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DTI of the Visual Pathway - White Matter Tracts and Cerebral Lesions
Published on: August 26, 2014
Melatonin attenuates white matter damage after focal brain ischemia in rats by regulating the TLR4/NF-κB pathway
Yansong Zhao1, Haiyu Wang2, Wei Chen3
1Department of Ophthalmology, Affiliated Hospital, Weifang Medical University, Weifang, Shandong 261031, China.
Objective:
To assess the possible neuroprotective effects of melatonin against brain white matter damage via the Toll-like receptor 4 (TLR4)/ nuclear factor-kappa B (NF-κB) signaling pathway in focal cerebral ischemic rats.
Methods:
Fifty-four Sprague-Dawley rats were randomly divided into the Sham, middle cerebral artery occlusion (MCAO), and melatonin groups. The successful MCAO models were evaluated by Laser Doppler flowmetry, magnetic resonance imaging (MRI) with T2-weighted imaging (T2WI) examination and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. White matter damage was assessed by myelin basic protein (MBP) immunohistochemical, Luxol Fast Blue (LFB) staining, and diffusion tensor imaging (DTI) examination. The proliferation of oligodendrocyte progenitor cells (OPCs) was examined by proliferating cell nuclear antigen (PCNA)/neural glial antigen 2 (NG2)/DAPI immunofluorescent staining. And the effects of melatonin therapy on the TLR4, NF-κB, and interleukin (IL)-1β proteins were examined by immunohistochemical staining. The correlation between the proliferating OPCs and TLR4 protein, IL-1β and TLR4 protein was respectively analyzed by linear regression analysis.
Results:
The infarct volume was significantly reduced and white matter damage was also significantly alleviated in the melatonin group as compared with the MCAO group (P < 0.05), and there were more TLR4+, NF-κB+ and IL-1β+ cells in the MCAO group compared with the melatonin group (P < 0.01). Similarly, more PCNA+NG2+ cells were observed in the subventricular zone and white matter areas in the melatonin group compared with the MCAO group (P < 0.01). The number of TLR4+ cells was closely positively correlated with that of IL-1β+ cells, and negatively correlated with that of PCNA+NG2+ cells.
Conclusions:
In summary, melatonin could promote the proliferation of endogenous OPCs and suppress the expression of IL-1β protein via inhibiting TLR4/NF-κB signaling, thus alleviate the white matter damage in focal cerebral ischemic rats.
Insights
Melatonin reduces brain white matter damage in ischemic rats by inhibiting the Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) pathway. This neuroprotective effect promotes oligodendrocyte progenitor cell proliferation and suppresses inflammation.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Focal cerebral ischemia can lead to significant brain white matter damage.
- The Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway is implicated in inflammatory responses following ischemic stroke.
- Oligodendrocyte progenitor cells (OPCs) are crucial for myelin repair, and their proliferation is affected by ischemic injury.
Purpose of the Study:
- To investigate the neuroprotective potential of melatonin in mitigating white matter damage in a rat model of focal cerebral ischemia.
- To elucidate the role of the TLR4/NF-κB signaling pathway in melatonin's effects on white matter integrity.
- To assess the impact of melatonin on OPC proliferation and inflammatory markers.
Main Methods:
- Establishment of a focal cerebral ischemia model in Sprague-Dawley rats (middle cerebral artery occlusion - MCAO).
- Evaluation of infarct volume and white matter damage using MRI (T2WI), DTI, and histological staining (LFB, MBP).
- Assessment of OPC proliferation (PCNA/NG2/DAPI) and inflammatory markers (TLR4, NF-κB, IL-1β) via immunohistochemistry and immunofluorescence.
Main Results:
- Melatonin treatment significantly reduced infarct volume and alleviated white matter damage compared to the MCAO group.
- Melatonin administration decreased the expression of TLR4, NF-κB, and IL-1β in the ischemic brain.
- Increased proliferation of OPCs was observed in the melatonin-treated group, with a negative correlation between TLR4 expression and OPC proliferation.
Conclusions:
- Melatonin exerts neuroprotective effects against white matter damage in focal cerebral ischemia.
- Melatonin inhibits the TLR4/NF-κB signaling pathway, leading to reduced IL-1β expression.
- Melatonin promotes endogenous OPC proliferation, contributing to white matter repair and neuroprotection.
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