Tumor Necrosis Factor-induced Decrease of Cochlear Blood Flow Can Be Reversed by Etanercept or JTE-013.
This study aimed to quantify the effects of tumor necrosis factor (TNF) inhibitor Etanercept and sphingosine-1-phosphate receptor 2 antagonist JTE-013 on cochlear blood flow in guinea pigs after TNF-induced decrease.



Sudden sensorineural hearing loss is a common cause for disability and reduced quality of life. Good understanding of the pathophysiology and strong evidence-based therapy concepts are still missing. In various inner ear disorders, inflammation and impairment of cochlear blood flow (CBF) have been considered factors in the pathophysiology. A central mediator of inflammation and microcirculation in the cochlea is TNF. S1P acts downstream in one TNF pathway.



Cochlea lateral wall vessels were exposed surgically and assessed by intravital microscopy in guinea pigs in vivo. Twenty-eight animals were randomly distributed into four groups of seven each. Exposed vessels were superfused by TNF (5.0 ng/ml) and afterward repeatedly either by Etanercept (1.0 μg/ml), JTE-013 (10 μmol/L), or vehicle (0.9 % NaCl solution or ethanol: phosphate-buffered saline buffer, respectively).



After decreasing CBF with TNF (p <0.001, two-way RM ANOVA), both treatments reversed CBF, compared with vehicle (p <0.001, two-way RM ANOVA). The comparison of the vehicle groups showed no difference (p = 0.969, two-way RM ANOVA), while there was also no difference between the treatment groups (p = 0.850, two-way RM ANOVA).



Both Etanercept and JTE-013 reverse the decreasing effect of TNF on cochlear blood flow and, therefore, TNF and the S1P-signalling pathway might be targets for treatment of microcirculation-related hearing loss.
*WBex-Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, München †Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Göttingen, Göttingen ‡Department of Otolaryngology, Head and Neck Surgery, University of Munich Hospital, München, Germany.
Kariem
K
Sharaf
Friedrich
F
Ihler
Mattis
M
Bertlich
Christoph A
CA
Reichel
Alexander
A
Berghaus
Martin
M
Canis
D000818:Animals; D003051:Cochlea / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D000068800:Etanercept / Q000494:pharmacology*; D006168:Guinea Pigs; D006319:Hearing Loss, Sensorineural / Q000209:etiology / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008833:Microcirculation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D007166:Immunosuppressive Agents; C471998:JTE 013; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept