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PTP1B Inhibitor Claramine Rescues Diabetes-Induced Spatial Learning and Memory Impairment in Mice

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Abstract

Accumulating clinical and epidemiological studies indicate that learning and memory impairment is more prevalent among people with diabetes mellitus (DM). PTP1B is a member of protein tyrosine phosphatase family and participates in a variety of pathophysiological effects including inflammatory, insulin signaling pathway, and learning and memory. This study was aimed to investigate the effects of CA, a specific inhibitor of PTP1B, on spatial learning and memory impairment in diabetic mice caused by high-fat diet and injection of streptozotocin. We found that the protein expressions of PTP1B increased in hippocampal CA1, CA3, and PFC regions of diabetic mice. Network pharmacology results showed that PTP1B might be one of the key targets between diabetes and cognitive dysfunction, and CA might alleviate DM-induced cognitive dysfunction. Animal experiments showed that CA ameliorated DM-induced spatial learning and memory impairment, and improved glucose and lipid metabolic disorders. Moreover, administration of CA alleviated hippocampal structure damage and enhanced the expressions of synaptic proteins, including PSD-95, SYN-1, and SYP in diabetic mice. Furthermore, CA treatment not only significantly down-regulated the expressions of PTP1B and NLRP3 inflammatory related proteins (NLRP3, ASC, Caspase-1, COX-2, IL-1β, and TNF-α), but also significantly up-regulated the expressions of insulin signaling pathway–related proteins (p-IRS1, p-PI3K, p-AKT, and p-GSK-3β) in diabetic mice. Taken together, these results suggested that PTP1B might be a targeted strategy to rescue learning and memory deficits in DM, possibly through inhibition of NLRP3 inflammasome and regulation of insulin signaling pathway.

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Data Availability

Data are available from the corresponding author on reasonable request.

Abbreviations

CA:

Claramine

DM:

Diabetes mellitus

AD:

Alzheimer disease

HFD:

High-fat diet

FBG:

Fasting blood glucose

STZ:

Streptozotocin

MWM:

Morris water maze

PTP1B:

Protein tyrosine phosphatase 1B

IRS1:

Insulin receptor substrates 1

AKT:

Protein kinase B

PI3K:

Phosphoinositide 3-kinase

GSK-3β:

Glycogen synthase kinase-3β

NLRP3:

Recombinant NLR family, pyrin domain containing protein 3

ASC:

Apoptosis-associated speck-like protein containing a CARD

Caspase-1:

Cysteinyl aspartate specific proteinase-1

TNF-α:

Tumor necrosis factor-α

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

IL-18:

Interleukin-18

PSD-95:

Postsynaptic density protein-95

SYN-1:

Synapsin-1

SYP:

Synaptophysin

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81870576) to FC, Hubei University of Science and Technology (2021WG01) to FC, and Department of Education of Hubei Province (T201921, B2021225) to FC and WL.

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  1. Mengyu Wu and Wenli Liao contributed equally to this work

Authors and Affiliations

  1. Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, 437100, China

    Mengyu Wu, Ruyi Zhang, Yuting Gao, Tao Chen, Liangliang Hua & Fei Cai

  2. Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China

    Mengyu Wu, Wenli Liao, Ruyi Zhang, Yuting Gao, Tao Chen, Liangliang Hua & Fei Cai

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  1. Mengyu Wu
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Contributions

MW: writing original draft, methodology, formal analysis. WL: methodology, formal analysis, funding acquisition. RZ: formal analysis, project administration. YG: methodology, performed immunofluorescence examination. TC: performed immunofluorescence examination. LH: performed Morris water maze test. FC: project administration, writing original draft, funding acquisition.

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Correspondence to Fei Cai.

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All animal experiments were approved by the Animal Care and Use Committee of Hubei University of Science and Technology (Approval No: 2018–03-019).

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Highlights

• The protein expressions of PTP1B increased in hippocampal CA1, CA3, and PFC regions of diabetic mice.

• PTP1B inhibitor claramine alleviated DM-induced spatial learning and memory impairment in mice.

• Inhibition of NLRP3 inflammasome and regulation of insulin signaling pathway were involved in the neuroprotective molecular mechanism of claramine.

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Wu, M., Liao, W., Zhang, R. et al. PTP1B Inhibitor Claramine Rescues Diabetes-Induced Spatial Learning and Memory Impairment in Mice. Mol Neurobiol 60, 524–544 (2023). https://doi.org/10.1007/s12035-022-03079-9

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