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Rosiglitazone protects neuroblastoma cells against advanced glycation end products-induced injury
Li Wang1, Chun-jiang Yu, Wei Liu
1Department of Geriatrics, the Second Affiliated Hospital of Harbin Medical University, China.
Aim:
To investigate the protective effects of rosiglitazone (RGZ) against the neuronal toxicity induced by advanced glycation end products (AGEs) and the underlying mechanisms.
Methods:
Neuroblastoma cell line SH-SY5Y was used. Cell viability and apoptosis were assessed using MTT assay and flow cytometry, respectively. Superoxide dismutase (SOD) and catalase activities were measured using biochemical methods. Intracellular reactive oxygen species (ROS) were monitored using 2',7'-dichlorodihydro-fluorescein diacetate (DCFH-DA). Secreted β-amyloid(1-42) (Aβ(1-42)) level was assessed by ELISA. The expression of mRNA of Bcl2, Bax, Caspase3, Aβ precursor protein (APP), β-site APP-cleaving enzyme 1 (BACE1), and insulin degrading enzyme (IDE) were measured using quantitative real-time PCR (Q-PCR), and their protein levels were examined using Western blot.
Results:
RGZ (0.1-10 μmol/L) significantly increased the cell viability that was reduced by AGEs (1000 μg/mL). RGZ (10 μmol/L) significantly ameliorated AGEs-triggered downregulation of SOD and catalase, and production of ROS. It also reversed Bcl2 downregulation, Bax upregulation and Caspase3 expression caused by AGEs. Moreover, it significantly attenuated AGEs-induced Aβ secretion and APP protein upregulation. RGZ did not affect BACE1 expression, but induced IDE expression, which promoted degradation of Aβ. All the effects were blocked by the specific PPARγ antagonist GW9662 (10 μmol/L).
Conclusion:
RGZ protects the euroblastoma cells against AGEs-induced injury via its anti-oxidative, anti-apoptotic and anti-inflammatory properties that seems to be mediated by PPARγ activation. The results suggest a beneficial role for RGZ in the treatment of Alzheimer's disease.
Insights
Rosiglitazone (RGZ) protects neuroblastoma cells from advanced glycation end product (AGEs) toxicity by reducing oxidative stress and apoptosis. This suggests RGZ may be beneficial for Alzheimer's disease treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Advanced glycation end products (AGEs) contribute to neuronal damage.
- Oxidative stress and apoptosis are implicated in neurodegenerative diseases like Alzheimer's.
- Understanding protective mechanisms against AGEs-induced neurotoxicity is crucial.
Purpose of the Study:
- To investigate the neuroprotective effects of rosiglitazone (RGZ) against AGEs-induced toxicity.
- To elucidate the underlying mechanisms of RGZ's protective action, including its impact on oxidative stress, apoptosis, and amyloid-beta (Aβ) metabolism.
- To explore the role of peroxisome proliferator-activated receptor gamma (PPARγ) in mediating RGZ's effects.
Main Methods:
- Utilized the SH-SY5Y neuroblastoma cell line.
- Assessed cell viability (MTT assay) and apoptosis (flow cytometry).
- Measured antioxidant enzyme activities (SOD, catalase), reactive oxygen species (ROS) levels, and Aβ(1-42) secretion (ELISA).
- Quantified gene and protein expression of apoptosis markers (Bcl2, Bax, Caspase3), amyloid precursor protein (APP), BACE1, and insulin-degrading enzyme (IDE) using Q-PCR and Western blot.
- Investigated the role of PPARγ using the antagonist GW9662.
Main Results:
- RGZ significantly increased cell viability and ameliorated AGEs-induced oxidative stress and apoptosis.
- RGZ reversed AGEs-induced changes in Bcl2, Bax, and Caspase3 expression.
- RGZ attenuated AGEs-induced Aβ secretion and APP upregulation, while inducing IDE expression, promoting Aβ degradation.
- All observed effects were abrogated by the PPARγ antagonist GW9662.
Conclusions:
- RGZ exhibits neuroprotective effects against AGEs-induced injury through antioxidant, anti-apoptotic, and anti-inflammatory mechanisms.
- These protective effects appear to be mediated by PPARγ activation.
- RGZ demonstrates potential as a therapeutic agent for Alzheimer's disease.
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