Therapeutic reduction of neurocan in murine intracerebral hemorrhage lesions promotes oligodendrogenesis and functional recovery
Abstract Background Intracerebral hemorrhage (ICH) causes prominent deposition of extracellular matrix molecules, particularly the chondroitin sulphate proteoglycan (CSPG) member neurocan. In tissue culture, neurocan impedes the properties of oligodendrocytes. Whether therapeutic reduction of neuroc...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-024-03331-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841559201075167232 |
|---|---|
| author | Hongmin Li Samira Ghorbani Olayinka Oladosu Ping Zhang Frank Visser Jeff Dunn Yunyan Zhang Chang-Chun Ling V. Wee Yong Mengzhou Xue |
| author_facet | Hongmin Li Samira Ghorbani Olayinka Oladosu Ping Zhang Frank Visser Jeff Dunn Yunyan Zhang Chang-Chun Ling V. Wee Yong Mengzhou Xue |
| author_sort | Hongmin Li |
| collection | DOAJ |
| description | Abstract Background Intracerebral hemorrhage (ICH) causes prominent deposition of extracellular matrix molecules, particularly the chondroitin sulphate proteoglycan (CSPG) member neurocan. In tissue culture, neurocan impedes the properties of oligodendrocytes. Whether therapeutic reduction of neurocan promotes oligodendrogenesis and functional recovery in ICH is unknown. Methods Mice were retro-orbitally injected with adeno-associated virus (AAV-CRISPR/Cas9) to reduce neurocan deposition after ICH induction by collagenase. Other groups of ICH mice were treated with vehicle or a drug that reduces CSPG synthesis, 4-4-difluoro-N-acetylglucosamine (difluorosamine). Rota-rod and grip strength behavioral tests were conducted over 7 or 14 days. Brain tissues were investigated for expression of neurocan by immunofluorescence microscopy and western blot analysis. Brain cryosections were also stained for microglia/macrophage phenotype, oligodendrocyte lineage cells and neuroblasts by immunofluorescence microscopy. Tissue structural changes were assessed using brain magnetic resonance imaging (MRI). Results The adeno-associated virus (AAV)-reduction of neurocan increased oligodendrocyte numbers and functional recovery in ICH. The small molecule inhibitor of CSPG synthesis, difluorosamine, lowered neurocan levels in lesions and elevated numbers of oligodendrocyte precursor cells, mature oligodendrocytes, and SOX2+ nestin+ neuroblasts in the perihematomal area. Difluorosamine shifted the degeneration-associated functional state of microglia/macrophages in ICH towards a regulatory phenotype. MRI analyses showed better fiber tract integrity in the penumbra of difluorosamine mice. These beneficial difluorosamine results were achieved with delayed (2 or 3 days) treatment after ICH. Conclusion Reducing neurocan deposition following ICH injury is a therapeutic approach to promote histological and behavioral recovery from the devastating stroke. |
| format | Article |
| id | doaj-art-3404c77a300f461c9176b6509e216d01 |
| institution | Kabale University |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-3404c77a300f461c9176b6509e216d012025-01-05T12:41:54ZengBMCJournal of Neuroinflammation1742-20942025-01-0122111910.1186/s12974-024-03331-0Therapeutic reduction of neurocan in murine intracerebral hemorrhage lesions promotes oligodendrogenesis and functional recoveryHongmin Li0Samira Ghorbani1Olayinka Oladosu2Ping Zhang3Frank Visser4Jeff Dunn5Yunyan Zhang6Chang-Chun Ling7V. Wee Yong8Mengzhou Xue9Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou UniversityHotchkiss Brain Institute and Department of Clinical Neurosciences, University of CalgaryHotchkiss Brain Institute and Department of Clinical Neurosciences, University of CalgaryDepartment of Chemistry, University of CalgaryHotchkiss Brain Institute and Department of Clinical Neurosciences, University of CalgaryDepartment of Radiology, University of CalgaryHotchkiss Brain Institute and Department of Clinical Neurosciences, University of CalgaryDepartment of Chemistry, University of CalgaryHotchkiss Brain Institute and Department of Clinical Neurosciences, University of CalgaryDepartment of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou UniversityAbstract Background Intracerebral hemorrhage (ICH) causes prominent deposition of extracellular matrix molecules, particularly the chondroitin sulphate proteoglycan (CSPG) member neurocan. In tissue culture, neurocan impedes the properties of oligodendrocytes. Whether therapeutic reduction of neurocan promotes oligodendrogenesis and functional recovery in ICH is unknown. Methods Mice were retro-orbitally injected with adeno-associated virus (AAV-CRISPR/Cas9) to reduce neurocan deposition after ICH induction by collagenase. Other groups of ICH mice were treated with vehicle or a drug that reduces CSPG synthesis, 4-4-difluoro-N-acetylglucosamine (difluorosamine). Rota-rod and grip strength behavioral tests were conducted over 7 or 14 days. Brain tissues were investigated for expression of neurocan by immunofluorescence microscopy and western blot analysis. Brain cryosections were also stained for microglia/macrophage phenotype, oligodendrocyte lineage cells and neuroblasts by immunofluorescence microscopy. Tissue structural changes were assessed using brain magnetic resonance imaging (MRI). Results The adeno-associated virus (AAV)-reduction of neurocan increased oligodendrocyte numbers and functional recovery in ICH. The small molecule inhibitor of CSPG synthesis, difluorosamine, lowered neurocan levels in lesions and elevated numbers of oligodendrocyte precursor cells, mature oligodendrocytes, and SOX2+ nestin+ neuroblasts in the perihematomal area. Difluorosamine shifted the degeneration-associated functional state of microglia/macrophages in ICH towards a regulatory phenotype. MRI analyses showed better fiber tract integrity in the penumbra of difluorosamine mice. These beneficial difluorosamine results were achieved with delayed (2 or 3 days) treatment after ICH. Conclusion Reducing neurocan deposition following ICH injury is a therapeutic approach to promote histological and behavioral recovery from the devastating stroke.https://doi.org/10.1186/s12974-024-03331-0Extracellular matrixNeurocanChondroitin sulphate proteoglycansOligodendrogenesisFunctional recoveryIntracerebral hemorrhage |
| spellingShingle | Hongmin Li Samira Ghorbani Olayinka Oladosu Ping Zhang Frank Visser Jeff Dunn Yunyan Zhang Chang-Chun Ling V. Wee Yong Mengzhou Xue Therapeutic reduction of neurocan in murine intracerebral hemorrhage lesions promotes oligodendrogenesis and functional recovery Journal of Neuroinflammation Extracellular matrix Neurocan Chondroitin sulphate proteoglycans Oligodendrogenesis Functional recovery Intracerebral hemorrhage |
| title | Therapeutic reduction of neurocan in murine intracerebral hemorrhage lesions promotes oligodendrogenesis and functional recovery |
| title_full | Therapeutic reduction of neurocan in murine intracerebral hemorrhage lesions promotes oligodendrogenesis and functional recovery |
| title_fullStr | Therapeutic reduction of neurocan in murine intracerebral hemorrhage lesions promotes oligodendrogenesis and functional recovery |
| title_full_unstemmed | Therapeutic reduction of neurocan in murine intracerebral hemorrhage lesions promotes oligodendrogenesis and functional recovery |
| title_short | Therapeutic reduction of neurocan in murine intracerebral hemorrhage lesions promotes oligodendrogenesis and functional recovery |
| title_sort | therapeutic reduction of neurocan in murine intracerebral hemorrhage lesions promotes oligodendrogenesis and functional recovery |
| topic | Extracellular matrix Neurocan Chondroitin sulphate proteoglycans Oligodendrogenesis Functional recovery Intracerebral hemorrhage |
| url | https://doi.org/10.1186/s12974-024-03331-0 |
| work_keys_str_mv | AT hongminli therapeuticreductionofneurocaninmurineintracerebralhemorrhagelesionspromotesoligodendrogenesisandfunctionalrecovery AT samiraghorbani therapeuticreductionofneurocaninmurineintracerebralhemorrhagelesionspromotesoligodendrogenesisandfunctionalrecovery AT olayinkaoladosu therapeuticreductionofneurocaninmurineintracerebralhemorrhagelesionspromotesoligodendrogenesisandfunctionalrecovery AT pingzhang therapeuticreductionofneurocaninmurineintracerebralhemorrhagelesionspromotesoligodendrogenesisandfunctionalrecovery AT frankvisser therapeuticreductionofneurocaninmurineintracerebralhemorrhagelesionspromotesoligodendrogenesisandfunctionalrecovery AT jeffdunn therapeuticreductionofneurocaninmurineintracerebralhemorrhagelesionspromotesoligodendrogenesisandfunctionalrecovery AT yunyanzhang therapeuticreductionofneurocaninmurineintracerebralhemorrhagelesionspromotesoligodendrogenesisandfunctionalrecovery AT changchunling therapeuticreductionofneurocaninmurineintracerebralhemorrhagelesionspromotesoligodendrogenesisandfunctionalrecovery AT vweeyong therapeuticreductionofneurocaninmurineintracerebralhemorrhagelesionspromotesoligodendrogenesisandfunctionalrecovery AT mengzhouxue therapeuticreductionofneurocaninmurineintracerebralhemorrhagelesionspromotesoligodendrogenesisandfunctionalrecovery |