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

Mohammad Iqbal H Bhuiyan; Khadija Habib; Md Tipu Sultan; Fenghua Chen; Israt Jahan; Zhongfang Weng; Md Shamim Rahman; Rabia Islam; Lesley M Foley; T Kevin Hitchens; Xianming Deng; Scott W Canna; Dandan Sun; Guodong Cao

doi:10.1111/cns.14654

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

CNS Neurosci Ther. 2024 Mar;30(3):e14654. doi: 10.1111/cns.14654.

Authors

Mohammad Iqbal H Bhuiyan^{1

2

3

4}, Khadija Habib¹, Md Tipu Sultan¹, Fenghua Chen², Israt Jahan^{1

2}, Zhongfang Weng², Md Shamim Rahman¹, Rabia Islam⁵, Lesley M Foley⁶, T Kevin Hitchens^{6

7}, Xianming Deng⁸, Scott W Canna⁹, Dandan Sun^{2

3

4}, Guodong Cao^{2

4}

Affiliations

¹ Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, Texas, USA.
² Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
³ Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁴ Veterans Affairs Pittsburgh Health Care System Pittsburgh Healthcare System, Geriatric Research Education and Clinical Center, Pittsburgh, Pennsylvania, USA.
⁵ Nostrum Hospital, Dhaka, Bangladesh.
⁶ Animal Imaging Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁷ Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁸ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
⁹ Department of Pediatric Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Abstract

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.

Keywords: BCAS; NKCC1; VCID; ZT-1a; astrogliosis; vascular dementia.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cognition
Cognitive Dysfunction*
Dementia, Vascular*
Disease Models, Animal
Gliosis / drug therapy
Inflammation
Mice

Abstract

Publication types

MeSH terms

Grants and funding