To evaluate the efficacy of the novel method for the targeted delivery of Mn++ to the inner ear and monitor calcium metabolism activity in the inner ear.
Materials and Methods:
Dynamic signal changes of Mn++ in the rat inner ear were followed using T1-weighted magnetic resonance imaging (MRI) after administration of 2.5 µl MnCl2 (500 mM) to the medial wall of the middle ear cavity.
Results:
Mn++ passed through both the oval and round windows and distributed in the perilymphatic compartments, where it formed bright sharp lines along the fluid-cellular borders 12 minutes post administration and entered the endolymph sufficiently after 45 minutes. After 6 hours, the distribution of Mn++ shifted from a fluid-dominant pattern to a cell-dominant pattern. Mn++ concentrated in the area of the basilar membrane, periphery process, and soma of the spiral ganglion on day 2; became more distinguishable on day 4; declined on day 8; and remained detectable for 16 days post administration.
Conclusions:
The novel targeted delivery method efficiently introduced Mn++ into the inner ear. The dynamic distribution pattern of Mn++ in the inner ear shown by MRI indicates that this method can be used to monitor calcium metabolism activity in the inner ear.
CrawfordACEvansMGFettiplaceR. The actions of calcium on the mechano-electrical transducer current of turtle hair cells. J Physiol. 1991;434:369-398.
2.
RicciAJFettiplaceR. Calcium permeation of the turtle hair cell mechanotransducer channel and its relation to the composition of endolymph. J Physiol. 1998;506(Pt 1):159-173.
3.
RobertsWMJacobsRAHudspethAJ. Colocalization of ion channels involved in frequency selectivity and synaptic transmission at presynaptic active zones of hair cells. J Neurosci. 1990;10(11):3664-3684.
4.
PaeSSSaundersJC. Intra- and extracellular calcium modulates stereocilia stiffness on chick cochlear hair cells. Proc Natl Acad Sci U S A. 1994;91(3):1153-1157.
5.
AubertABernardCVaudryH. Effects of modifications of extracellular and intracellular calcium concentrations on the bioelectrical activity of the isolated frog semicircular canal. Brain Res. 1993;607(1-2):301-306.
6.
IkedaKKusakariJTakasakaTSaitoY. The Ca2+ activity of cochlear endolymph of the guinea pig and the effect of inhibitors. Hear Res. 1987;26(1):117-125.
7.
YoshiharaTIgarashiM. Cytochemical localization of Ca++-ATPase activity in the lateral cochlear wall of the guinea pig. Arch Otorhinolaryngol. 1987;243(6):395-400.
8.
YoshiharaTIgarashiMUsamiSKandaT. Cytochemical studies of Ca++-ATPase activity in the vestibular epithelia of the guinea pig. Arch Otorhinolaryngol. 1987;243(6):417-423.
9.
MoriYAmanoTSasaMYajinK. Cytochemical and patch-clamp studies of calcium influx through voltage-dependent Ca2+ channels in vestibular supporting cells of guinea pigs. Eur Arch Otorhinolaryngol. 1998;255(5):235-239.
10.
YoshiharaTSatohMIgarashiM. Ultracytochemical localization of Ca2+-ATPase activity in the endolymphatic sac of the chick. Med Electron Microsc. 2000;33(3):130-134.
11.
ImonKAmanoTIshiharaKSasaMYajinK. Existence of voltage-dependent Ca2+ channels in vestibular dark cells: cytochemical and whole-cell patch-clamp studies. Eur Arch Otorhinolaryngol. 1997;254(6):287-291.
12.
FerraryETran Ba HuyPRoinelNBernardCAmielC. Calcium and the inner ear fluids. Acta Otolaryngol Suppl. 1988;460:13-17.
13.
SauerGRichterCPKlinkeR. Sodium, potassium, chloride and calcium concentrations measured in pigeon perilymph and endolymph. Hear Res. 1999;129(1-2):1-6.
14.
PautlerRGSilvaACKoretskyAP. In vivo neuronal tract tracing using manganese-enhanced magnetic resonance imaging. Magn Reson Med. 1998;40(5):740-748.
15.
DryseliusSGrapengiesserEHellmanBGylfeE. Voltage-dependent entry and generation of slow Ca2+ oscillations in glucose-stimulated pancreatic beta-cells. Am J Physiol. 1999;276(3 Pt 1):E512-E518.
16.
WatanabeTFrahmJMichaelisT. Manganese-enhanced MRI of the mouse auditory pathway. Magn Reson Med. 2008;60(1):210-212.
JinSULeeJJHongKS. Intratympanic manganese administration revealed sound intensity and frequency dependent functional activity in rat auditory pathway. Magn Reson Imaging. 2013;31(7):1143-1149.
19.
YuXWadghiriYZSanesDHTurnbullDH. In vivo auditory brain mapping in mice with Mn-enhanced MRI. Nat Neurosci. 2005;8(7):961-968.
20.
HoltAGBissigDMirzaNRajahGBerkowitzB. Evidence of key tinnitus-related brain regions documented by a unique combination of manganese-enhanced MRI and acoustic startle reflex testing. PloS One. 2010;5(12):e14260.
21.
GroschelMMullerSGotzeRErnstABastaD. The possible impact of noise-induced Ca2+-dependent activity in the central auditory pathway: a manganese-enhanced MRI study. Neuroimage. 2011;57(1):190-197.
22.
GroschelMHubertNMullerSErnstABastaD. Age-dependent changes of calcium related activity in the central auditory pathway. Exp Gerontol. 2014;58:235-243.
23.
AndrewsMGigerMLRomanBB. Manganese-enhanced MRI detection of impaired calcium regulation in a mouse model of cardiac hypertrophy. NMR Biomed. 2015;28(2):255-263.
24.
FernandesJLStoreyPda SilvaJAde FigueiredoGSKalafJMCoelhoOR. Preliminary assessment of cardiac short term safety and efficacy of manganese chloride for cardiovascular magnetic resonance in humans. J Cardiovasc Magn Reson. 2011;13:6.
25.
ZouJYoshidaTRamadanUAPyykkoI. Dynamic enhancement of the rat inner ear after ultra-small-volume administration of Gd-DOTA to the medial wall of the middle ear cavity. ORL J Otorhinolaryngol Relat Spec. 2011;73(5):275-281.
26.
ZouJPengRZhengG. Improvement in the inner ear symptoms of patients with Meniere’s disease after treatment using low-frequency vibration: a preliminary report. Edorium J Otolaryngol. 2015;2:5-13.
27.
LeeHJYooSJLeeS. Functional activity mapping of rat auditory pathway after intratympanic manganese administration. Neuroimage. 2012;60(2):1046-1054.
28.
ShibataSBCortezSRWilerJASwiderskiDLRaphaelY. Hyaluronic acid enhances gene delivery into the cochlea. Hum Gene Ther. 2012;23(3):302-310.
29.
JuhnSKJungMKHoffmanMD. The role of inflammatory mediators in the pathogenesis of otitis media and sequelae. Clin Exp Otorhinolaryngol. 2008;1(3):117-138.
30.
YamauchiDNakayaKRaveendranNN. Expression of epithelial calcium transport system in rat cochlea and vestibular labyrinth. BMC Physiol. 2010;10:1.
31.
MaurerJMannWBaggelmannM. Histochemical localization of calcium ATPase in the cochlea of the guinea pig. Eur Arch Otorhinolaryngol. 1992;249(3):176-180.
32.
IkedaKSaitoYTakasakaT. Vanadate-induced intracellular calcium elevation in the stria vascularis of the guinea pig: fluorescence ratio imaging microscopy. Eur Arch Otorhinolaryngol. 1990;248(1):19-20.
33.
MoriYWatanabeMInuiT. Ca(2+) regulation of endocochlear potential in marginal cells. J Physiol Sci. 2009;59(5):355-365.
34.
BeurgMEvansMGHackneyCMFettiplaceR. A large-conductance calcium-selective mechanotransducer channel in mammalian cochlear hair cells. J Neurosci. 2006;26(43):10992-11000.
35.
ZouJMinasyanAKeisalaT. Progressive hearing loss in mice with a mutated vitamin D receptor gene. Audiol Neurootol. 2008;13(4):219-230.
36.
KochGL. The endoplasmic reticulum and calcium storage. Bioessays. 1990;12(11):527-531.
37.
MeldolesiJPozzanT. The endoplasmic reticulum Ca2+ store: a view from the lumen. Trends Biochem Sci. 1998;23(1):10-14.
38.
VenkatachalamKvan RossumDBPattersonRLMaHTGillDL. The cellular and molecular basis of store-operated calcium entry. Nat Cell Biol. 2002;4(11):E263-272.
39.
LaytonMGRobertsonDEverettAWMuldersWHYatesGK. Cellular localization of voltage-gated calcium channels and synaptic vesicle-associated proteins in the guinea pig cochlea. J Mol Neurosci. 2005;27(2):225-244.
40.
Rask-AndersenHSchrott-FischerAPfallerKGlueckertR. Perilymph/modiolar communication routes in the human cochlea. Ear Hear. 2006;27(5):457-465.
41.
ZouJPyykkoIBjelkeBDastidarPToppilaE. Communication between the perilymphatic scalae and spiral ligament visualized by in vivo MRI. Audiol Neurootol. 2005;10(3):145-152.
