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Published on: August 15, 2012
Cypermethrin Induces the Activation of Rat Primary Microglia and Expression of Inflammatory Proteins
Saumya Mishra1,2, Charul Rajput1,2, Mahendra Pratap Singh3,4
1Toxicogenomics and Predictive Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.
Abstract:
Cypermethrin activates microglia, which is found to be decisive in neurodegeneration in the experimental rats. While the involvement of microglial activation in toxicant-induced neurodegeneration is reported, the effect of low concentration of cypermethrin on the expression of inflammatory proteins from the rat primary microglia is not yet properly understood. The study intended to delineate the effect of low concentration of cypermethrin on the expression and release of proteins from the microglia. Rat primary microglial cells were treated with cypermethrin to check the expression of inflammatory proteins. Cypermethrin-treated microglia conditioned media and cells were collected to measure the expression and release of inflammatory proteins. Cypermethrin augmented the protein kinase C-δ (PKC-δ), inducible nitric oxide synthase (iNOS), phosphorylated mitogen-activated protein kinase (MAPK) p38 and p42/44, matrix metalloproteinase (MMP)-3, and MMP-9 levels in the cell lysate and tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels in the microglia conditioned media. Pre-treatment with minocycline, a microglial activation inhibitor or rottlerin, a PKC-δ inhibitor, notably reduced the release of TNF-α in the conditioned media and expression of iNOS protein in the microglia. Minocycline reduced the expression of PKC-δ, phosphorylated p38 and p42/44 MAPKs, MMP-3, and MMP-9 proteins in the microglia. While cypermethrin-treated conditioned media induced the toxicity in the rat primary neurons, minocycline or rottlerin reduced the cypermethrin treated microglia conditioned media-induced toxicity. The outcomes of the present study suggest that cypermethrin activates microglia and releases TNF-α and IL-1β as well as up-regulates the expression of PKC-δ, iNOS, phosphorylated p38 and p42/44 MAPKs, MMP-3, and MMP-9 proteins, which could contribute to neurodegeneration.
Insights
Cypermethrin exposure activates microglia, increasing inflammatory proteins linked to neurodegeneration. Inhibiting microglial activation or PKC-δ reduces this toxicity, suggesting therapeutic targets for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Microglial activation is implicated in neurodegeneration.
- The specific effects of low-concentration cypermethrin on microglial inflammatory protein expression remain unclear.
Purpose of the Study:
- To investigate how low concentrations of cypermethrin affect the expression and release of inflammatory proteins in rat primary microglia.
- To explore the role of protein kinase C-delta (PKC-δ) and microglial activation in cypermethrin-induced neurotoxicity.
Main Methods:
- Rat primary microglial cells were treated with cypermethrin.
- Expression of inflammatory proteins (PKC-δ, iNOS, MAPK, MMPs, TNF-α, IL-1β) was measured.
- Inhibitors of microglial activation (minocycline) and PKC-δ (rottlerin) were used to assess their effects.
Main Results:
- Cypermethrin increased levels of PKC-δ, iNOS, phosphorylated MAPKs, MMP-3, MMP-9, TNF-α, and IL-1β.
- Minocycline and rottlerin inhibited TNF-α release and iNOS expression.
- Minocycline also reduced PKC-δ, p38/p42/44 MAPK, MMP-3, and MMP-9 expression.
- Cypermethrin-induced neuronal toxicity was mitigated by minocycline or rottlerin.
Conclusions:
- Cypermethrin activates microglia, upregulating inflammatory proteins and releasing cytokines that contribute to neurodegeneration.
- PKC-δ and microglial activation are key mediators of cypermethrin's neurotoxic effects.
- Targeting microglial activation and PKC-δ may offer therapeutic strategies against cypermethrin-induced neurotoxicity.
