SIRT1 activation by SRT1720 attenuates bone cancer pain via preventing Drp1-mediated mitochondrial fission

Area of Science:

• Neuroscience
• Oncology
• Molecular Biology

Background:

• Bone cancer pain (BCP) involves peripheral and central sensitization.
• Mammalian silent information regulator 2 homolog (SIRT1) plays a role in BCP mechanisms.
• Dynamin-related protein 1 (Drp1) regulates mitochondrial fission and is implicated in pain pathways.

Purpose of the Study:

• To investigate the role of SIRT1 and Drp1 in a rat model of bone cancer pain.
• To determine if activating SIRT1 can alleviate BCP and its underlying mechanisms.
• To explore the therapeutic potential of SIRT1 activation for BCP.

Main Methods:

• Established a BCP rat model by injecting MRMT-1 cells into the tibia.
• Assessed BCP severity through radiographs, histology, and mechanical pain tests.
• Administered SRT1720 (SIRT1 agonist) intrathecally and evaluated its effects on pain behavior, protein expression (SIRT1, Drp1, Bcl-2/BAX, cleaved caspase-3), and mitochondrial apoptosis in the spinal cord.
• Conducted in vitro experiments to assess SRT1720's effects on Drp1 expression, mitochondrial membrane potential, apoptosis, and proliferation.

Main Results:

• BCP rats exhibited bone destruction, mechanical hyperalgesia, increased inflammation, and apoptosis in the spinal cord.
• BCP was associated with reduced SIRT1 expression/phosphorylation and increased Drp1 expression.
• SRT1720 treatment reversed pain behaviors, reduced Drp1 expression, inhibited spinal cord apoptosis, and normalized mitochondrial function.
• In vitro, SRT1720 reduced Drp1 expression, protected mitochondrial membrane potential, and reduced apoptosis.

Conclusions:

• SIRT1 activation by SRT1720 attenuates bone cancer pain.
• The mechanism involves the inhibition of Drp1-mediated mitochondrial fission and apoptosis in the spinal cord.
• Targeting SIRT1 offers a promising therapeutic strategy for managing bone cancer pain.