XEN-496 and XEN-1101 seem to be quite similar as you're probably aware, and RL-81 also seems to be much the same thing. A big difference I can see is that RL-81 is being developed with tinnitus in mind whereas the Xenon drugs are for epilepsy.
"Selective activation of P2Y receptors increased type II afferent excitability by the closure of KCNQ-type potassium channels, a potential mechanism for the painful hypersensitivity (that we term "noxacusis" to distinguish from hyperacusis without pain) that can accompany hearing loss. Exposure to the KCNQ channel activator retigabine suppressed the type II fiber's response to hair cell damage. Type II afferents may be the cochlea's nociceptors, prompting avoidance of further damage to the irreparable inner ear."
"KCNQ activators would be expected to silence type II afferents among other targets."
I see quotes like the above here and there in various papers, and I'm quite surprised by the lack of excitement about it for noxacusis because it seems to be suggesting the answer (or a huge part of it) right there. (I'm never sure whether to refer to these as blockers or openers/activators either. From what I read the aim is to 'open' the channels so is the term 'blocker' used as in blocking the thing that's activating the P2Y receptors that causes the closure of the channel, glutamate?)
I think the focus is now homing in on the relationship between cochlea ATP and sensitized type II afferents. Setbacks happen I do believe, down to this relationship, but it's not as simple as it seems and could be down to a couple of fundamentally different contributing factors. I've been thinking more about how ATP is a natural thing that is required for normal hearing in the cochlea anyway so it's not purely ATP presence that is causing any significant damage, it seems more likely that it's the amount of ATP or the broken regulation of ATP / excess / leaking ATP that's causing the problem (particularly when it comes to actual sensitization, I think there must be some kind of overload). But I really think the most crucial part of the problem is the sensitized type II afferents. From what I've read, everybody is susceptible to noise induced excess ATP from time to time, but it's the sensitized type II afferents that seem to be the crucial difference between what makes loud noise loud but tolerable, enjoyable even, to normal ears vs. loud and painful to damaged ears. Several things I've read recently also seem to suggest that OHC death is not necessarily a certainty with additional ATP build up which could explain why the type II's can seemingly become sensitized, bringing with it the joys of noxacusis, while retaining very good hearing.
@Aaron91 Here's a recent quote that
@Diesel found, I believe from John Hopkins.
"Type II nerves will not be activated unless the entire pool of OHCs they are connected to are maximally stimulated by only the most intense sound levels." I'd be interested to know if they necessarily do die or could possibly sensitize the type II while remaining intact.
@FGG has really helped with this and I finally think I get where she is coming from. To give you a scenario, say you had FX-322 and SPI-1005, and fixed all your hair cells and ATP returned to a normal level in the cochlea, and there was no other leakage. Normal noise is now back to normal, but my worry would still be that once you started to experience the kind of levels that were simply loud but not painful to normal people who would shrug off any excess ATP, we would once again be at the mercy of our sensitized type II afferents and their nociceptor response to it. We wouldn't get away it because that crucial part is still broken and would respond differently than un-sensitized type II's.
I can see FX-322 being good for hopefully lessening the amount of excess ATP leakage by support cells, and I can see SPI-1005 being good for clearing up inflammation, so basically it's a win anyway because the typical 'recovery' timeline would be reduced from years / months down to however long it took for these meds to work, and FX-322's part of the fix would be permanent and SPI-1005 part of the fix would be presumably either ongoing or as needed. I still think we'd be susceptible to setbacks though if not careful with noise due to the sensitized type II's, which is where Xenon or RL-81 would need to fit in.
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