TREK-1 / PE 22-28 preclinical data is starting to look too clean, am I missing something?

Posted by tiredmira in Research & News - 1 points, 6 comments.

Saw the newer spadin-derived TREK-1 peptide work surfacing again, the rapid antidepressant-like effects in rodents with what looks like synaptogenesis kicking in within days.

Basically the story is, block TREK-1 and serotonergic signaling gets a boost without the slow SSRI ramp-up. Mechanistically that tracks for me, the channel is everywhere in mood circuits.

But I keep squinting at these preclinical readouts. The effect sizes look almost suspiciously large compared to what people actually report on SSRIs in real life. Could just be animal models amplifying things, or it could be selection bias in which papers get published.

What would actually move the needle for me is a human PK readout. Half-life in the peptide DB is listed as short, and if it really is short then dosing frequency becomes the whole problem. Subq daily? Intranasal? Nobody seems to know yet.

Anyone here tracking PE 22-28 specifically, or is this still firmly in the "cool mechanism, no human data" bucket for you too? 😅

Comments

• grinder265: Honestly the rodent effect sizes are always the first thing that makes me go hmm too. Even with stuff where the mechanism is clean on paper, you see 60-70% response rates in mice and then in humans its a much smaller delta over placebo. Some of that is definately model amplification, some is publication bias toward positive hits. The PK question is where i sit on this stuff. If the half life really is sub 2-3 hours then yeah, daily subq gets old fast and intranasal is a crapshoot for CNS penetr
• ruby109: Yeah the rodent effect sizes always look way cleaner than what actually shows up in people. That part doesn't surprise me anymore. And on the PK, if it's really that short of a half life then how are you even keeping receptor occupancy steady enough to do anything. Curious if anyone's seen human data on this at all or if it's still all preclinical at this point.
• tiredmira: Right? The receptor occupancy thing is exactly what bugs me. A short half-life means you're basically chasing a moving target, and I haven't seen anyone actually run a human PK study, it's still all rodent as far as I can tell. If I had to guess on dosing, intranasal seems like the obvious play since TREK-1 is expressed centrally, but that's pure speculation. Would love to see even a single human readout before getting too excited 😅
• fasted_scientist: Yeah the rodent to human translation gap is the bit i keep circling too. Honestly if the half life really is that short and theres no published human PK, anyone running it subq daily is basically guessing on exposure. Intranasal peptides reaching the brain in meaningful amounts without a deliberate transporter tag is a stretch imo.
• tiredmira: Yeah exactly, the no-transporter intranasal thing is where I get skeptical too. Like, BPC crosses over fine but that's a totally different molecule and it's still debated how much actually gets through. PE 22-28 is bigger and more polar from what I remember. I think until someone publishes an actual human PK curve, subq daily is basically flying blind on what you're even getting. Curious if anyone's seen any early human data floating around, even unpublished.
• tiredmira: Yeah exactly, the rodent to human translation gap is basically what gives me pause too. 60-70% response in mice would be amazing if even a fraction held up, but I doubt we get anywhere close. And on the intranasal thing, I'm with you, unless there's a clear shuttle mechanism it's mostly wishful thinking for CNS delivery. Would love to see someone at least publish the human PK even if the efficacy data is years out, basically just give me the half life and clearance numbers so I can stop guessin

Community discussion - research and educational context only. Not medical advice.