Toxicological Profile of the Pain-Relieving Antioxidant Compound Thioctic Acid in Its Racemic and Enantiomeric Forms

Abstract

Thioctic acid is a multipotent antioxidant compound existing as dextrorotatory (+), eutomer and naturally occurring and levorotatory (−). It has been proven to help fight many pathologies and is sold as racemate. In agreement with studies claiming a greater biopotency of the eutomer compared to the levorotatory compound, we recently preclinically and clinically showed that (+) thioctic acid is a pain-reliever as effective as double-dosed racemate. We investigated acute and subchronical toxicity of (+/−) thioctic acid, (−) thioctic acid, (+) thioctic acid and (+) salt thioctic acid on Sprague–Dawley rats. For acute toxicity, compounds were administered intraperitoneally (i.p.) with a single-injection at 125, 240, 360, 480 µmol/kg, then rodents were tested for motorial coordination and minimum lethal dose (LDmin). A subtoxic dose (360 µmol/kg) was administered i.p. for 15 days and we finally evaluated motorial impairment, glycemia, organ toxicity, and apoptosis state. Acutely administered, the highest doses of all thioctic acid compounds negatively affected motorial ability and (−) thioctic acid LDmin resulted higher than the others. Subchronic administrations caused overall body weight loss, motorial impairment, mass loss in some organs. (+/−) and (−) thioctic acid injections enhanced caspase-3 activity in some organs, (−) enantiomer-treated animals displayed more marked organ toxicity signs. Together with our previous study on the biologic role of enantiomers, these data suggest a therapeutic use of (+) enantiomer-based formulations, thus lowering dose and toxicity without affecting the positive effects brought by the drug.

Antioxidant Properties of Alpha-Lipoic (Thioctic) Acid Treatment on Renal and Heart Parenchyma in a Rat Model of Hypertension

“…The supplementation of lipoic acid as natural antioxidant has already been demonstrated to be safe in clinical trials [83], and to have multiple beneficial effects [57]. In particular, (+)-ALA showed the most pronounced activity, with extremely few acute and subchronic toxicities, compared to all the forms of ALA [84].…”

Comparative Assessment of the Activity of Racemic and Dextrorotatory Forms of Thioctic (Alpha-Lipoic) Acid in Low Back Pain: Preclinical Results and Clinical Evidences From an Open Randomized Trial

“…The results of the clinical study confirmed the efficacy of the antioxidant thioctic acid in the treatment of the peripheral neuropathy without differences in male and female ( Memeo and Loiero, 2008 ; Ranieri et al, 2009 ; Agathos et al, 2018 ; Mrakic-Sposta et al, 2018 ; Salehi et al, 2019 ; Passiatore et al, 2020 ) being also characterized by good safety profile which makes it suitable for prolonged treatment even in the chronic phase of this disease ( Ametov et al, 2003 ; Ziegler et al, 2006 ). Anyway, it should be carefully prescribed and monitored since the possibility of side effects as recently emerged in a preclinical toxicologic study ( Lucarini et al, 2020 ). The results of clinical study show a greater effectiveness of (+)-thioctic acid compared to (+/−)-thioctic acid in terms of major impact on pain symptoms, rapidity of therapeutic effects onset and, more generally, better quality of life, as confirmed by the response rate to therapy.…”

Evaluation of the protective roles of alpha-lipoic acid supplementation on nanomaterial-induced toxicity: A meta-analysis of in vitro and in vivo studies

“…There was evidence that (+)-ALA was more active than (±)- or (-)-enantiomers in reducing oxidative stress and may be more effective against nanomaterial-induced injuries ( 55 , 56 ). However, no included studies reported the isomer information of used ALA. Sixth, although our subgroup analyses suggested the ALA dose seemed not to influence the anti-oxidant, anti-inflammatory and chelation effects, it was known that ALA was also not completely free from side effects, particularly (–) enantiomer-treated animals that were found to display more marked organ toxicity signs ( 57 ). Thus, low-dose ALA should be recommended theoretically.…”

“…Clinically, ALA is commonly used for the treatment of diseases related to the nervous system ( 53 , 54 ). Although the neuroprotective mechanisms may be complex, anti-oxidant and anti-inflammatory effects of ALA play main roles ( 53 – 57 ), indicating ALA supplementation may antagonize nanomaterial-induced neurotoxicity. In line with the expectation, we found the AchE, an enzyme that mediates the neuromuscular impulse transmission and promotes regeneration of neurites, in rats exposed to nanomaterials was significantly increased by ALA treatment, which was accompanied by improved pathological changes of cerebrum neuron ( 19 , 35 ).…”