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.

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.

Treatment of Non-Alcoholic Steatosis: Preclinical Study of a New Nutraceutical Multitarget Formulation.

Multifactorial pathogenesis of non-alcoholic steatohepatitis (NASH) disease, a wide-spread liver pathology associated with metabolic alterations triggered by hepatic steatosis, should be hit by multitarget therapeutics. We tested a multicomponent food supplement mixture (AP-NHm), whose components have anti-dislipidemic, antioxidant and anti-inflammatory effects, on in vitro and in vivo models of NASH. In vitro, hepatic cells cultures were treated for 24 h with 0.5 mM oleic acid (OA): in the co-treatment set cells were co-treated with AP-NH mixtures (AP-NHm, 1:3:10 ratio) and in the post-injury set AP-NHm was added for 48 h after OA damage. In vivo, C57BL/6 mice were fed with high-fat diet (HFD) for 12 weeks, inducing NASH at 7th week, and treated with AP-NHm at two dosages (1:3 ratio) in co-treatment or post-injury protocols, while a control group was fed with a standard diet. In in vitro co-treatment protocol, alterations of redox balance, proinflammatory cytokines release and glucose uptake were restored in a dose-dependent manner, at highest dosages also in post-injury regimen. In both regimens, pathologic dyslipidemias were also ameliorated by AP-NHm. In vivo, high-dose-AP-NHm-co-treated-HFD mice dose-dependently gained less body weight, were protected from dyslipidemia, and showed a lower liver weight. Dose-dependently, AP-NHm treatment lowered hepatic LDL, HDL, triglycerides levels and oxidative damage; co-treatment regimen was anti-inflammatory, reducing TNF-α and IL-8 levels. Hepatic lipidic infiltration significantly decreased in co-treated and post-injury-AP-NHm-HFD animals. The multitarget approach with AP-NHm was effective in preventing and reducing NASH-related pathologic features, warranting for the clinical development of this compound.

Phaseolus vulgaris L. Extract: Alpha-Amylase Inhibition against Metabolic Syndrome in Mice.

To examine the effects of the alpha-amylase inhibitor isoform 1 called phaseolamin, a standardized extract from white kidney beans (Phaseolus vulgaris L) was tested against the hallmarks of metabolic syndrome. The efficacy of a per os repeated treatment with P. vulgaris extract (500 mg/kg) was compared with metformin (100 mg/kg) and atorvastatin (10 mg/kg) in a model of metabolic syndrome evoked by prolonged high fat diet (HFD; week 1 to week 19) in C57BL/6 mice. Bean extract and compounds administration started after metabolic syndrome establishment (week 11). P. vulgaris extract reduced the body weight overtime, as well as effectively lowered glycaemia, triglycerides, and cholesterol. On week 19, bean extract normalized the HFD-evoked tolerance to glucose and insulin. According to the phytochemical characterization, it inhibited the alpha-amylase activity. Animals treated with the extract were rescued from motor impairments and nociceptive threshold alterations induced by HFD. Specific organs analysis revealed that P. vulgaris extract decreased hepatic steatosis and lipid peroxidation in liver. It protected the heart from HFD oxidative alterations increasing the expression of the detoxifying enzymes catalase and glutathione reductase, and normalizing NADH dehydrogenase level. The histological analysis of aorta showed a protection about the development of fatty streaks in the muscular layers. In conclusion, a prolonged treatment with the standardized extract of P. vulgaris significantly reduced several pathological features related to a metabolic syndrome-like condition; a multifactorial approach that candidates this vegetal product as a possible therapeutic option against metabolic syndrome.

Intra-articular mucilages: behavioural and histological evaluations for a new model of articular pain.

OBJECTIVES: The creation of a new valid preclinical model of articular pain by the intra-articular (i.a.) injection of mucilages for the screening of new treatments against arthritis. METHODS: A single intra-articular injection (20 µl) of mucilages (from Althaea officinalis roots and Linum usitatissimun seeds) or vegetal components (Amorphophallus konjac gum powder and ß-glucan, used as reference standard) were assessed in the rat. The pathology progression was monitored by behavioural measurements (paw pressure test, von Frey test, incapacitance test and beam balance test) and compared to that induced by the i.a. injections of monoiodioacetate (MIA) and Complete Freund's Adjuvant (CFA), well-recognized models of osteoarthritis and rheumatoid arthritis, respectively. KEY FINDINGS: Among all, the mucilage of L. usitatissimun showed the best pro-algic profile inducing a painful long-lasting condition. Hypersensitivity was characterized as a mixed form of inflammatory and neuropathic pain by the responsiveness to ibuprofen (100 mg/kg, p.o.) and pregabalin (30 mg/kg, p.o.). The histological evaluation of joint showed a damage that represents both MIA and CFA features. CONCLUSIONS: In conclusion, a single i.a. injection of L. usitatissimun mucilage can represent a valid model to assess articular pain in the rat for the screening of new treatments against arthritis.

Effect of glucoraphanin and sulforaphane against chemotherapy-induced neuropathic pain: Kv7 potassium channels modulation by H2 S release in vivo.

The beneficial effects of isothiocyanate-based compounds, as well as their safety, have been shown in neuropathological disorders, such as neuropathic pain. Aim of the present work was to study the efficacy of the glucosinolate glucoraphanin (GRA) and the derived isothiocyanate sulforaphane (SFN), secondary metabolites occurring exclusively in Brassicales, on chemotherapy-induced neuropathic pain. Mice were repeatedly treated with oxaliplatin (2.4 mg kg-1 ip) for 14 days to induce neuropathic pain. GRA and SFN effects were evaluated after a single administration on Day 15 or after a daily repeated oral and subcutaneous treatment starting from the first day of oxaliplatin injection until the 14th day. Single subcutaneous and oral administrations of GRA (4.43-119.79 µmol kg-1 ) or SFN (1.33-13.31 µmol kg-1 ) reduced neuropathic pain in a dose-dependent manner. The repeated administration of GRA and SFN (respectively 13.31 and 4.43 µmol kg-1 ) prevented the chemotherapy-induced neuropathy. The co-administration of GRA and SFN in mixture with the H2 S binding molecule, haemoglobin, abolished their pain-relieving effect, which was also reverted by pretreating the animals with the selective blocker of Kv7 potassium channels, XE991. GRA and SFN reduce neuropathic pain by releasing H2 S and modulating Kv7 channels and show a protective effect on the chemotherapy-induced neuropathy.