Pharmacologic Inhibition of JAK1/2 Potentiates Aminoglycoside-Induced Ototoxicity

Hypothesis: In our study, we investigated the ototoxic interaction of Janus kinase (JAK) inhibition in combination with aminoglycosides. Background: The therapeutic landscape of JAK inhibitors has undergone a significant transformation since 2018, characterized by a rapid increase in FDA approvals for this class of drugs. Initially approved for conditions like myelofibrosis and polycythemia vera, the indications have expanded to include several inflammatory conditions, such as psoriatic arthritis, ulcerative colitis, and rheumatoid arthritis, leading to a substantial increase in patients exposed to these therapies. The potential interactions of this drug class with ototoxins are unknown. Methods: C57Bl/6N mice corrected for Cadherin23 (Cdh23 tm2.1/kjn ) were treated with kanamycin (KM), (500 mg/kg, subcutaneously, twice daily for 14 d) either alone or with lipopolysaccharide (LPS) (1 mg/kg, intraperitoneally, 3 times during the treatment) to mimic inflammation from gram-negative infections. A separate group also received momelotinib (MMB), a dual JAK1/JAK2 inhibitor, at 50 mg/kg or 20 mg/kg by oral gavage twice daily for 14 days alongside KM and LPS. Hearing function was assessed through auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE), while cochlear damage and hair cell loss were evaluated using whole mount staining for phalloidin and myosin 7a. Results: Inhibition of JAK1 and JAK2 by MMB caused a substantial increase in the hearing loss and cochlear damage in animals exposed KM and LPS as measured by ABR, DPOAE, and outer hair cell (OHC) counts. Conclusion: JAK1 and JAK2 inhibition worsens cochlear damage in mice exposed to aminoglycosides.