Abstract
Peripheral neuropathies, characterized by altered nociceptive and muscular functions, are related to oxidative stress. Thioctic acid is a natural antioxidant existing as two optical isomers, but most clinically used as racemic mixture. The present study investigated the central nervous system’s changes which followed loose-ligation-derived compression of sciatic nerve, the putative neuroprotective role of thioctic acid and the pain-alleviating effect on low-back pain suffering patients. Loose ligation of the right sciatic nerve was performed in spontaneously hypertensive rats (SHR), a model of increased oxidative stress, and in normotensive Wistar-Kyoto rats (WKY). Animals with sciatic nerve ligation were left untreated or were treated intraperitoneally for 15 days with 250 μmol·kg−1·die−1 of (+/−)-thioctic acid; 125 μmol·kg−1·die−1 of (+/−)-thioctic acid; 125 μmol·kg−1·die−1 of (+)-thioctic acid lysine salt; 125 μmol·kg−1·die−1 of (−)-thioctic acid; 300 μmol·kg−1·die−1 pregabalin. Control SHR and WKY rats received the same amounts of vehicle. The clinical trial NESTIORADE (Sensory-Motor Neuropathies of the Sciatic Nerve: Comparative evaluation of the effect of racemic and dextro-rotatory forms of thioctic acid) examined 100 patients (49 males and 51 females aged 53 ± 11 years) dividing them into two equal-numbered groups, each treated daily for 60 days with 600 mg of (+/−)-thioctic acid or (+)-thioctic acid, respectively. The trial was registered prior to patient enrollment at EudraCT website (OSSC Number: 2011-000964-81). In the preclinical study, (+)-thioctic acid was more active than (+/−)- or (−)-enantiomers in relieving pain and protecting peripheral nerve as well as in reducing oxidative stress and astrogliosis in the spinal cord. Main findings of NESTIORADE clinical trial showed a greater influence on painful symptomatology, a quicker recovery and a better impact on quality of life of (+)-thioctic acid vs. (+/−)-thioctic acid. These data may have a pharmacological and pharmacoeconomical relevance and suggest that thioctic acid, above all (+)-enantiomer, could be considered for treatment of low-back pain involving neuropathy.
Highlights
Neuropathic pain is a form of chronic pain caused by lesions to central or peripheral nervous system, which may be consequent to mechanical damage or diseases
We aimed to investigate if the (+)-thioctic acid is more active than its racemic congener on painful symptoms of sensory-motor neuropathies of the sciatic nerve in both a preclinical and clinical setting
At the end of the treatment, mechanical hypersensitivity was evaluated in all the experimental groups of both strains, Wistar-Kyoto rats (WKY) (Figure 2A) and spontaneously hypertensive rats (SHR) (Figure 2B), via paw pressure test on ipsilateral and contralateral paw (1 h after the last treatment)
Summary
Neuropathic pain is a form of chronic pain caused by lesions to central or peripheral nervous system, which may be consequent to mechanical damage or diseases. It is characterized by altered nociceptive threshold and pain response, resulting in allodynia and hyperalgesia (Riego et al, 2018). The excessive and unbalanced presence of reactive oxygen and nitrogen species causes oxidative stress, which alters the structure of the biomolecules and induces neuronal damage (Adibhatla and Hatcher, 2010), inflammatory events and negative loop of excitotoxicity of afferent nociceptors, contributing to pain chronicization. Antioxidant agents, like thioctic (alpha-lipoic) acid, proved a therapeutic potential against neuropathy (Shay et al, 2009; Oyenihi et al, 2015)
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