SK Channels Modulation Accelerates Equilibrium Recovery in Unilateral Vestibular Neurectomized Rats

Abstract

We have previously reported in a feline model of acute peripheral vestibulopathy (APV) that the sudden, unilateral, and irreversible loss of vestibular inputs induces selective overexpression of small conductance calcium-activated potassium (SK) channels in the brain stem vestibular nuclei. Pharmacological blockade of these ion channels by the selective antagonist apamin significantly alleviated the evoked vestibular syndrome and accelerated vestibular compensation. In this follow-up study, we aimed at testing, using a behavioral approach, whether the antivertigo (AV) effect resulting from the antagonization of SK channels was species-dependent or whether it could be reproduced in a rodent APV model, whether other SK channel antagonists reproduced similar functional effects on the vestibular syndrome expression, and whether administration of SK agonist could also alter the vestibular syndrome. We also compared the AV effects of apamin and acetyl-DL-leucine, a reference AV compound used in human clinic. We demonstrate that the AV effect of apamin is also found in a rodent model of APV. Other SK antagonists also produce a trend of AV effect when administrated during the acute phase of the vertigo syndrome. Conversely, the vertigo syndrome is worsened upon administration of SK channel agonist. It is noteworthy that the AV effect of apamin is superior to that of acetyl-DL-leucine. Taken together, these data reinforce SK channels as a pharmacological target for modulating the manifestation of the vertigo syndrome during APV.

Effect of Fluoxetine and Acacetin on Central Vestibular Compensation in an Animal Model of Unilateral Peripheral Vestibulopathy

“…SK channels are positively regulated in the UVN model. This may explain the beneficial effect of apamin (a pharmacological agent of the SK channel blockers family) on both the cat [ 8 ] and rat [ 9 ] UVN models. It is, therefore, likely that the TTA model does not induce the same SK channels upregulation in the VN.…”

“…We can hypothesize that an action on the VN SK channels is not privileged in the TTA model, as documented below for Acacetin. A possible reason is that the arsanilic model does not affect the expression of SK channels in deafferented VNs as observed in the UVN model [ 8 , 9 ]. Altering serotonin concentration at the level of the VNs by acute (non-preventive) or subchronic (preventive) treatment with Fluoxetine would probably impact the excitability of the VN neurons through the 5-HT receptors.…”

“…In this study, i.p. administrations have been chosen for two main reasons: (i) to avoid useless stress which is, for example, observed with the per os route, and of which it is known that it significantly alters the vestibular compensation; (ii) to be able to compare this present study with our previous studies on the same vestibular pathology model using other i.p.-administered pharmacological compounds [ 9 , 27 , 41 ].…”

“…It was also demonstrated that apamin administration, a specific blocker of the SK channels, during the acute phase of the vestibular syndrome, significantly reduced both the posturo-locomotor and vestibulo-ocular deficits induced by the UVN in cats [ 8 ]. We recently demonstrated that the antivertigo (AV) effect of apamin is also found in a UVN rodent model, and that other SK antagonists produce a trend of AV effect when administrated during the acute phase of the vertigo syndrome [ 9 ]. Conversely, the vertigo syndrome is worsened upon administration of the SK channel agonist.…”

Ca2+-Sensitive Potassium Channels

“…K Ca 2.x channels are members of the voltage-insensitive calcium-activated potassium channel family that are stimulated by the elevation of the cytosolic calcium concentration. Upon activation, K Ca 2.x channels allow K + ions to leave the cell as a function of the difference between the depolarized cell and the K + equilibrium potentials [ 49 ]. K Ca 2.x subunits are encoded by the KCNN1 (K Ca 2.1; SK1), KCNN2 (K Ca 2.2; SK2), and KCNN3 (K Ca 2.3; SK3) genes [ 50 ], while IKα (K Ca 3.1; SK4) are encoded by the KCNN4 gene [ 51 ].…”