Abstract
Chronic cerebral hypoperfusion (CCH) is the leading cause of chronic cerebral dysfunction syndrome with its complex pathological mechanisms involving cortical and hippocampal neuronal loss, white matter lesions, and neuroinflammation. I-C-F-6 is a septapeptide, which has anti-inflammatory and anti-fibrotic effects. This study aimed to evaluate the neuroprotective effect of I-C-F-6 in chronic cerebral hypoperfusion (CCH)-induced neurological injury. C57BL/6 J mice were subjected to bilateral common carotid artery stenosis (BCAS), and BV2 microglia cells were induced with oxygen-glucose deprivation (OGD). In vivo, mice were divided randomly into four groups: Sham, BCAS, GBE (30 mg/kg), and I-C-F-6 (0.5 mg/kg). In vitro, microglia were divided randomly into four groups: control, OGD, I-C-F-6 (25 μg/mL), and Shikonin (800 nmol/L). Through LFB, TUNEL, and NeuN staining, we found that I-C-F-6 was able to mitigate myelin pathology and reduce the number of apoptotic neurons. Furthermore, immunofluorescence staining revealed that I-C-F-6 was able to reduce microglia clustering and downregulate NF-κB p65. We also observed a significant downregulation of M1 phenotype microglia signature genes, such as TNF-α, iNOS, and upregulation of anti-inflammatory cytokines, such as Arg-1 and IL-10, indicating that I-C-F-6 may mainly reduce polarization towards the M1 phenotype in microglia. Notably, I-C-F-6 downregulated the expression of NF-κB signaling pathway-related proteins IKK-β and NF-κB p65, as well as pro-inflammatory cytokines IL-1β and iNOS. In conclusion, I-C-F-6 can improve neurological damage, alleviate neuroinflammation, and inhibit microglia polarization to the M1 phenotype via the NF-κB signaling pathway.
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Data availability
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- WML:
-
White matter lesion
- BCAS:
-
Bilateral common carotid artery stenosis
- CCA:
-
Common carotid artery
- OGD:
-
Oxygen-glucose deprivation
- CCH:
-
Chronic cerebral hypoperfusion
- GBE:
-
Ginkgo biloba extract
- MAPK:
-
Mitogen-activated protein kinase
- NF-κB:
-
Nuclear factor kappa-B
- IL-1β:
-
Interleukin-1β
- TNF-α:
-
Tumor necrosis factor-α
- MMPs:
-
Metalloproteinases
- ROS:
-
Reactive oxygen species
- VCI:
-
Vascular cognitive impairment
- CSVD:
-
Cerebral small vascular disease
- CNS:
-
Central nervous system
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This work was supported by the grants from National key R&D program for the key research project of modernization of traditional Chinese medicine (2019YFC1711602).
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S.D. and Y.G. carried out this study. M.L., X.L., Y.M., and Y.G. drafted the manuscript text and prepared the figures. Y.Z. and T.L. conceived the project, interpreted the data, and revised and finalized the manuscript. M.L. and X.L. constructed the animal model. Y.M. and Y.G. revised the manuscript. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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All animal experiments and surgical procedures were overseen by the Institutional Animal Care and Use Committee at Shanghai University and followed international guidelines for ethical use of experimental animals (No. ECSHU 2023-009).
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Deng, S., Gao, Y., Lv, M. et al. I-C-F-6 attenuates chronic cerebral hypoperfusion-induced neurological injury in mice by modulating microglia polarization. Naunyn-Schmiedeberg's Arch Pharmacol 397, 3917–3928 (2024). https://doi.org/10.1007/s00210-023-02783-0
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DOI: https://doi.org/10.1007/s00210-023-02783-0