Modulation of the proteoglycan receptor PTPσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice
Abstract Background Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality rates. However, extant investigations have mainly focused on gray matter injury within the primary injury site after ICH rather than on white matter (WM) injury in the brain and spinal cord. This focus...
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02561-4 |
| _version_ | 1818000189260038144 |
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| author | Min Yao Jie Fang Jiewei Li Anson Cho Kiu Ng Jiaxin Liu Gilberto Ka Kit Leung Fanglai Song Jian Zhang Chunqi Chang |
| author_facet | Min Yao Jie Fang Jiewei Li Anson Cho Kiu Ng Jiaxin Liu Gilberto Ka Kit Leung Fanglai Song Jian Zhang Chunqi Chang |
| author_sort | Min Yao |
| collection | DOAJ |
| description | Abstract Background Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality rates. However, extant investigations have mainly focused on gray matter injury within the primary injury site after ICH rather than on white matter (WM) injury in the brain and spinal cord. This focus partly accounts for the diminished therapeutic discovery. Recent evidence suggests that chondroitin sulphate proteoglycans (CSPG), which can bind to the neural transmembrane protein tyrosine phosphatase-sigma (PTPσ), may facilitate axonal regrowth and remyelination by ameliorating neuroinflammation. Methods A clinically relevant ICH model was established using adult C57BL/6 mice. The mice were then treated systemically with intracellular sigma peptide (ISP), which specifically targets PTPσ. Sensorimotor function was assessed by various behavioral tests and electrophysiological assessment. Western blot was used to verify the expression levels of Iba-1 and different inflammatory cytokines. The morphology of white matter tracts of brain and spinal cord was evaluated by immunofluorescence staining and transmission electron microscopy (TEM). Adeno-associated virus (AAV) 2/9 injection was used to assess the ipsilateral axonal compensation after injury. Parallel in vitro studies on the effects of CSPG interference on oligodendrocyte–DRG neuron co-culture explored the molecular mechanism through which ISP treatment promoted myelination capability. Results ISP, by targeting PTPσ, improved WM integrity and sensorimotor recovery via immunomodulation. In addition, ISP administration significantly decreased WM injury in the peri-hematomal region as well as cervical spinal cord, enhanced axonal myelination and facilitated neurological restoration, including electrophysiologically assessed sensorimotor functions. Parallel in vitro studies showed that inhibition of PTPσ by ISP fosters myelination by modulating the Erk/CREB signaling pathway. Conclusions Our findings revealed for the first time that manipulation of PTPσ signaling by ISP can promote prolonged neurological recovery by restoration of the integrity of neural circuits in the CNS through modulation of Erk/CREB signaling pathway. |
| first_indexed | 2024-04-14T03:18:54Z |
| format | Article |
| id | doaj.art-454db4ba978140e5a7d28741b8d76c95 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-14T03:18:54Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-454db4ba978140e5a7d28741b8d76c952022-12-22T02:15:22ZengBMCJournal of Neuroinflammation1742-20942022-08-0119111810.1186/s12974-022-02561-4Modulation of the proteoglycan receptor PTPσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in miceMin Yao0Jie Fang1Jiewei Li2Anson Cho Kiu Ng3Jiaxin Liu4Gilberto Ka Kit Leung5Fanglai Song6Jian Zhang7Chunqi Chang8School of Pharmaceutical Sciences, Health Science Centre, Shenzhen UniversitySchool of Biomedical Engineering, Health Science Center, Shenzhen UniversitySchool of Biomedical Engineering, Health Science Center, Shenzhen UniversityDepartment of Surgery, LKS Faculty of Medicine, The University of Hong KongDepartment of Surgery, LKS Faculty of Medicine, The University of Hong KongDepartment of Surgery, LKS Faculty of Medicine, The University of Hong KongSchool of Biomedical Engineering, Health Science Center, Shenzhen UniversitySchool of Pharmaceutical Sciences, Health Science Centre, Shenzhen UniversitySchool of Biomedical Engineering, Health Science Center, Shenzhen UniversityAbstract Background Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality rates. However, extant investigations have mainly focused on gray matter injury within the primary injury site after ICH rather than on white matter (WM) injury in the brain and spinal cord. This focus partly accounts for the diminished therapeutic discovery. Recent evidence suggests that chondroitin sulphate proteoglycans (CSPG), which can bind to the neural transmembrane protein tyrosine phosphatase-sigma (PTPσ), may facilitate axonal regrowth and remyelination by ameliorating neuroinflammation. Methods A clinically relevant ICH model was established using adult C57BL/6 mice. The mice were then treated systemically with intracellular sigma peptide (ISP), which specifically targets PTPσ. Sensorimotor function was assessed by various behavioral tests and electrophysiological assessment. Western blot was used to verify the expression levels of Iba-1 and different inflammatory cytokines. The morphology of white matter tracts of brain and spinal cord was evaluated by immunofluorescence staining and transmission electron microscopy (TEM). Adeno-associated virus (AAV) 2/9 injection was used to assess the ipsilateral axonal compensation after injury. Parallel in vitro studies on the effects of CSPG interference on oligodendrocyte–DRG neuron co-culture explored the molecular mechanism through which ISP treatment promoted myelination capability. Results ISP, by targeting PTPσ, improved WM integrity and sensorimotor recovery via immunomodulation. In addition, ISP administration significantly decreased WM injury in the peri-hematomal region as well as cervical spinal cord, enhanced axonal myelination and facilitated neurological restoration, including electrophysiologically assessed sensorimotor functions. Parallel in vitro studies showed that inhibition of PTPσ by ISP fosters myelination by modulating the Erk/CREB signaling pathway. Conclusions Our findings revealed for the first time that manipulation of PTPσ signaling by ISP can promote prolonged neurological recovery by restoration of the integrity of neural circuits in the CNS through modulation of Erk/CREB signaling pathway.https://doi.org/10.1186/s12974-022-02561-4Intracerebral hemorrhagePTPσISPNeural circuits integrityNeuroinflammation |
| spellingShingle | Min Yao Jie Fang Jiewei Li Anson Cho Kiu Ng Jiaxin Liu Gilberto Ka Kit Leung Fanglai Song Jian Zhang Chunqi Chang Modulation of the proteoglycan receptor PTPσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice Journal of Neuroinflammation Intracerebral hemorrhage PTPσ ISP Neural circuits integrity Neuroinflammation |
| title | Modulation of the proteoglycan receptor PTPσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice |
| title_full | Modulation of the proteoglycan receptor PTPσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice |
| title_fullStr | Modulation of the proteoglycan receptor PTPσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice |
| title_full_unstemmed | Modulation of the proteoglycan receptor PTPσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice |
| title_short | Modulation of the proteoglycan receptor PTPσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice |
| title_sort | modulation of the proteoglycan receptor ptpσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice |
| topic | Intracerebral hemorrhage PTPσ ISP Neural circuits integrity Neuroinflammation |
| url | https://doi.org/10.1186/s12974-022-02561-4 |
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