Inhibition of the proteoglycan receptor PTPσ promotes functional recovery on a rodent model of preterm hypoxic-ischemic brain injury

Ran Wang; Tiantian Li; Sihao Diao; Chao Chen

doi:10.1016/j.expneurol.2023.114564

Inhibition of the proteoglycan receptor PTPσ promotes functional recovery on a rodent model of preterm hypoxic-ischemic brain injury

Exp Neurol. 2023 Dec:370:114564. doi: 10.1016/j.expneurol.2023.114564. Epub 2023 Oct 6.

Authors

Ran Wang¹, Tiantian Li², Sihao Diao², Chao Chen³

Affiliations

¹ Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China; Key Laboratory of Neonatal Diseases, National Health Commission, China; Department of Developmental and Behavioral Pediatrics, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
² Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China; Key Laboratory of Neonatal Diseases, National Health Commission, China.
³ Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China; Key Laboratory of Neonatal Diseases, National Health Commission, China. Electronic address: chaochen@fudan.edu.cn.

PMID: 37806512
DOI: 10.1016/j.expneurol.2023.114564

Abstract

Background: Preterm white matter injury (WMI) is the most common brain injury in preterm infants and is associated with long-term adverse neurodevelopmental outcomes. Protein tyrosine phosphatase sigma (PTPσ) was discovered as chondroitin sulfate proteoglycan (CSPG) receptor that played roles in inhibiting myelin regeneration in spinal injury, experimental autoimmune encephalomyelitis, and stroke models. However, the role of PTPσ in perinatal WMI is not well understood.

Aims: This study examines the effect of PTPσ inhibition on neurodevelopmental outcomes, myelination, and neuroinflammation in a mouse model of preterm WMI.

Materials and methods: Modified Rice-Vannucci model was performed on postnatal day 3 (P3) C57BL/6 mice. Intracellular Sigma Peptide (ISP) or vehicle was administrated subcutaneously one hour after injury for an additional 14 consecutive days. A battery of behavioral tests was performed to evaluate the short- and long-term effects of ISP on neurobehavioral deficit. Real time qPCR, western blot, immunofluorescence, and transmission electron microscopy were performed to assess white matter development. qPCR and flow cytometry were performed to evaluate neuroinflammation and microglia/macrophage phenotype.

Results: The expression of PTPσ was increased after preterm WMI. ISP improved short-term neurological outcomes and ameliorated long-term motor and cognitive function of mice after preterm WMI. ISP promoted oligodendrocyte differentiation, maturation, myelination, and improved microstructure of myelin after preterm WMI. Furthermore, ISP administration fostered a beneficial inflammatory response in the acute phase after preterm WMI, inhibited the infiltration of peripheral macrophages, and promoted anti-inflammatory phenotype of microglia/macrophages.

Conclusion: PTPσ inhibition can ameliorate neurofunctional deficit, promote white matter development, modulate neuroinflammation and microglia/macrophage phenotype after preterm WMI. Thus, ISP administration may be a potential therapeutic strategy to improve neurodevelopmental outcomes of perinatal WMI.

Keywords: Myelination; Neurodevelopmental outcomes; Neuroinflammation; Preterm white matter injury; Protein tyrosine phosphatase sigma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Injuries* / drug therapy
Female
Humans
Infant, Newborn
Infant, Premature
Mice
Mice, Inbred C57BL
Neuroinflammatory Diseases
Peptides / therapeutic use
Pregnancy
Proteoglycans / metabolism
Receptor-Like Protein Tyrosine Phosphatases, Class 2 / metabolism
Rodentia / metabolism
White Matter* / metabolism

Substances

Proteoglycans
Receptor-Like Protein Tyrosine Phosphatases, Class 2
Peptides