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Three-dimensional Confocal Analysis of Microglia/macrophage Markers of Polarization in Experimental Brain Injury
Published on: September 4, 2013
I-C-F-6 attenuates chronic cerebral hypoperfusion-induced neurological injury in mice by modulating microglia
Shanshan Deng1, Yuan Gao1, Mengting Lv1
1School of Medicine, Shanghai University, Shanghai, China.
Insights
The study shows that I-C-F-6 peptide protects against chronic cerebral hypoperfusion (CCH) by reducing neuroinflammation and neuronal apoptosis. It inhibits M1 microglia polarization via the NF-κB pathway, offering potential therapeutic benefits for neurological damage.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Chronic cerebral hypoperfusion (CCH) is a major cause of neurological dysfunction, characterized by neuronal loss, white matter damage, and neuroinflammation.
- Microglia play a critical role in CCH-induced neuroinflammation, with M1 phenotype polarization exacerbating damage.
Purpose of the Study:
- To investigate the neuroprotective effects of the septapeptide I-C-F-6 in a mouse model of CCH.
- To elucidate the mechanisms underlying I-C-F-6's action, particularly its impact on microglia activation and inflammatory pathways.
Main Methods:
- In vivo: C57BL/6J mice underwent bilateral common carotid artery stenosis (BCAS) and were treated with I-C-F-6.
- In vitro: BV2 microglia cells were subjected to oxygen-glucose deprivation (OGD) and treated with I-C-F-6.
- Histological analyses included Luxol Fast Blue (LFB), TUNEL, and NeuN staining; immunofluorescence was used to assess microglia and NF-κB p65.
- Gene and protein expression of inflammatory markers and signaling pathways were analyzed.
Main Results:
- I-C-F-6 treatment mitigated myelin pathology and reduced neuronal apoptosis in BCAS mice.
- I-C-F-6 decreased microglia clustering and downregulated NF-κB p65 expression.
- The peptide inhibited M1 microglia polarization, reducing pro-inflammatory cytokines (TNF-α, iNOS) and increasing anti-inflammatory cytokines (Arg-1, IL-10).
- I-C-F-6 suppressed the NF-κB signaling pathway by downregulating IKK-β and NF-κB p65, as well as IL-1β and iNOS.
Conclusions:
- I-C-F-6 demonstrates significant neuroprotective effects against CCH-induced neurological injury.
- The mechanism involves alleviating neuroinflammation and inhibiting M1 microglia polarization through the NF-κB signaling pathway.
- I-C-F-6 represents a potential therapeutic agent for conditions associated with chronic cerebral hypoperfusion and neuroinflammation.
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.
