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Effects of malonate C60 derivatives on activated microglia
Shun-Fen Tzeng1, Jia-Ling Lee, Jon-Sun Kuo
1Department of Biology, National Cheng Kung University, Tainan City, Taiwan. stzeng@mail.ncku.edu
Abstract:
Activated microglia in acute and chronic neurodegenerative disease of the central nervous system (CNS) can produce large amounts of free radicals, such as reactive oxygen species (ROS), which subsequently contribute to neuropathogenesis. Thus, it is believed that the induction of microglial deactivation can reduce neuronal injury. Buckminsterfullerene (C60) derivatives that possess free radical scavenging properties have been demonstrated to prevent neuronal cell death caused by excitotoxic insult. In this study, we investigated the biological role of two malonic acid C60 derivatives referred as trans-2 and trans-3 on microglia in the presence of the endotoxin lipopolysaccharide (LPS). Treatment of LPS-activated microglia with trans-2 and trans-3 induced a significant degree of transformation of amoeboid microglia to the ramified phenotype. To understand the mechanism underlying this C60 mediated microglial morphological transformation, we examined the production of proinflammatory cytokines, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), as well as the final NO products (nitrate and nitrite) in the microglial culture supernatant. Although inducible nitric oxide (iNOS) mRNA and protein expression in LPS-activated microglia were slightly decreased by trans-2 and trans-3, levels of nitrate and nitrite were unaffected. Paradoxically, trans-2 and trans-3 were found to increase the release of IL-1beta in the activated microglial culture. However, trans-2 and trans-3 improved the activity of the antioxidant enzyme, superoxide dismutase (SOD) in LPS-treated microglia. Therefore, our results suggest that the C60 derivatives might increase microglial SOD enzymatic activity which causes microglial morphological transformation from the activated amoeboid phenotype to the resting ramified form.
Insights
Buckminsterfullerene C60 derivatives, trans-2 and trans-3, transform activated microglia to a resting state by increasing antioxidant enzyme activity. This suggests a potential therapeutic strategy for neurodegenerative diseases by reducing neuronal injury.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Activated microglia contribute to neuropathogenesis in neurodegenerative diseases via reactive oxygen species (ROS).
- Microglial deactivation is a potential strategy to reduce neuronal injury.
- Buckminsterfullerene (C60) derivatives with free radical scavenging properties may protect against excitotoxic neuronal death.
Purpose of the Study:
- To investigate the biological role of malonic acid C60 derivatives (trans-2 and trans-3) on microglia activated by lipopolysaccharide (LPS).
- To elucidate the mechanism underlying C60-mediated microglial morphological transformation.
Main Methods:
- Treatment of LPS-activated microglia with trans-2 and trans-3.
- Assessment of microglial morphological transformation from amoeboid to ramified phenotype.
- Measurement of proinflammatory cytokines (IL-1beta, TNF-alpha), nitric oxide (NO) products (nitrate, nitrite), inducible nitric oxide synthase (iNOS) expression, and superoxide dismutase (SOD) activity.
Main Results:
- Trans-2 and trans-3 induced significant morphological transformation of microglia towards a ramified phenotype.
- While iNOS expression was slightly decreased, NO product levels remained unaffected.
- Trans-2 and trans-3 paradoxically increased IL-1beta release but enhanced SOD activity in LPS-treated microglia.
Conclusions:
- C60 derivatives (trans-2 and trans-3) promote microglial morphological transformation.
- Enhanced SOD activity is suggested as the mechanism driving this transformation.
- These findings indicate a potential therapeutic approach for neurodegenerative conditions by modulating microglial activity.