affairs Pittsburgh Health Care System Pittsburgh Healthcare System, Geriatric Research Education and Clinical Center, Pittsburgh, Pennsylvania, USA.
Jazyk: angličtina
Zdroj: CNS neuroscience & therapeutics [CNS Neurosci Ther] 2024 Mar; Vol. 30 (3), pp. e14654.
DOI: 10.1111/cns.14654
Abstrakt: 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.
(© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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