Combined selective MAO-A-i + MAO-B-i fails COX-amnestic rescue that parent MB restores
STATUS_LABEL: NEGATIVE
polarity: negative swarm_id: N12 card_sha256: cb86137c93a214288bf581114de415ad4410837269d49d928aab62abdeb892cd risk_class: research-discussion note: PASS_NEGATIVE — shipped as discussion (not claim/hypothesis). Soft-complete 0; dual selective MAOI vs parent MB on COX-amnestic assay UNKNOWN. N5–N11 are not proof — do not collapse N10+N11 into dual proof.
Claim
On a pre-registered cytochrome-oxidase / COX-inhibitor amnestic retention assay where parent methylene blue restores memory, a combined selective MAO-A inhibitor (clorgyline-class) + selective MAO-B inhibitor (selegiline/rasagiline-class) fails to match that rescue — retention Δ ≤70% of MB (or outside a pre-registered MB-equivalence band).
Why it matters
Closes dual-isoform escape on the Gonzalez-Lima COX-amnestic assay after N10 (selective MAO-A alone) and N11 (selective MAO-B alone): even if each single arm fails, A+B could still match MB; N12 tests that combo vs parent MB. If COX-amnestic rescue were dual-MAO-driven, A+B should match MB; preferential redox / COX-facing framing and MB’s preferential MAO-A enzyme profile both predict the dual selective combo underperforms. Distinct from N10/N11 (single-isoform), N5 (MAO-A generic WM), N8 (Azure B), N9 (redox-dead) — none ran dual selective MAOI vs parent MB on this assay. Soft-claims: discussion — soft-complete 0; H2H UNKNOWN; N5–N11 are not proof — do not collapse N10+N11 into dual proof.
Mechanism sketch
Redox-vs-MAO assumption-kill on the COX-amnestic / metabolic-memory class: parent MB restores retention after COX inhibition and is a preferential reversible MAO-A inhibitor; selective MAO-A and MAO-B tools exist (clorgyline-class; rasagiline/selegiline-class) but no published dual-combo COX-amnestic retention H2H vs MB. Dual-isoform escape: N10/N11 leave open that A+B together could still match MB; N12 closes that escape on the same assay. Competing caveats: occupancy / exposure matching (underperformance could be under-dosing — assay MAO-A/B occupancy without a dosing card); soft-complete empty ≠ demonstrated failure; MAO IC50 ≠ brain rescue PD.
Prior art
- PMID 12384216 / DOI 10.1016/s0304-3940(02)00827-3 — low-dose MB restores spatial memory retention impaired by a cytochrome oxidase inhibitor (Callaway / Gonzalez-Lima class) — no dual selective MAOI arm.
- PMID 21087672 / DOI 10.1016/j.neuroimage.2010.11.023 / PMC3026638 — MB beneficial network effects in an amnestic model (metabolic/network framing) — no dual selective MAOI arm.
- PMID 17721552 / DOI 10.1038/sj.bjp.0707430 / PMC2078225 — MB potent reversible preferential MAO-A inhibition (serotonin-toxicity prediction; Ramsay 2007) — enzyme / isoform prior, not COX-amnestic dual H2H.
- PMID 26142126 / DOI 10.1016/j.neurobiolaging.2015.05.009 — rasagiline (selective MAO-B-i) improves cognitive deficits and related cascades in aged mice (Weinreb 2015) — MAO-B tool prior, not dual-combo COX-amnestic retention vs MB.
Baseline claimed
On a COX-inhibitor amnestic model where parent MB restores retention, combined selective MAO-A-i + MAO-B-i fails to match that rescue (or N5–N11 already closed MAO ownership / dual-isoform escape of metabolic memory).
Baseline measured
MB COX-amnestic / amnestic-network rescue LITERATURE (PMID 12384216; 21087672). MB preferential reversible MAO-A inhibition LITERATURE (PMID 17721552). Rasagiline selective MAO-B tool LITERATURE (PMID 26142126). Dual selective MAO-A-i + MAO-B-i vs parent MB on the same COX-amnestic rescue / retention panel UNKNOWN (soft-complete dual selective MAOI∩MB∩COX-amnestic = 0; adjacent clorgyline∩selegiline∩memory hits are PET/behavioral non-matches). ≤70% MB-equivalence fail PREDICTION. N5–N11 do not already prove this — N10/N11 single arms leave dual escape open; N5 generic WM; N8 Azure B; N9 redox-dead; soft-complete empty ≠ failure.
Actionable limitations
- Do not treat N5–N11 as proving N12 — N10/N11 are single-isoform arms (H2H UNKNOWN there too); N5 was A-biased / generic WM; N8/N9 ran metabolite / redox-dead arms, not a dual selective MAOI combo; soft-complete empty ≠ demonstrated dual-combo failure on COX-amnestic.
- MAO IC50 ≠ brain rescue PD — Ramsay is preferential MAO-A enzyme inhibition; Weinreb 26142126 is aged-cognition / cascades; clorgyline 26825854 is monoamine/affective HD — none is dual-combo COX-amnestic retention vs MB.
- Dual-isoform escape + occupancy matching — do not collapse N10+N11 into dual proof; underperformance could be under-dosing relative to MB’s MAO profile; assay MAO-A/B occupancy / monoamine readout without a dosing card; use the same COX-inhibitor amnestic class where parent MB restores. No dosing.
Method
propose-assay
Prediction variables
| name | kind | assay | threshold |
|---|---|---|---|
| MB_COX_amnestic_spatial_retention_rescue | LITERATURE | Low-dose MB restores spatial memory retention after cytochrome oxidase inhibitor (Callaway 2002) | MB restores retention impaired by COX inhibition (PMID 12384216) — no dual selective MAOI comparator |
| MB_amnestic_network_effects | LITERATURE | MB beneficial network effects in an amnestic model (Rojas / Gonzalez-Lima 2011) | metabolic/network framing of MB amnestic benefit (PMID 21087672) — no dual selective MAOI arm |
| MB_preferential_MAO_A_inhibition | LITERATURE | MB potent reversible preferential MAO-A inhibition (Ramsay 2007) | enzyme / isoform prior predicting dual selective MAOI underperformance vs redox MB (PMID 17721552) — not COX-amnestic H2H; no KD invented |
| rasagiline_selective_MAO_B_tool_prior | LITERATURE | Rasagiline improves cognitive deficits and related cascades in aged mice (Weinreb 2015) | selective MAO-B tool prior (PMID 26142126) — not dual-combo COX-amnestic retention vs MB |
| same_COX_amnestic_dual_selective_MAOI_vs_MB_panel | UNKNOWN | Same COX-inhibitor amnestic / retention panel — dual selective MAO-A-i (clorgyline-class) + MAO-B-i (selegiline/rasagiline-class) vs parent MB (± optional N10/N11 single arms / MAO occupancy readout) | dedicated dual selective MAOI vs MB COX-amnestic rescue panel not found (soft-complete 0; adjacent PET/behavioral non-matches) — UNKNOWN |
| dual_selective_MAOI_fails_MB_equivalence_on_COX_amnestic_rescue | PREDICTION | Pre-registered COX-inhibitor amnestic spatial or discrimination retention; clorgyline-class + selegiline/rasagiline-class dual selective MAOI vs parent MB under exposure-aware conditions | dual-combo retention Δ ≤70% of MB (or outside pre-registered MB-equivalence band); α/N pre-specified — do not invent observed Δ or dosing |
| competing_dual_occupancy_or_PK_explains_underperformance | PREDICTION | Same design; falsifier path if dual selective MAOI matches MB once MAO-A/B occupancy / brain exposure is matched | dual-occupancy-matched equivalence / PK-matched equivalence allowed as pre-registered competing outcomes — does not invent those results |
Ablate
- remove same COX-amnestic / retention contrast of dual selective MAO-A-i + MAO-B-i vs parent MB: Without the behavioral H2H on the Gonzalez-Lima class assay, MB rescue LITERATURE and single-isoform tool LITERATURE cannot show dual selective MAOI fails to match MB rescue.
- remove dual selective MAO-A + MAO-B identity (clorgyline-class + selegiline/rasagiline-class) with parent-MB preferential-MAO-A / redox framing: Without a verified dual selective MAOI combo, underperformance is just “weak monoaminergic stack,” not an assumption-kill of dual-MAO-owned COX-amnestic rescue or of dual-isoform escape after N10/N11.
- remove N5–N11≠proof + soft-complete-empty≠failure + MAO-IC50≠brain-PD + occupancy-matching + N10+N11≠dual-proof discipline: Treating N5–N11 single arms / metabolite / redox-dead cards or empty/adjacent PubMed or Ramsay/Weinreb enzyme-disease priors as already deciding dual selective MAOI COX-amnestic failure would invent a negative result left UNKNOWN.
Refute if
On the pre-registered COX-inhibitor amnestic retention assay, the dual selective MAO-A-i + MAO-B-i matches parent MB within the MB-equivalence band (retention Δ >70% of MB or inside band) — especially under exposure/MAO-A/B-occupancy-matched conditions — so dual-MAO-necessity for metabolic-memory rescue survives and redox-required framing fails.
Ask a human
Lock COX-inhibitor amnestic assay identity (spatial vs discrimination retention class where parent MB restores), clorgyline-class + selegiline/rasagiline-class dual selective MAOI tools, exposure/MAO-A/B-occupancy readout, and optional N10/N11 single arms before treating any MB metabolic-memory rescue as redox-owned vs dual-MAO-owned; do not treat N5–N11 as already proving dual selective MAOI COX-amnestic failure; no dosing.
Cheap IP
kill_cost_tier=1 · time_to_refute=4w · ip_class=redox-vs-MAO · vault_hold=no
Execution
execution_status=NOT_RUN · fto_status=UNKNOWN · related_prior=N5–N11 (single-isoform / metabolite / redox-dead ≠ dual selective MAOI COX-amnestic proof; N10+N11 ≠ dual proof)