Role of Drp1, a Protein Involved in Mitochondrial Dynamics, in the Control of Paclitaxel-Induced Neurotoxicity and Neuropathy

• Grant number: 25/06967-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: November 01, 2025
• End date: December 31, 2028
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Vanessa Olzon Zambelli
• Grantee: Mariana Caprio Schiess
• Host Institution: Instituto Butantan. São Paulo , SP, Brazil

Abstract

Paclitaxel (PTX) is a widely used chemotherapy drug for cancer treatment. Although effective, it induces neuropathy in approximately 70% of patients who use it. It is known that PTX stabilizes microtubules, interrupting axonal transport, and induces impairment in mitochondrial bioenergetic metabolism, leading to the development of neuropathies. Data from our group have shown that paclitaxel modifies the mitochondrial dynamics of sensory neurons in vivo and in culture, promoting mitochondrial fragmentation and dysfunction. Mitochondrial dynamics are mediated by the balance between fusion and fission, processes mediated by GTPases, regulatory enzymes capable of activating signaling cascades and regulating cell morphology. Given the inefficiency of current treatments for chemotherapy-induced peripheral neuropathy (CIPN), the use of pharmacological inhibitors for Drp1 (a protein involved in mitochondrial fission) may be a promising strategy for the prevention of this type of pain. Previous studies have shown that the peptide P110 and the small molecule SC9 selectively inhibit Drp1 and have beneficial effects in models of neurodegenerative diseases. However, the action of these molecules in CIPN models has not yet been explored. Considering that PTX promotes neurodegeneration accompanied by excessive mitochondrial fragmentation in neurons, we hypothesize that pharmacological inhibitors of Drp1 may prevent or reduce neuropathy. Thus, the objective of this project is to investigate the neuroprotective and antinociceptive effects of P110 and SC9. For this purpose, we will use a culture model of sensory neurons and an in vivo model of PTX-induced neuropathy. Considering that Drp1 is the main GTPase involved in pathological contexts, the use of pharmacological inhibitors of this protein may offer a relevant strategy for preventing these effects.