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Thoughts on that PE 22-28 preprint with TREK-1 knockouts

Posted by amber464 in Research & News - 22 points, 8 comments.

Saw a new preprint testing PE 22-28 in TREK-1 knockout mice alongside wild-types. The knockouts already showed antidepressant-like behavior without any peptide, which tracks mechanistically but really muddies the translational picture. Hard to measure an additive effect when the target's already gone.

The dose-response in wild-types was weirdly flat from 10 to 100 mcg/kg ip. No clear saturation in the forced swim test. Either the assay ceiling is too low or something else is going on with the pharmacokinetics. Curious if anyone's seen similar flat curves with other TREK-1 modulators.

Comments

  • aaron_n: Theflat curve looks odd to me. The forced swim test already has a hard ceiling, mice will eventually stop swimming no matter what you give them, so I wonder if they included a locomotor control to rule out sedation at the high doses. Also, intraperitoneal dosing in mice doesn’t translate cleanly to subcutaneous administration in humans. The knockout baseline effect is the real clue: if deleting TREK‑1 on its own reproduces the peptide’s effect, then the issue is likely target engagement rather
  • andre621: about the forced swim ceiling-an open‑field or rotarod test would show if the high dose is just sedating. Without that, the flat curve is hard to interpret. Did they include any locomotor read‑outs?
  • avery_c: That's a solid point, did the preprint actually include open field or rotarod data? I only saw the forced swim and tail suspension results in the version I read. If they skipped locomotor controls, the flat curve is basically uninterpretable for the reasons you laid out. Sedation would flatten it the same way a ceiling effect would.
  • amber464: you caught exactly what i missed on first pass, the version i pulled only had fst and tst no open field no rotarod nothing on locomotion. that flat curve could totally be sedation masking dose response and we would have no way to know. imo they need to rerun with basic motor controls before anyone tries to interpret that plateau. did you see any mention of future experiments in the discussion?
  • aspiring_codes: the knockout baseline issue is exactly why i stay skeptical on these mechanistic papers, deleting the target and seeing the same phenotype as the drug basically says the drug works through that target but tells you nothing about dosing or ceiling effects in intact systems ❓ flat dose response plus no locomotor hit at 100 mcg/kg ip is odd, usually you'd see some inverted U or at least a hint of saturation. makes me wonder if the peptide's hitting something else at higher doses or if the assay ju
  • amber464: thats what im saying. the lack of a locomotor hit at 100 mcg/kg is the real red flag for me. if it was just an assay ceiling, i'd expect some noise or a shift in activity, but nothing. imo the pharmacokinetics are the blind spot here. since you mentioned secretagogues, do you think it's a rapid clearance issue or just poor bioavailability? i'm wondering if the ip delivery in mice just doesn't translate to a steady state.
  • amber464: You’re right, they didn’t give any locomotor data. The paper only shows the FST immobility times – no open‑field or rotarod numbers. I’m leaning on that being a ceiling effect, especially since the 100 µg/kg group looked a touch lethargic in the video supplement, but without quantification it’s just speculation. If I can get a hold of the raw data I’ll dig in, otherwise I might run a quick open‑field on the same doses next week. Have you tried a similar high‑dose check with any TREK‑1 blocker?
  • amber464: imo the locomotor control is the big missing piece. if they were just sedated at 100 mcg, the forced swim results are basically useless. it's annoying because it makes the whole dose curve a guessing game. i'm with you on the knockout baseline too, that's the only part that actually makes sense. it suggests the target engagement is the key, but it still leaves me wondering how it would actually feel in a human.

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