Selenium and zinc: Two key players against cadmium-induced neuronal toxicity.

Cadmium (Cd), a worldwide occupational pollutant, is an extremely toxic heavy metal, capable of damaging several organs, including the brain. Its toxicity has been related to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The neurotoxic potential of Cd has been attributed to the changes induced in the brain enzyme network involved in counteracting oxidative stress. On the other hand, it is also known that trace elements, such as zinc (Zn) and selenium (Se), required for optimal brain functions, appears to have beneficial effects on the prevention of Cd intoxication. Based on this protective effect of Zn and Se, we aimed to investigate whether these elements could protect neuronal cells from Cd-induced excitotoxicity. The experiments, firstly carried out on SH-SY5Y catecholaminergic neuroblastoma cell line, demonstrated that the treatment with 10 µM cadmium chloride (CdCl2) for 24 h caused significant modifications both in terms of oxidative stress and neuronal sprouting, triggered by endoplasmic reticulum (ER) stress. The evaluation of the effectiveness of 50 µM of zinc chloride (ZnCl2) and 100 nM sodium selenite (Na2SeO3) treatments showed that both elements were able to attenuate the Cd-dependent neurotoxicity. However, considering that following induction with retinoic acid (RA), the neuroblastoma cell line undergoes differentiation into a cholinergic neurons, our second aim was to verify the zinc and selenium efficacy also in this neuronal phenotype. Our data clearly demonstrated that, while zinc played a crucial role on neuroprotection against Cd-induced neurotoxicity independently from the cellular phenotype, selenium is ineffective in differentiated cholinergic cells, supporting the notion that the molecular events occurring in differentiated SH-SY5Y cells are critical for the response to specific stimuli.

Pain relieving and protective effects of Astragalus hydroalcoholic extract in rat arthritis models.

OBJECTIVES: The evaluation of the pharmacological profile of the dried 50% hydroalcoholic extract (50%HA) of Astragali radix in two different animal models of articular damage resembling osteoarthritis and rheumatoid arthritis. METHODS: Sodium monoiodoacetate (MIA) or complete Freund's adjuvant (CFA) was intra-articular injected (day 0) in the rat tibiotarsal joint to induce damages mimicking osteoarthritis or rheumatoid arthritis. Pain measurements (responses to non-noxious and noxious stimuli, spontaneous pain, articular pain) were assessed on days 7 and 14. On day 14, the tibiotarsal joints were explanted in order to measure the diameter and to assess histological evaluations. Furthermore, the plasmatic concentrations of inflammatory and anti-inflammatory cytokines were measured. KEY FINDINGS: A single administration of 50%HA (300 mg/kg per os) significantly reduced both MIA-induced pain and CFA-induced pain (78% and 96% pain relief, respectively). The repeated administration prevented the development of hypersensitivity on day 14. The haematoxylin/eosin staining revealed that 50% HA attenuated joint alterations in MIA-injected rats, and furthermore, the joint inflammatory infiltrate was reduced in both models (by about 50%). In CFA-treated rats, 50%HA lowered the plasmatic levels of the pro-inflammatory cytokines interleukin-1ß and tumour necrosis factor-α as well as the joint diameter. CONCLUSIONS: The 50% hydroalcoholic extract of Astragali radix is a valuable candidate for the adjuvant treatment of articular diseases.

Effects of a water extract of Lepidium meyenii root in different models of persistent pain in rats.

Lepidium meyenii (Walp.), commonly called maca, is an Andean crop belonging to the Brassicaceae family. Maca hypocotils are habitually consumed as customary food as well as traditional remedies for pathological conditions such as infertility. Moreover, the characterization of maca extracts revealed the presence of compounds that are able to modulate the nervous system. Aimed to evaluate the efficacy of L. meyenii in persistent pain, the present study analyzed the effects of a commercial root extract from maca in different animal models reproducing the most common causes of chronic painful pathologies. A qualitative characterization of this commercial extract by high performance liquid chromatography-mass spectrometry and tandem mass spectrometry analyses allowed us to confirm the presence of some macamides known as bioactive constituents of this root and the absence of the main aromatic glucosinolates. The acute oral administration of maca extract is able to reduce mechanical hypersensitivity and postural unbalance induced by the intra-articular injection of monoiodoacetate and the chronic-constriction injury of the sciatic nerve. Furthermore, L. meyenii extract reverts pain threshold alterations evoked by oxaliplatin and paclitaxel. A good safety profile in mice and rats was shown. In conclusion, the present maca extract could be considered as a therapeutic opportunity to relieve articular and neuropathic pain.

Astragali radix: could it be an adjuvant for oxaliplatin-induced neuropathy?

Neurotoxicity is a major side effect of platinum derivatives both during and after treatment. In the absence of effective pharmacological compounds, the opportunity to identify safe adjuvant treatments among medicinal plants seems appropriate. Astragali radix is an adaptogenic herbal product recently analyzed in platinum-treated cancer patients. With the aim of evaluating the anti-neuropathic profile of Astragali radix, a previously characterized aqueous (Aqu) and two hydroalcoholic (20%HA and 50%HA) extracts were tested in a rat model of oxaliplatin-induced neuropathy. Repeated administrations significantly reduced oxaliplatin-dependent hypersensitivity with 50%HA, the most effective, fully preventing mechanical and thermal hypersensitivity. Ex vivo, 50%HA reduced morphometric and molecular alterations induced by oxaliplatin in peripheral nerve and dorsal-root-ganglia. In the spinal cord and in brain areas, 50%HA significantly decreased activation of microglia and astrocytes. Furthermore, 50%HA prevented the nephro- and hepato-toxicity induced by the anticancer drug. The protective effect of 50%HA did not alter oxaliplatin-induced apoptosis in colon tumors of Pirc rats, an Apc-driven model of colon carcinogenesis. The hydroalcoholic extract (50%HA) of Astragali radix relieves pain and promotes the rescue mechanisms that protect nervous tissue from the damages triggering chronic pain. A safe profile strongly suggests the usefulness of this natural product in oxaliplatin-induced neuropathy.

Anti-neuropathic effects of Rosmarinus officinalis L. terpenoid fraction: relevance of nicotinic receptors.

Traditional uses and current results highlight the neuroprotective properties of Rosmarinus officinalis L. The compelling need for novel strategies able to relieve neuropathic pain encouraged us to analyze different rosemary leaf extracts in rats following chronic constriction injury (CCI) of sciatic nerve. Ethanol, acetone, and the innovative ultrasound-hexane extractive methods were used to obtain: EE, AE, and for hexane extracts UREprel and URE. Extracts were characterized in terms of typical constituents and repeatedly administered to CCI-rats (13-days treatment, from the day of surgery). URE showed the best efficacy and potency in reducing hypersensitivity to noxious- and non-noxious stimuli and spontaneous pain. URE contained the higher quantity of the terpenoid carnosic acid (CA) and its efficacy was compared to pure CA. Histological analysis of the sciatic nerve revealed that URE prevented axon and myelin derangement, edema and inflammatory infiltrate. In the dorsal horn of the spinal cord, URE did not reduce astrocyte activation. Both the pain reliever and the neuroconservative effects of URE were significantly prevented by the nicotinic receptor (nAChR) antagonist mecamylamine. In conclusion, the hexane-ultrasound rosemary extract is able to reduce neuropathic hypersensitivity and protect nervous tissues. Effectiveness is mainly related to the terpenoid fraction by mechanisms involving nAChRs.

Acute effect of Capparis spinosa root extracts on rat articular pain.

ETHNOPHARMACOLOGICAL RELEVANCE: Capparis spinosa L. originates from dry regions of Asia and Mediterranean basin. In traditional medicine of these areas, infusions from caper root are considered to be beneficial for the treatment of rheumatism, gout and against abdominal pains. AIM OF THE STUDY: To evaluate the pain relieving properties of a Syrian cultivar of Capparis spinosa roots in rat models of osteoarthritis and rheumatoid arthritis. MATERIALS AND METHODS: Decoction (DEC) and hydroalcoholic extract (EtH2O) were obtained from powdered roots; the latter was further separated in CH2Cl2 and aqueous (H2O-Res) fractions. The extracts were characterized in terms of spermidine alkaloids by HPLC/DAD/MS and stachydrine by NMR. Different amount of free and glycosilated forms of capparispine and analogues (from 0.5% w/w for DEC up to 7.6% w/w for CH2Cl2 fraction) were detected. Rat models of rheumatoid arthritis and osteoarthritis were induced by the intra-articular administration of Complete Freund's Adjuvant (CFA) or monosodium iodoacetate (MIA), respectively. RESULTS: Fourteenth days after CFA or MIA injection, the different preparations of Capparis spinosa (3, 30, 100 and 300mgkg-1) were acutely administered p.o.. Powdered roots (300mgkg-1), DEC (100mgkg-1), and EtH2O (300mgkg-1) significantly reduced hypersensitivity to mechanical noxious stimuli as well as spontaneous pain evaluated as hind limb bearing alterations in both models. The CH2Cl2 and the H2O-Res (30mgkg-1) were the most potent in reverting pain threshold alterations despite the different content of free alkaloids. CONCLUSIONS: Capparis spinosa extracts relieved pain related to rheumatoid arthritis and osteoarthritis after single administration. A synergistic effect due to a specific "phytochemical mixture" is suggested.

A model of neuropathic pain induced by sorafenib in the rat: Effect of dimiracetam.

BACKGROUND: Sorafenib is a kinase inhibitor anticancer drug whose repeated administration causes the onset of a peripheral painful neuropathy. Notably, the efficacy of common analgesic drugs is not adequate and this often leads pre-mature discontinuation of anticancer therapy. The aim of this study was to establish a rat model of sorafenib-induced neuropathic pain, and to assess the effect of the new anti-neuropathic compound dimiracetam in comparison with gabapentin, pregabalin and duloxetine. METHODS: Male Sprague-Dawley rats were treated i.v. (10 mg kg(-1)), i.p. (10 and 30 mg kg(-1)) or p.o. (80 and 160 mg kg(-1)) with sorafenib once daily for 21 days. Pain behaviour measurements (cold plate, paw pressure, electronic von Frey) were performed on days 0, 7, 14 and 21. RESULTS: Sorafenib lowered the paw-licking threshold to non-noxious cold stimuli on day 14 of all protocols evaluated. The i.p. administration resulted in greater efficacy than the other administration routes. Sorafenib treatments did not affect paw-withdrawal responses to non-noxious or to noxious mechanical stimuli. On day 14, dimiracetam (300 mg kg(-1)), gabapentin (100 mg kg(-1)), pregabalin (30 mg kg(-1)) and duloxetine (30 mg kg(-1)) were acutely administered p.o. in sorafenib i.p.-treated rats. A single oral dose of dimiracetam induced a statistically significant increase of the pain threshold 15 min after administration. Pregabalin induced a comparable effect, whereas gabapentin and duloxetine were ineffective. Repeated twice-daily administration of dimiracetam (150 mg kg(-1) p.o.), starting on the first day of i.p sorafenib administration, significantly protected rats from sorafenib-induced decrease in the paw-licking threshold. CONCLUSIONS: A rat model of sorafenib-induced hypersensitivity to cold stimulation has been established. Dimiracetam and pregabalin are effective in prevention of sorafenib-induced neuropathy in this model.