Phosphorothioate oligodeoxynucleotides can selectively alter neuronal activity in the cochlea

Area of Science:

• Neuroscience
• Otolaryngology
• Molecular Biology

Background:

• Extracellular adenosine triphosphate (ATP) plays a significant role in cochlear function.
• Ionotropic ATP receptor (P2X2) antagonists impact cochlear potentials and distortion product otoacoustic emissions (DPOAEs).

Purpose of the Study:

• To investigate if antisense oligodeoxynucleotides (ODNs) could reduce P2X2 ATP receptor expression in the cochlea.
• To determine if ODNs mimic functional deficits caused by ATP receptor antagonists.

Main Methods:

• Administration of phosphorothioate (S-ODN) and phosphodiester (P-ODN) antisense ODNs to the guinea pig cochlea.
• Chronic administration (7 days) via the perilymph compartment.
• Monitoring of sound-evoked cochlear potentials (cochlear microphonic, summating potential, compound action potential (CAP)) and DPOAEs.

Main Results:

• Phosphorothioate ODNs (both antisense and random sense) suppressed the CAP and prolonged N1 latency.
• Phosphodiester ODNs showed no significant effects on any measured parameters.
• The observed effects of S-ODNs were independent of targeting P2X2 ATP receptor mRNA.

Conclusions:

• The study concludes that phosphorothioate ODNs do not affect cochlear function by binding to P2X2 ATP receptor mRNA.
• The observed neuronal effects of S-ODNs are likely mediated through a non-specific mechanism.
• Phosphodiester ODNs were ineffective in modulating cochlear function in this model.