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Intravitreous Injection for Establishing Ocular Diseases Model
Published on: October 1, 2007
Integrin-dependent microgliosis mediates ketamine-induced neuronal apoptosis during postnatal rat retinal development
Kan Zhang1, Lei Wu1, Kana Lin2
1Department of Anesthesiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Center for Brain Science, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Purpose:
Remodeling of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) plays a pivotal role for microglia in developing retina. We tested whether integrin-dependent microgliosis mediates ketamine-induced neuronal apoptosis in the developing rat retina.
Methods:
We performed immunofluorescence assays to investigate the role of integrin receptors expressed in the microglia in ketamine-induced neuronal apoptosis. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) were used to investigate the protein and mRNA levels of cytokines (TNF-α, IL-1β) and/or chemokines (CCL2, CXCL6, CXCL10, and CXCL12). Experiments were performed using whole-mount retinas dissected from P7 Sprague-Dawley rats.
Results:
Integrin receptors expressed in microglia were upregulated in ketamine-induced neuronal apoptosis in the early developing rat retina. Downregulating integrin receptors with RGD peptide ameliorated ketamine-induced microgliosis through: 1) ameliorating the change in microglia morphology from immature ramified microglia to an amoeboid state; 2) decreasing the number of microglia and intensity of activated microglia in the retinal ganglion cell layer (GCL); and 3) decreasing cytokine (TNF-α and IL-1β) and chemokine (CCL2, CXCL10) levels in the retinal tissue. Inhibition of activated microglia with minocycline or the blockade of cytokines (TNF-α and IL-1β) with a receptor antagonist (RA) attenuated neuronal apoptosis after exposure to ketamine.
Conclusions:
The upregulation of integrin β1 receptors in the microglia acts as a signaling molecule, triggering microgliosis to aggravate ketamine-induced neuronal apoptosis via the release of TNF-α and IL-1β in the early developing rat retina.
Insights
Ketamine exposure triggers microgliosis and neuronal apoptosis in developing rat retinas by upregulating integrin receptors on microglia. Inhibiting these receptors reduces microgliosis and protects against neuronal death.
Area of Science:
- Neuroscience
- Ophthalmology
- Immunology
Background:
- Extracellular matrix (ECM) remodeling by matrix metalloproteinases (MMPs) is crucial for microglia function in developing retinas.
- Microglia play a significant role in retinal development and immune responses.
Purpose of the Study:
- To investigate if integrin-dependent microgliosis mediates ketamine-induced neuronal apoptosis in the developing rat retina.
- To elucidate the role of microglia and integrin receptors in ketamine neurotoxicity.
Main Methods:
- Immunofluorescence assays to detect integrin receptors on microglia.
- Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) to measure cytokine and chemokine levels.
- Experiments conducted on whole-mount retinas from P7 Sprague-Dawley rats.
Main Results:
- Integrin receptors were upregulated on microglia during ketamine-induced neuronal apoptosis.
- Downregulating integrin receptors with RGD peptide ameliorated microgliosis, reducing amoeboid morphology and microglia activation.
- Cytokine (TNF-α, IL-1β) and chemokine (CCL2, CXCL10) levels were decreased following integrin receptor downregulation.
Conclusions:
- Upregulation of integrin β1 receptors in microglia acts as a signaling molecule.
- This signaling triggers microgliosis, exacerbating ketamine-induced neuronal apoptosis.
- The process involves the release of TNF-α and IL-1β in the developing rat retina.
