Objective To demonstrate that TNFα, via sphingosine-1-phosphate (S1P) signaling, has the potential to alter cochlear blood flow and thus, cause ischemic hearing loss. Methods and Results TNFα induced a pro-constrictive state throughout the cochlear microvasculature, which reduced capillary diameter and cochlear blood flow in vivo. In vitro isolated preparations of the spiral modiolar artery and spiral ligament capillaries confirmed these observations. Antagonizing S1P receptor 2 subtype signaling (1µmol/L JTE013) attenuated the effects of TNFα in all models. TNFα activated Sk1 and induced its translocation to the smooth muscle cell membrane. Expression of a dominant-negative Sk1 mutant (Sk1G82D) eliminated both baseline spiral modiolar artery calcium sensitivity and TNFα effects, while a non-phosphorylatable Sk1 mutant (Sk1S225A) only blocked the effects of TNFα. A small group of etanercept-treated hearing loss patients recovered with a one-phase exponential decay (t½=1.56±0.20 weeks), which matched a kinetic predicted for a vascular origin. Conclusions TNFα indeed reduces cochlear blood flow via the activation of vascular S1P signaling. This integrates hearing loss into the family of ischemic microvascular pathologies, with implications for risk stratification, diagnosis and treatment.

DWI can identify ischemic lesions of the optic nerve. As in acute multiple sclerosis lesions, optic neuritis can also present in rare circumstances with diffusion restriction and can therefore not be ruled out solely by DWI MRI.

Nitric oxide (NO) activates the NO-sensitive soluble guanylate cyclase (NO-GC, sGC) and triggers intracellular signaling pathways involving cGMP. For survival of cochlear hair cells and preservation of hearing, NO-mediated cascades have both protective and detrimental potential. Here we examine the cochlear function of mice lacking one of the two NO-sensitive guanylate cyclase isoforms [NO-GC1 knockout (KO) or NO-GC2 KO]. The deletion of NO-GC1 or NO-GC2 did not influence electromechanical outer hair cell (OHC) properties, as measured by distortion product otoacoustic emissions, neither before nor after noise exposure, nor were click- or noise-burst-evoked auditory brainstem response thresholds different from controls. Yet inner hair cell (IHC) ribbons and auditory nerve responses showed significantly less deterioration in NO-GC1 KO and NO-GC2 KO mice after noise exposure. Consistent with a selective role of NO-GC in IHCs, NO-GC 1 mRNA was found in isolated IHCs but not in OHCs. Using transgenic mice expressing the fluorescence resonance energy transfer-based cGMP biosensor cGi500, NO-induced elevation of cGMP was detected in real-time in IHCs but not in OHCs. Pharmacologic long-term treatment with a NO-GC stimulator altered auditory nerve responses but did not affect OHC function and hearing thresholds. Interestingly, NO-GC stimulation exacerbated the loss of auditory nerve response in aged animals but attenuated the loss in younger animals. We propose NO-GC2 and, to some degree, NO-GC1 as targets for early pharmacologic prevention of auditory fiber loss (synaptopathy). Both isoforms provide selective benefits for hearing function by maintaining the functional integrity of auditory nerve fibers in early life rather than at old age.

Abstract-Urocortin, a vasodilatory peptide related to corticotropin-releasing factor, may be an endogenous regulator of blood pressure. In vitro, rat tail arteries are relaxed by urocortin by a cAMP-mediated decrease in myofilament Ca 2ϩ sensitivity through a still unclear mechanism. Here we show that contraction of intact mouse tail arteries induced with 42 mmol/L KCl or 0.5 mol/L noradrenaline was associated with a Ϸ2-fold increase in the phosphorylation of the regulatory subunit of myosin phosphatase (SMPP-1M), MYPT1, at Thr696, which was reversed in arteries relaxed with urocortin. Submaximally (pCa 6.1) contracted mouse tail arteries permeabilized with ␣-toxin were relaxed with urocortin by 39Ϯ3% at constant [Ca 2ϩ ], which was associated with a decrease in myosin light chain (MLC 20 Ser19 ), MYPT1 Thr696 , and MYPT1 Thr850 phosphorylation by 60%, 28%, and 52%, respectively. The Rho-associated kinase (ROK) inhibitor Y-27632 decreased MYPT1 phosphorylation by a similar extent. Inhibition of PP-2A with 3 nmol/L okadaic acid had no effect on MYPT1 phosphorylation, whereas inhibition of PP-1 with 3 mol/L okadaic acid prevented dephosphorylation. Urocortin increased the rate of dephosphorylation of MLC 20 Ser19 Ϸ2.2-fold but had no effect on the rate of contraction under conditions of, respectively, inhibited kinase and phosphatase activities. The effect of urocortin on MLC 20Ser19 and MYPT1 phosphorylation was blocked by Rp-8-CPT-cAMPS and mimicked by Sp-5,6-DCl-cBIMPS. In summary, these results provide evidence that Ca 2ϩ -independent relaxation by urocortin can be attributed to a cAMP-mediated increased activity of SMPP-1M which at least in part is attributable to a decrease in the inhibitory phosphorylation of MYPT1. ) is a 40 amino acid polypeptide that belongs to the corticotropin-releasing factor (CRF) family. 1 Urocortin-like immunoreactivity 2 and expression of the peripheral subtype of CRF receptors, CRF-2R, 3 has been detected in the circulatory system. Urocortin, which has a higher affinity for CRF-2R than CRF itself, relaxes blood vessels both in vitro 4 and in vivo, 5 causing a CRF-2R-mediated decrease in the mean arterial blood pressure. 6 Interestingly, in CRF-2R-deficient mice, the resting blood pressure was elevated. 6 These findings suggest that urocortin is an endogenous regulator of blood pressure and blood flow. In addition, urocortin, the plasma levels of which are increased in human heart failure, 7 has beneficial effects in experimental heart failure. 8 The mechanism by which urocortin relaxes blood vessels appears to be complex, eg, vasodilation has been reported to be both endothelium dependent and independent. 3,4,9,10 The endothelium-independent vasodilation was suggested to be mediated by activation of the cAMP/protein kinase A (PKA) signaling cascade, 2,11 which is in line with the observation that activation of CRF-2R increases cAMP levels in Ltk cells. 12 In some vessels, activation of PKA was associated with activation of potassium channels and membrane potential hype...

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Introduction During surgery in patients with labyrinthine fistula the mandatory complete removal of the cholesteatoma while preserving inner ear and vestibular function is a challenge. Options so far have been either the complete removal of the cholesteatoma or leaving the matrix on the fistula. We evaluated an alternative “under water” surgical technique for complete cholesteatoma resection, in terms of preservation of postoperative inner ear and vestibular function. Methods From 2013 to 2019, 20 patients with labyrinthine fistula due to cholesteatoma were operated. We used the canal wall down approach and removal of matrix on the fistula was done as the last step during surgery using the “under water technique”. The pre and postoperative hearing tests and the vestibular function were retrospectively examined. Results There was no significant difference between pre and post-operative bone conduction thresholds; 20% experienced an improvement of more than 10 dB, with none experiencing a postoperative worsening of sensorineural hearing loss. Among seven patients who presented with vertigo, two had transient vertigo postoperatively but eventually recovered. Conclusion Our data show that the “under water technique” for cholesteatoma removal at the labyrinthine fistula is a viable option in the preservation of inner ear function and facilitating complete cholesteatoma removal.

Regulation of cochlear blood flow is critical for hearing due to its exquisite sensitivity to ischemia and oxidative stress. Many forms of hearing loss such as sensorineural hearing loss and presbyacusis may involve or be aggravated by blood flow disorders. Animal experiments and clinical outcomes further suggest that there is a gender preference in hearing loss, with males being more susceptible. Autoregulation of cochlear blood flow has been demonstrated in some animal models in vivo, suggesting that similar to the brain, blood vessels supplying the cochlea have the ability to control flow within normal limits, despite variations in systemic blood pressure. Here, we investigated myogenic regulation in the cochlear blood supply of the Mongolian gerbil, a widely used animal model in hearing research. The cochlear blood supply originates at the basilar artery, followed by the anterior inferior cerebellar artery, and inside the inner ear, by the spiral modiolar artery and the radiating arterioles that supply the capillary beds of the spiral ligament and stria vascularis. Arteries from male and female gerbils were isolated and pressurized using a concentric pipette system. Diameter changes in response to increasing luminal pressures were recorded by laser scanning microscopy. Our results show that cochlear vessels from male and female gerbils exhibit myogenic regulation but with important differences. Whereas in male gerbils, both spiral modiolar arteries and radiating arterioles exhibited pressure-dependent tone, in females, only radiating arterioles had this property. Male spiral modiolar arteries responded more to L-NNA than female spiral modiolar arteries, suggesting that NO-dependent mechanisms play a bigger role in the myogenic regulation of male than female gerbil cochlear vessels.

Purpose We here report about the first surgical experience and audiological outcome using a new, perimodiolar malleable cochlear implant electrode array for hearing rehabilitation after subtotal cochleoectomy for intralabyrinthine schwannoma (ILS). Method Based on a cochlear implant with MRI compatibility of the magnet in the receiver coil up to 3 T, a cochlear implant electrode array was developed that is malleable and can be placed perimodiolar after tumor removal from the cochlea via subtotal cochleoectomy. Malleability was reached by incorporating a nitinol wire into the silicone of the electrode array lateral to the electrode contacts. The custom-made device was implanted in four patients with intracochlear, intravestibulocochlear or transmodiolar schwannomas. Outcome was assessed by evaluating the feasibility of the surgical procedure and by measuring sound field thresholds and word recognition scores. Results After complete or partial tumor removal via subtotal cochleoectomy with or without labyrinthectomy, the new, perimodiolar malleable electrode array could successfully be implanted in all four patients. Six months after surgery, the averaged sound field thresholds to pulsed narrowband noise in the four patients were 36, 28, 41, and 35 dB HL, and the word recognitions scores for monosyllables at 65 dB SPL were 65, 80, 70, and 25% (one patient non-German speaking). Conclusion The surgical evaluation demonstrated the feasibility of cochlear implantation with the new, perimodiolar malleable electrode array after subtotal cochleoectomy. The audiological results were comparable to those achieved with another commercially available type of perimodiolar electrode array from a different manufacturer applied in patients with ILS.