Inhibition of phosphodiesterase 3, 4, and 5 induces endolymphatic hydrops in mouse inner ear, as evaluated with repeated 9.4T MRI

Abstract

Conclusion: The data indicate important roles for phosphodiesterase (PDE) 3, 4, 5, and related cAMP and cGMP pools in the regulation of inner ear fluid homeostasis. Thus, dysfunction of these enzymes might contribute to pathologies of the inner ear.

Objective: The mechanisms underlying endolymphatic hydrops, a hallmark of inner ear dysfunction, are not known in detail; however, altered balance in cAMP and cGMP signaling systems appears to be involved. Key components of these systems are PDEs, enzymes that modulate the amplitude, duration, termination, and specificity of cAMP and cGMP signaling.

Method: To evaluate the role of PDE3, 4, and 5 and associated cAMP and cGMP pools in inner ear function, the effect of cilostamide (PDE3 inhibitor), rolipram (PDE4 inhibitor), and sildenafil (PDE5 inhibitor), administrated via mini-osmotic pumps, on mouse inner ear fluid homeostasis was evaluated using 9.4T in vivo MRI in combination with intraperitoneally administered Gadolinium contrast. Also, using human saccule as a model, the expression of PDEs and related signaling molecules and targets was studied using immunohistochemistry.

Results: PDE3, PDE4, as well as PDE5 inhibitors resulted in the development of endolymphatic hydrops. Furthermore, PDE3B, PDE4D, and some related signaling components were shown to be expressed in the human saccule.

Keywords:

• Aquaporin2
• cilostamide
• cochlea
• Ménière’s disease
• rolipram
• sildenafil

Acknowledgments

We want to thank Anki Knutsson and Uwe Rauch at the Department of Experimental Medical Sciences, the Medical Faculty, Lund University for expert advice and support regarding the mini-osmotic pumps and immunohistochemistry, and Adnan Bibic at Lund University Bioimaging Center (LBIC) for advice and support on post-processing of images. LBIC, Lund University, is gratefully acknowledged for providing experimental resources. The authors would also like to acknowledge Dr Sven Lindberg at the Department of Clinical Sciences, Section for Otorhinolaryngology, Lund University Hospital, and the staff at the surgical ward at the Department of Neurosurgery for providing the human saccules.

Disclosure statement

The authors report no conflict of interest. The authors alone are responsible for the content and writing the paper.

Funding

The work was supported by grants from the Swedish Diabetes Association, the Albert Påhlsson Foundation and from the Swedish Research Council 2014-8958-112921-89.