NF-κB/p53-activated inflammatory response involves in diquat-induced mitochondrial dysfunction and apoptosis

Area of Science:

• Neuroscience
• Toxicology
• Cell Biology

Background:

• Environmental toxicants, such as pesticides, are implicated in neurodegenerative diseases.
• Inflammation is a potential mechanism contributing to neuronal cell damage.

Purpose of the Study:

• To investigate how inflammatory responses contribute to apoptosis in PC12 cells treated with diquat.
• To elucidate the molecular mechanisms of diquat-induced cytotoxicity.

Main Methods:

• PC12 cells were treated with diquat to induce apoptosis.
• Assessed caspase activation, nuclear condensation, mitochondrial complex I activity, ATP levels, and dopamine levels.
• Measured reactive oxygen species (ROS) production and the effects of antioxidants.
• Investigated the expression of cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α).
• Analyzed NF-κB and p53 protein nuclear accumulation and the effects of their inhibitors.
• Examined the impact of a COX-2 inhibitor (meloxicam) on diquat-induced effects.

Main Results:

• Diquat induced apoptosis, mitochondrial dysfunction (inhibited complex I, decreased ATP), and ROS production in PC12 cells.
• Diquat reduced dopamine levels, indicating dopaminergic neuronal component cytotoxicity.
• Inflammatory mediators, COX-2 and TNF-α, were upregulated by diquat.
• Diquat promoted NF-κB nuclear accumulation, which in turn led to p53 accumulation and subsequent inflammatory responses.
• Inhibitors of NF-κB, p53, and COX-2 attenuated diquat-induced apoptosis and mitochondrial dysfunction.

Conclusions:

• Diquat-induced apoptosis and mitochondrial damage in PC12 cells are mediated by ROS production and inflammatory signaling.
• The NF-κB-mediated p53 pathway plays a crucial role in diquat-induced inflammatory responses and cell damage.
• These findings highlight a potential link between inflammatory responses, mitochondrial damage, and neurodegenerative diseases.