Clioquinol Neurotoxicity May Stem From Oxidative Destruction of Active Vitamin B1
Clioquinol, once linked to SMON in Japan, appears to drive oxidative stress that inactivates thiamine pyrophosphate, impairing mitochondria. TPP or NAC reduced the toxicity in cells and mice.
Résumé
Clioquinol (CQ), an antibiotic withdrawn after causing subacute myelo-optic neuropathy in Japan, was later explored as an Alzheimer's therapy. This study asked how CQ relates to thiamine (vitamin B1) deficiency. In human neuroblastoma cells, CQ lowered thiamine pyrophosphate (TPP), the active coenzyme form, without blocking thiamine uptake or directly inhibiting the TPP-making enzyme TPK1. Instead, CQ raised oxidative stress, which promoted thiamine oxidation and inhibited TPK1 activity. The result was weaker mitochondrial respiration, a shift toward glycolysis, and mitochondrial damage. In APP/PS1 Alzheimer's mice, CQ increased brain oxidative stress, lowered brain TPP, and injured neurons. Adding TPP or the antioxidant N-acetylcysteine (NAC) reduced the toxicity and enhanced CQ's amyloid plaque clearance. The findings are preclinical, but suggest a possible way to make CQ-like drugs safer.
Résumé détaillé
Clioquinol (CQ) was widely used as an oral antiparasitic until the 1970s, when it was withdrawn after being linked to subacute myelo-optic neuropathy (SMON) in Japan. It later drew interest as an Alzheimer's candidate because it chelates metals and can reduce amyloid, but a phase II trial showed no cognitive benefit and reported neurological symptoms, including visual and color disturbances. Thiamine deficiency has been suspected as a contributor to CQ neurotoxicity, but the mechanism was unclear.
The researchers used human SH-SY5Y neuroblastoma cells (CQ IC50 about 15 μM) and APP/PS1 Alzheimer's model mice. Targeted metabolomics flagged thiamine pyrophosphate (TPP), the active coenzyme form of vitamin B1, as one of the metabolites most affected by CQ. They then measured thiamine and TPP by HPLC, examined transporter and synthesis genes and proteins, tested TPK1 enzyme activity, and assessed oxidative stress markers. Mitochondrial function was profiled with JC-1, ATP assays and Seahorse analysis. Mice received 90 mg/kg/day CQ by gavage for 30 days, with or without 150 mg/kg/day NAC or TPP (n = 6 per group).
In cells, 15 μM CQ significantly lowered TPP and total thiamine (thiamine + TPP) without a significant change in free thiamine. Thiamine or TPP supplementation (1 mM) reduced CQ cytotoxicity, with TPP more effective. CQ did not suppress thiamine transport or synthesis machinery. Transporter and TPK1 expression rose, which the authors interpret as feedback to TPP deficiency. CQ also did not inhibit recombinant TPK1 directly, but thiamine oxidation products (thiamine disulfide and thiochrome) did. CQ raised ROS and MDA, lowered SOD and CAT activity, increased thiochrome in the culture medium and reduced medium thiamine. In cell extracts, CQ inhibited TPK1 activity and NAC restored it. The excerpt notes CQ-induced TPP deficiency reduced mitochondrial oxidative phosphorylation, enhanced glycolysis and caused TPP-dependent mitochondrial damage.
In APP/PS1 mice, per the abstract, CQ increased brain oxidative stress, lowered brain TPP and caused neuronal injury. TPP or NAC alleviated this neurotoxicity and enhanced CQ-mediated amyloid plaque clearance. Together, the data support a model in which CQ-driven oxidative stress oxidizes thiamine species and inhibits TPK1, depleting TPP and driving mitochondrial dysfunction and metabolic reprogramming.
The work suggests that co-administering antioxidants or TPP, or designing CQ derivatives with less pro-oxidant activity, might preserve benefits while limiting neurotoxicity. Caveats are that the evidence is preclinical, uses a cancer-derived cell line and a small mouse cohort, and that the full text provided was truncated, so some in vivo and mitochondrial details rely on the abstract. Human relevance of the doses and the SMON link remains unproven.
Principales conclusions
- CQ at ~15 μM selectively lowered TPP and total thiamine in SH-SY5Y cells, and TPP rescued CQ toxicity better than thiamine.
- CQ did not directly inhibit TPK1; thiamine oxidation products did, and NAC restored TPK1 activity in CQ-treated cells.
- CQ raised ROS and MDA, reduced SOD and CAT activity, and increased thiochrome in medium, indicating thiamine oxidation.
- CQ-induced TPP deficiency reduced mitochondrial oxidative phosphorylation, increased glycolysis, and damaged mitochondria (per abstract).
- In APP/PS1 mice, TPP or NAC mitigated CQ neurotoxicity and enhanced CQ-mediated amyloid plaque clearance (per abstract).
Méthodologie
Preclinical study combining targeted metabolomics, HPLC thiamine quantification, gene and protein expression, TPK1 enzyme assays, oxidative stress assays and Seahorse metabolic profiling in SH-SY5Y cells. APP/PS1 mice (n = 6 per group) received CQ ± NAC or TPP by gavage for 30 days, followed by Nissl, Aβ42 IHC and 4-HNE staining.
Limites de l'étude
Evidence is limited to a single cancer-derived neuronal cell line and small mouse groups, with no human data. The provided text was truncated, so detailed mitochondrial and in vivo results rely on the abstract, and the doses and causal link to SMON remain unverified.
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