hydroxymatairesinol and Disease-Models--Animal

Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNc). The proinflammatory response can occur early in the disease, contributing to nigrostriatal degeneration. Identification of the new molecules, which are able to slow down the degenerative process associated with PD, represents one of the main interests. Recently, natural polyphenols, especially lignans, have raised attention for their anti-inflammatory, antioxidant, and estrogenic activity at a peripheral level. The aim of this study was to evaluate the central effects of chronic treatment with lignan 7-hydroxymatairesinol (HMR/lignan) on neurodegenerative, neuroinflammatory processes and motor deficits induced by a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA) in rats to evaluate the potential neuroprotective properties of this compound.. Sprague-Dawley male rats underwent lignan (10 mg/kg) or vehicle treatment (oral) for 4 wk starting from the day of 6-OHDA injection. The degree of nigrostriatal damage was evaluated by immunohistochemistry. Moreover, we performed a quantitative and qualitative assessment of neuroinflammatory process, including phenotypic polarization of microglia and astrocytes. The motor performance was assessed by behavioral tests.. We demonstrated that chronic treatment with HMR/lignan was able to slow down the progression of degeneration of striatal dopaminergic terminals in a rat model of PD, with a consequent improvement in motor performance. Nevertheless, the anti-inflammatory effect of HMR/lignan observed in SNc was not sufficient to protect dopaminergic cells bodies.. These results suggest intriguing properties of HMR/lignan at neuroprotective and symptomatic levels in the context of PD.

Topics: Animals; Corpus Striatum; Disease Models, Animal; Dopaminergic Neurons; Lignans; Male; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Rats; Rats, Sprague-Dawley

Clinical intervention studies and experimental studies with lignan-rich diets suggest that lignans may have inhibitory effects on prostate cancer, but no clinical or experimental studies with purified lignans have been published. The purpose of this study was to investigate the effect of a plant lignan 7-hydroxymatairesinol (HMR) on LNCaP human prostate cancer xenografts in athymic mice. Athymic nude male mice were injected subcutaneously with LNCaP cells. Starting 3 days after tumor cell injections, a control diet or a control diet supplemented with 0.15% or 0.30% of HMR was administered to mice and the tumor take rate and growth was observed for 9 weeks. HMR diet inhibited the growth of LNCaP tumors. Mice treated with HMR had smaller tumor volume, lower tumor take rate, increased proportion of nongrowing tumors, and higher tumor cell apoptotic index compared with controls. Furthermore, the cell proliferation index was reduced in mice receiving the 0.30% HMR diet compared with mice receiving the control diet. Our results suggest that dietary HMR started at the early phase of the tumor development inhibits the growth of the LNCaP human prostate cancer xenografts in athymic male mice.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Carcinoma; Cell Proliferation; Diet; Disease Models, Animal; Humans; Isoflavones; Lignans; Male; Mice; Mice, Nude; Models, Biological; Neoplasm Transplantation; Phytoestrogens; Prostate-Specific Antigen; Prostatic Neoplasms; Time Factors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The antioxidant properties of hydroxymatairesinol (HM-3000) were studied in vitro in lipid peroxidation, superoxide and peroxyl radical scavenging, and LDL-oxidation models in comparison with the known synthetic antioxidants Trolox (a water-soluble vitamin E derivative), butylated hydroxyanisol (BHA) and butylated hydroxytoluene (BHT). On a molar basis HM-3000 was a more effective antioxidant than Trolox in all assays and more effective than BHT or BHA in lipid peroxidation and superoxide scavenging test. The in vivo antioxidative effect (evaluated as the weight gain of C57BL/6J mice fed an alpha-tocopherol-deficient diet) of HM-3000 (500 mg/kg per day) was comparable to that of DL-alpha-tocopherol (766 mg/kg per day). The antitumor activity of HM-3000 was studied in dimethylbenz[a]anthracene (DMBA)-induced rat mammary cancer. HM-3000 had a statistically significant inhibitory effect on tumor growth. Prevention of tumor formation was also evaluated in the Apc(Min) mice model, which develops intestinal polyps spontaneously. HM-3000 was given in diet at 30 mg/kg per day and decreased the formation of polyps and prevented beta-catenin accumulation into the nucleus, the pathophysiological hallmark of polyp formation in this mouse model. In short-term toxicity studies (up to 28 days) HM-3000 was essentially non-toxic when given p.o. to rats and dogs (daily doses up to 2000 and 665 mg/kg, respectively); HM-3000 was shown to be well absorbed (> 50% of the dose) and rapidly eliminated. In human studies HM-3000 has been given in single doses up to 1350 mg to healthy male volunteers without treatment-related adverse events. Rapid absorption from the gastrointestinal tract and partial metabolism to enterolactone in humans was demonstrated. In summary, HM-3000 is a safe, novel enterolactone precursor lignan with antioxidant and antitumor properties.

Topics: Animals; Antioxidants; Biological Availability; Disease Models, Animal; Female; Lignans; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C57BL; Plant Extracts; Random Allocation; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity

The potential for the extraction of the plant lignan hydroxymatairesinol (HMR) in large scale from Norway spruce (Picea abies) has given us the opportunity to study the metabolism and biological actions of HMR in animals. HMR, the most abundant single component of spruce lignans, was metabolized to enterolactone (ENL) as the major metabolite in rats after oral administration. The amounts of urinary ENL increased with the dose of HMR (from 3 to 50 mg/kg), and only minor amounts of unmetabolized HMR isomers and other lignans were found in urine. HMR (15 mg/kg body wt po) given for 51 days decreased the number of growing tumors and increased the proportion of regressing and stabilized tumors in the rat dimethylbenz[a]anthracene-induced mammary tumor model. HMR (50 mg/kg body wt) did not exert estrogenic or antiestrogenic activity in the uterine growth test in immature rats. HMR also showed no antiandrogenic responses in the growth of accessory sex glands in adult male rats. Neither ENL nor enterodiol showed estrogenic or antiestrogenic activity via a classical alpha- or beta-type estrogen receptor-mediated pathway in vitro at < 1.0 microM. HMR was an effective antioxidant in vitro.

Topics: 4-Butyrolactone; Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Disease Models, Animal; Female; Furans; Genitalia, Male; Lignans; Male; Mammary Neoplasms, Experimental; Phytotherapy; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Trees; Uterus