Redox-dead MB analogue fails to match methylene blue on WM
STATUS_LABEL: NEGATIVE
Claim
On a pre-registered rodent working-memory task, a redox-disabled methylene blue analogue (primary: N-acetyl-MB per Wen 2011; optional confirmatory 10-N SAR analogue per Wen 2012) fails to match parent MB — WM Δ ≤70% of MB (or outside a pre-registered MB-equivalence band).
Why it matters
Popular frame: if MB working memory tracks mitochondrial redox cycling, killing the redox center should abolish the WM signal even when related phenothiazine chemistry remains. N5/N6 left redox-dead×WM and Azure B×WM soft-complete UNKNOWN; Wen endpoints ≠ WM. They are not proof of this failure. Soft-claims: discussion — N-acetyl-MB∩memory soft-complete 0; behavioral mismatch remains UNKNOWN.
Mechanism sketch
Redox-vs-MAO assumption-kill: if WM tracks mitochondrial redox, redox-disabled N-acetyl / 10-N analogues underperform parent MB on the same WM task; if WM tracks MAO-A or non-redox phenothiazine features, a redox-dead analogue that retains MAO may still match. Wen 2011: N-acetyl / redox-disabled MB loses mitochondrial electron-transfer / OCR / neuroprotection (not WM). Wen 2012: 10-N / side-chain SAR drops protective potency and mitochondrial ET enhancement (still neuroprotection/ROS, not WM). Gonzalez-Lima: low-dose MB improves discrimination / metabolic memory without a redox-dead arm. Ramsay: MB is a potent reversible MAO-A inhibitor. Competing caveats: analogue identity (pick one primary kill tool); MAO occupancy of the chosen analogue UNKNOWN; soft-complete empty ≠ demonstrated failure.
Prior art
- PMID 21454572 / DOI 10.1074/jbc.M110.208447 / PMC3091255 — MB alternative electron transfer; N-acetyl redox-dead loses mitochondrial complex activity / OCR / neuroprotection (Wen 2011) — not WM.
- PMID 23118969 / DOI 10.1371/journal.pone.0048279 / PMC3485214 — 10-N / side-chain SAR: large drop in protective potency and mitochondrial ET enhancement vs glutamate (Wen 2012) — neuroprotection/ROS, not WM.
- PMID 17428524 / PMC2040387 — low-dose MB improves discrimination learning / metabolic memory with COX framing (Gonzalez-Lima class) — no redox-dead arm.
- PMID 17721552 / DOI 10.1038/sj.bjp.0707430 / PMC2078225 — MB potent reversible MAO-A inhibitor; serotonin-toxicity prediction (Ramsay 2007).
Baseline claimed
MB working-memory benefit is explained by mitochondrial redox cycling, so a redox-disabled analogue should fail to match parent MB on the same WM task (or N5/N6 already settled redox ownership of WM).
Baseline measured
Wen redox-dead kills mito ET/neuroprotection LITERATURE (PMID 21454572). Wen 10-N SAR drops protective potency / mito ET LITERATURE (PMID 23118969). Gonzalez-Lima discrimination/metabolic memory LITERATURE without redox-dead arm (PMID 17428524). MB MAO-A potency LITERATURE (PMID 17721552). Head-to-head same-WM: parent MB vs redox-disabled analogue UNKNOWN (soft-complete N-acetyl-MB∩memory/cognition/WM = 0). ≤70% MB-equivalence fail PREDICTION. N5/N6 do not already prove this failure — Wen bridge and soft-complete empties only.
Actionable limitations
- Do not treat N5/N6 as proving N7 — N5 asked selective MAO-A-i ≠ MB; N6 asked Azure B ≠ MB; neither measured redox-dead vs parent on WM.
- Endpoint bridge — Wen≠WM; Gonzalez-Lima lacks a redox-dead arm; bridging both to one WM panel is inference.
- Analogue identity + MAO confound — pick one primary analogue (prefer N-acetyl); MAO IC50/occupancy of that analogue is not re-measured here; soft-complete empty ≠ negative result.
Method
propose-assay
Prediction variables
| name | kind | assay | threshold |
|---|---|---|---|
| Wen_redox_dead_mitochondrial_not_WM | LITERATURE | N-acetyl-MB vs MB on mitochondrial complex activities / OCR / neuroprotection (Wen 2011) | redox center disabled → loses mitochondrial ET signal (PMID 21454572) — not a WM endpoint |
| Wen_10N_SAR_neuroprotection_not_WM | LITERATURE | 10-N / side-chain substituted MB analogues vs parent on glutamate neuroprotection / mitochondrial ET (Wen 2012) | large drop in protective potency and mito ET enhancement (PMID 23118969) — not a WM endpoint |
| GonzalezLima_MB_discrimination_memory_no_redox_dead_arm | LITERATURE | Low-dose MB discrimination / metabolic memory + COX framing | memory improve with metabolic enhancement; no redox-disabled comparator (PMID 17428524) |
| MB_MAO_A_potency | LITERATURE | Reversible MAO-A inhibition (Ramsay 2007) | potent MAO-A block; serotonin-toxicity class warning (PMID 17721552) |
| same_WM_redox_dead_vs_MB_panel | UNKNOWN | Same WM task — parent MB vs redox-disabled analogue (N-acetyl primary; optional 10-N confirmatory) ± MAO occupancy / exposure readout | dedicated redox-dead vs MB same-WM panel not found (soft-complete 0) — UNKNOWN |
| redox_dead_fails_MB_equivalence_on_WM | PREDICTION | Pre-registered delayed alternation / Gonzalez-Lima-style discrimination; redox-disabled analogue vs parent MB | redox-dead WM Δ ≤70% of MB (or outside pre-registered MB-equivalence band); α/N pre-specified — do not invent observed Δ or dosing |
| competing_MAO_retention_explains_match | PREDICTION | Same design; falsifier path if redox-dead matches MB with comparable MAO-A occupancy | MAO-matched equivalence allowed as pre-registered competing outcome |
Ablate
- remove same-task WM contrast of redox-disabled analogue vs parent MB: Without the behavioral H2H, Wen mito/neuroprotection LITERATURE and Gonzalez-Lima memory LITERATURE cannot show redox-dead fails to match MB on WM.
- remove redox-disabled identity (N-acetyl primary or locked 10-N confirmatory) vs parent: Without a defined redox-dead tool, underperformance is just “some analogue weak,” not an assumption-kill of redox-explains-WM.
- remove N5/N6≠proof + soft-complete-empty≠failure + Wen≠WM endpoint discipline: Treating N5/N6 or empty PubMed as already deciding redox-dead WM failure would invent a negative result left UNKNOWN.
Refute if
On the pre-registered WM task, the locked redox-disabled analogue matches parent MB within the MB-equivalence band (WM Δ >70% of MB or inside band) — especially if MAO occupancy is comparable — so redox-necessity for WM fails and mild-MAO / non-redox phenothiazine stories remain live.
Ask a human
Lock WM task (delayed alternation vs discrimination vs OR), primary redox-dead tool (prefer N-acetyl-MB; optional 10-N confirmatory), and MAO occupancy / exposure readout before treating any MB cognitive signal as redox-owned; do not treat N5/N6 as already proving redox-dead WM 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/N6 (not proof of redox-dead WM failure)