Piplartine Attenuates Aminoglycoside-Induced TRPV1 Activity and Protects from Hearing Loss in Mice

Medicinal Chemistry Neurology Chemistry Biochemistry Life Sciences Pharmacy Medicine
hearing loss aminoglycosides TRPV1 mouse model protective mechanism

Piplartine Attenuates Aminoglycoside-Induced TRPV1 Activity and Protects from Hearing Loss in Mice

Academic Background

Hearing loss is a serious global health problem affecting over 400 million people worldwide, according to the World Health Organization. Aminoglycoside antibiotics, while widely used in medicine due to their broad-spectrum antibacterial properties and effectiveness against multi-drug resistant bacteria, have significant side effects, including irreversible neurotoxicity and sensorineural hearing loss. Approximately 40% to 60% of patients receiving aminoglycoside treatment eventually lose their hearing. With no FDA-approved drugs currently available to prevent or treat this type of hearing loss, finding a drug that can prevent or treat aminoglycoside-induced hearing loss is particularly urgent.

Paper Source

This paper titled “Piplartine attenuates aminoglycoside-induced TRPV1 activity and protects from hearing loss in mice” was conducted by 12 researchers including Marisa Zallocchi, from institutions such as Creighton University School of Medicine, University of Zürich, University of Toledo, and University of Nebraska Medical Center. The paper was published in Science Translational Medicine on August 7, 2024.

Research Process

The researchers first identified a plant-derived molecule called Piplartine (PL) through a high-throughput screening of a small molecule library, which showed potential in preventing aminoglycoside-induced ototoxicity. Subsequently, they conducted in-depth studies on the pharmacological properties of PL and its mechanism of action in aminoglycoside-induced hearing damage through multiple experiments.

Summary of Research Steps:

a) Research Process:

  1. Initial Screening Experiment: Screening a small molecule library in zebrafish to find candidate drugs with otoprotective effects.
  2. In Vitro Characterization of PL: Toxicity assessment in HEI-CO1 cell line; ototoxicity tests in avian and fish to determine effective concentrations of PL; evaluation of its protective effect on proximal tubule function.
  3. Drug Interaction Experiments: Using fluorescence-based ELISA and disk diffusion assays to assess PL’s impact on cytochrome and antibacterial activity.
  4. Protection Experiments in Mouse Models: Testing PL’s protective effect in aminoglycoside-induced ototoxicity in mice through Auditory Brainstem Response (ABR) and Distortion Product Otoacoustic Emissions (DPOAE).
  5. Mechanism Studies: Analyzing PL’s mechanism of action through phosphoproteomics, immunoblotting, immunohistochemistry, and molecular dynamics simulations.

b) Main Research Findings:

  1. Protective Effect Assessment: PL significantly reduced aminoglycoside-induced hair cell loss in zebrafish, with a median effective concentration (EC50) of 0.125 nM. In mouse models, co-administration of PL significantly reduced aminoglycoside-induced hearing loss, with complete recovery at lower frequencies and partial recovery at higher frequencies.
  2. Mechanism Study: Analysis revealed that PL upregulates key signaling pathways (such as AKT1) and blocks the entry of aminoglycosides into the ear by modulating the expression and gating properties of TRPV1 (Transient Receptor Potential Vanilloid 1 channel).

c) Research Conclusions and Significance:

The study clearly demonstrates that PL mitigates aminoglycoside-induced ototoxicity by modulating TRPV1 and AKT1 signaling pathways, showing significant hearing protection effects. This finding provides a new potential therapeutic strategy for preventing and treating aminoglycoside-induced hearing damage, with important scientific and clinical application value.

d) Research Highlights:

  1. Discovery of PL’s Otoprotective Effect: This is the first study to clearly demonstrate that PL can effectively protect against aminoglycoside-induced ototoxicity.
  2. Mechanism Exploration: The study revealed PL’s mechanism of action through detailed molecular mechanism studies, enriching the understanding of aminoglycoside-induced ototoxicity.
  3. Large-scale Screening and Validation: Experimental validation in both zebrafish and mouse models confirmed the broad protective effect of PL, providing a solid foundation for future clinical applications.

Summary

This paper not only reveals a new therapeutic potential of PL but also provides detailed molecular basis for its protective mechanism. These results will aid in future drug development and clinical research aimed at protecting the hearing of numerous patients worldwide affected by aminoglycoside ototoxicity.