Effect of the peripherally selective κ-opioid agonist,asimadoline, on adjuvant arthritis

1. Opioids, though widely used as analgesics, have not been seriously considered as therapy for rheumatoid arthritis. The present study evaluated the dose-effect and time-dependence relationships of a new peripherally selective κ agonist, asimadoline, in rats with adjuvant arthritis.
2. The arthritis was assessed by a pooled severity index combining the comprehensive criteria of oedema, radiography and histological changes, in the hind limbs. Asimadoline was extremely effective in attenuating joint damage (by up to 80%) when administered parenterally (0.5 to 10 mg kg⁻¹ day⁻¹, i.p.) throughout the disease or during its early phase; treatment was less successful if confined to the latter stages. Ten fold higher doses were effective orally.
3. Equimolar doses of a peripherally-selective antagonist, naloxone methiodide, and the κ-selective antagonist, MR2266, fully reversed the peripheral anti-arthritic effects of asimadoline (5 mg kg⁻¹ day⁻¹), indicating that asimadoline acts through peripheral κ-opioid receptors. However, an equivalent dose of MR2266 did not fully reverse the anti-arthritic effects of the highest dose of asimadoline (40 mg kg⁻¹ day⁻¹), suggesting a loss of κ-selectivity at this dose.
4. Asimadoline also exhibited analgesic effects (mechanical nociceptive thresholds) in arthritic but not non-arthritic rats, indicating that inflammation is necessary for asimadoline-induced analgesia.
5. These data confirm our previous findings that κ-opioids possess anti-arthritic properties and that these effects are mediated via peripheral κ-receptors. The present results are new in showing that the peripherally acting κ-opioid agonist, asimadoline, is a potent anti-arthritic agent. Such novel drugs, essentially lacking central side effects, herald new treatments for rheumatoid arthritis.

     

Effect of Indigofera aspalathoides on complete Freund’s adjuvant-induced arthritis in rats

The effect of ethanol extract of stems of Indigofera aspalathoides Vahl (Papilionaceae) (EIA) was evaluated for anti-arthritic activity on complete Freund’s adjuvant-induced (CFA-induced) arthritis in rats. The EIA was administered orally at doses of 250 and 500?mg/kg daily for 30 days. The paw volume was measured on days 7, 14, 21 and 30. At the end of day 30, the rats were sacrificed and various biochemical parameters such as serum aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total cholesterol and triglycerides were estimated. Antioxidant enzymes, such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and lipid peroxide (LPO) in the liver and kidney of normal, arthritic control and EIA treated rats were studied. Oral administration of EIA effectively inhibits rat paw edema in a dose-dependent manner. EIA significantly (P?<0.01) altered the biochemical parameters which were affected in arthritic rats. There was significant alteration in LPO, SOD, catalase, and GPx levels when compared to arthritic control rats. Our findings showed a significant anti-arthritic effect of EIA against CFA-induced arthritis in rats.     

Effect of aqueous extract of Semen Cassiae on endogenous metabolomics in urine of rats北大核心CSCD

OBJECTIVE: To investigate the effect of aqueous extract of Semen Cassiae (AESC) on endogenous metabolites in urine of rats by metabolomics based on ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) to reveal the possible ways of metabolism and mechanism of action in rats caused by AESC. METHODS: Twsenty-eight male Sprague-Dawley (SD) rats were randomly equally divided into 4 groups: such normal control group, AESC 1.5, 5 and 15 g·kg-1 groups. After intragastric administration for 14 d, the urine was collected with metabolic cages. The urine metabolic profiling was analyzed using UPLC-QTOF-MS, based on which the principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) models were established for metabolomic analysis. Potential biomarkers were screened using variable importance in the projection (VIP) and t test. RESULTS: The results of PCA showed that samples of each group were clustered, all the groups were separated, and that the distance between AESC groups and normal control group was increased in a dose-dependent manner. The relative content of proline betaine and uric acid were 18.4±2.3 and 15.7±2.0, 16.3±4.5 and 14.7±3.0 in the AESC 5 and 15 g· kg-1 groups, significantly lower than that of the normal control group, which was 25.0±3.4 and 29.0±4.8(P<0.01), but that of AESC 1.5 g · kg-1 group did not statistically differ from that of normal control group. In AESC 1.5, 5 and 15 g·kg-1 groups, the relative content of glycine and taurine was 10.0±1.4 and 8.0±1.4, 3.6±0.7 and 66.5±7.3, 45.8±23.6 and 23.0±9.8, which was significantly lower than that of the normal control group, which was 14.6±1.9 and 102.5±25.8(P<0.01). The relative content of 1,7-dimethylguanosine was 4.5±1.2 and 4.6±0.1 in AESC 1.5 and 15 g·kg-1 groups, significantly lower than that of the normal control group, which was 6.5±0.8(P<0.05), but AESC 5 g·kg-1 group did not statistically differ from normal control group. The relative content of citric acid was 26.6±6.3 in the AESC 15 g·kg-1 group, significantly lower than that of the normal control group, which was 67±14(P< 0.01). The relative content of citric acid was 104+20 in the AESC 1.5 g·kg-1 group, significantly higher than that of the normal control group (P<0.01), but AESC 5g·kg-1 group did not statistically differ from normal control group. CONCLUSION: AESC can remarkably change endogenous metabolites and mainly affect the pathways of taurine,purine, amino acid and energy metabolism.     

A comparative study on the efficacy of rofecoxib in monoarticular arthritis induced by latex of Calotropis procera and Freund’s complete adjuvant

The role of prostaglandins in Calotropis procera latex induced inflammation and hyperalgesia has been well established. The acute inflammation induced by the dried latex (DL) of this plant could be effectively ameliorated by standard anti-inflammatory drugs. In present study we have evaluated the efficacy of rofecoxib, a COX-2 inhibitor in monoarthritis induced by intra-articular injection of DL and compared it with that against Freund’s Complete Adjuvant (FCA). DL and FCA were injected into the right ankle joint of the rat and the joint diameter was measured by a micrometer screw gauge on day 0, 4, 8, 12, 20 and 28. Concomitantly the hyperalgesic response was also evaluated by motility test, stair climbing ability test, dorsal flexion pain test and compression test. The effect of rofecoxib was evaluated on these parameters in both the models. Both DL and FCA produced peak inflammation on day 4 that was associated with decreased pain threshold and functional impairment. Although rofecoxib was more effective in improving motility in the DL model, its effect on joint inflammation, hyperalgesia and stair climbing ability was comparable in both the models. Thus, our study indicates that DL induced monoarthritis could be used as a model for the screening and evaluation of anti-inflammatory and anti-arthritic drugs.     

Effects of kava-kava extract on the sleep–wake cycle in sleep-disturbed rats

Rationale Kava-kava extract may be useful as an herbal medicine for treatment of insomnia and anxiety.Objectives The present study was undertaken to investigate the effects of kava-kava extract on the sleep–wake cycle in comparison with that of flunitrazepam using sleep-disturbed rats.Methods Electrodes for measurement of electroencephalogram (EEG) and electromyogram (EMG) were implanted into the frontal cortex and the dorsal neck muscle of rats. EEG and EMG were recorded with an electroencephalogram. SleepSign ver.2.0 was used for EEG and EMG analysis. Total times of wakefulness, non-rapid eye movement (non-REM) and REM sleep were measured from 09:00 to 15:00.Results A significant shortening of the sleep latency in sleep-disturbed rats was observed following the administration of kava-kava extract at a dose of 300 mg/kg, while no effects were observed on the total waking and non-REM sleep time. On the other hand, flunitrazepam showed a significant shortening in sleep latency, decrease in total waking time and increase in total non-REM sleep time. Although the effects of flunitrazepam were antagonized by the benzodiazepine receptor antagonist flumazenil, the effect of kava-kava extract was not antagonized by flumazenil. Kava-kava extract showed a significant increase in delta activity during non-REM sleep in sleep-disturbed rats, whereas a significant decrease in delta power during non-REM sleep was observed with flunitrazepam. Flumazenil caused no significant effect on the changes in delta activity induced by both kava-kava extract and flunitrazepam.Conclusions Kava-kava extract is an herbal medicine having not only hypnotic effects, but also sleep quality-enhancement effects.     

Effect of α2-adrenoceptor agonists on the expression of morphine-withdrawal in rats

Summary Previous studies using clonidine indicate that ₂-adrenoceptors are involved in suppressing opiate-withdrawal symptoms. However, clonidine may act as a partial agonist at ₂-adrenoceptors and it also possesses significant ₁-receptor agonist activity.The aim of this study was to determine the role of ₂-adrenoceptors in the expression of opiate withdrawal signs using morphine-dependent rats. A range of agonists were selected for study on the basis of their differential preferences for -adrenoceptors.Hooded Wistar rats were made physically dependent on morphine (s.c. injection of an emulsion releasing a total of 250 mg/kg of morphine base over 48 h). Test drugs were injected s.c. followed by naloxone (10 mg/kg i.p.) 20 min later. The incidence of 5 selected withdrawal signs was recorded during the following 20 min. The ₂-adrenoceptor agonists displayed different profiles of activity. Azepexole (1–10 mg/kg) reduced all signs. Clonidine (80–800 g/kg) reduced all signs except paw shakes while guanfacine (25–250 g/kg) reduced all except jumping and diarrhoea. Talipexole (0.1–1 mg/kg) reduced all signs except diarrhoea which was not affected and jumping which was markedly enhanced. UK 14,304 (80–800 g/kg) reduced jumps, potentiated paw shakes but did not affect body shakes, teeth chattering or diarrhoea. The results suggest that there are subpopulations of ₂-adrenoceptors that modulate the expression of opiate withdrawal signs and/or that some of the drugs used affect receptors other than ₂-adrenoceptors.     

A study of Semen Strychni-induced renal injury and herb–herb interaction of Radix Glycyrrhizae extract and/or Rhizoma Ligustici extract on the comparative toxicokinetics of strychnine and brucine in rats

Recently, the renal injury caused by Semen strychni and its major toxic constituents, strychnine and brucine, was reported in many clinical cases. Hence, this study was conducted to investigate the renal injury induced by Semen Strychni and the protective effects of Radix Glycyrrhizae and Rhizoma Ligustici. The protective mechanisms were related to the comparative toxicokinetics of strychnine and brucine. Serum and urine uric acid and creatinine were used as renal function markers to evaluate the condition of kidney, and renal injury was directly reflected by histopathological changes. Compared with rats in blank group and protective herb groups, rats in Semen Strychni high-dose group showed significant differences in the results of renal function markers, and various glomerular and tubular degenerations were found in the histopathological study. The decreased AUC (only strychnine) and C_max, the increased T_max by Radix Glycyrrhizae and the decreased T_1/2 by Radix Glycyrrhizae and Rhizoma Ligustici were found in model groups. Results indicated that high dose of Semen Strychni might induce renal injury. Radix Glycyrrhizae and Rhizoma Ligustici might work together and have effects on the elimination of strychnine and brucine. The protective effects of Radix Glycyrrhizae might also be explained by the slow absorption of the alkaloids.     

Establishment and characteristic analysis of fibroblast-like synoviocytes in rats with adjuvant arthritis北大核心CSCD

Aims To establish the methods of primary culture of fibroblast-like synoviocytes in rats with adjuvant arthritis (AA-FLS) and analyze the feature and to investigate the possibility of AA-FLS as the model for the RA in vitro. Methods The synovial cells obtained from the SD rats were immunized by the Mtb and identified by morphology and immunocytochemistry. The viability of AA-FLS was assessed by Cell Counting Kit-8. ELISA was applied to detect TNF-α and IL-lβ in cell media. Apoptosis was measured by Hochest 33258. The expressions of mitochondrial apoptosis-re-lated molecules, including Bcl-2, Bax, Pro-caspase-3 and Cleave-caspase-3 were determined by Western Blot. Result In isolated primary synovial cells, more than 95% of AA-FLSs were fusiform. Immunocyto-chemistry result showed a positive expression of vimen-tin and a negative expression of CD68 in AA-FLS. Cell proliferation of AA-FLS was higher than FLS and cell apoptosis of AA-FLS was curbed. Western blot data demonstrated that the protein expressions of Bcl-2, Bax were regulated and the expression of caspase-3 was activated in AA-FLS. Conclusions AA-FLS is biologically characterized by high level proliferation activity and inflammatory cytokines and apoptosis suppression. AA-FLS can be used as the model for the RA in vitro.     

The study of aqueous extract of Pterocarpus marsupium Roxb. on cytokine TNF-α in type 2 diabetic rats

Objective:

This study was designed to investigate the effect of aqueous extract of Pterocarpus marsupium Roxb. on elevated inflammatory cytokine, tumor necrosis factor (TNF)-α in type 2 diabetic rats.

Materials and Methods:

Type 2 diabetes was induced by administering streptozotocin (90 mg/kg, i.p.) in a neonatal rat model. Aqueous extract of P. marsupium at a dose of 100 and 200 mg/kg was given orally to desired group of animals for a period of 4 weeks. After 4 weeks of drug treatment, parameters such as fasting blood glucose, postprandial blood glucose, and TNF-α in serum were analyzed.

Results:

Aqueous extract of P. marsupium at both doses, i.e., 100 and 200 mg/kg, decreased the fasting and postprandial blood glucose in type 2 diabetic rats. The 200 mg/kg had more pronounced effect on postprandial hyperglycemia. The drug also improved the body weight of diabetic animals. Cytokine TNF-α was found to be elevated in untreated diabetic rats due to chronic systemic inflammation. The aqueous extract at both doses significantly (P < 0.001) decreased the elevated TNF-α level in type 2 diabetic rats.

Conclusion:

Modulation of cytokine TNF-α by the rasayana drug P. marsupium is related with its potential anti-diabetic activity.     

Effect of age on the prejunctional α-adrenoceptor-mediated feedback in the heart of spontaneously hypertensive rats and normotensive Wistar Kyoto rats

Summary The prejunctional ₂-adrenoceptor-mediated feed-back in the heart of pithed young and adult spontaneously hypertensive rats (SHR) and corresponding normotensive Wistar Kyoto rats (WKY) was studied. After electrical stimulation of the sympathetic outflow from the spinal cord to the heart, B-HT 920 induced an inhibition of the cardiac response, which was significant at stimulation frequencies up to 1 Hz in young SHR and WKY and up to 2 Hz in the adult animals. Rauwolscine produced a potentiation of the cardiac response to electrical stimulation in SHR, which was significant from 0.2–10 Hz in young SHR and from 0.1–10 Hz in adult SHR. In young WKY, rauwolscine did not potentiate the increase in heart rate to sympathetic nerve stimulation, whereas in adult WKY ₂-adrenoceptor blockade by rauwolscine significantly potentiated the cardiac response to electrical stimulation at frequencies in the range of 0.2–10 Hz. In SHR the potentiation of the cardiac response to sympathetic nerve stimulation by rauwolscine was much stronger than in WKY.These results suggest that in adult animals the prejunctional ₂-adrenoceptor mediated feedback is more developed than in young rats. In contrast with young WKY, a significant endogenous feedback can be demonstrated in adult WKY. In SHR, however, the physiological role of prejunctional ₂-adrenoceptors is much more important.     

The comparative study of Sprague–Dawley and Lewis rats in adjuvant-induced arthritis

The outbred Sprague–Dawley (SD) rats, similar to the inbred Lewis (LEW) rats, have been recently demonstrated to be highly susceptible to adjuvant-induced arthritis (AIA). We herein compared AIA in SD and LEW rats in terms of clinical, histological, radiological, and immuno-inflammatory features. The results showed that, following inoculation with a ground Mycobacterium tuberculosis (MT) suspension, SD and LEW rats manifested closely similar disease progression, with 100% incidence and similar severity. The development of arthritis was accompanied by significantly higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels than in control rats. Radiographic examination of the hind paws showed that both SD and LEW AIA rats manifested conspicuous soft tissue swelling, bone matrix resorption, periosteal new bone formation and bone erosion, while histopathological analysis of the synovial joints revealed marked cellular infiltration, angiogenesis, synovial hyperplasia, pannus formation, narrowing of joint space, and cartilage and bone destruction. Moreover, in relation to disease progression, serum tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 levels were markedly overexpressed in both SD and LEW AIA versus control rats, and SD and LEW AIA rats exhibited divergent profiles for the expression of TNF-α and IL-1β. Taken together, these results demonstrated that the SD rat AIA model shares several arthritic features with the comparable model in LEW rats. Hence, given the more favorable characteristics of SD rats than LEW rats (i.e., lower cost, wider availability, and heterogenic background), this SD rat AIA model is more cost effective and advantageous for screening and testing novel anti-arthritic agents.     

Effect of W -7 on the acquisition and expression of morphine-induced place preference in rats

The effect of intraventricular application of a calmodulin （CaM） inhibitor, W - 7, on the rewarding effect of morphine was investigated using the conditioned place preference （CPP） paradigm in rats. Morphine （2. 5 -20 mg/kg, i. p. ） produced a dose-related place preference for the drug - paired side. However, intraventricular application of W - 7 did not produced place preference or aversion, nor affected locomotor activity.     

Apoptotic effect of Aralia echinocaulis extract on fibroblast-like synoviocytes in rats with adjuvant-induced arthritis via inhibiting the Akt/Hif-1α signaling pathway in vitro

Aralia echinocaulis is used for the treatment of rheumatoid arthritis by Tujia Minority in China. A previous study demonstrated that A. echinocaulis had a significant anti-arthritic effect on adjuvant arthritis (AA) rats in vivo. However, it remains unclear whether A. echinocaulis can induce the apoptosis of fibroblast-like synoviocytes (FLS) from AA rats and the underlying mechanism is unknown. In this paper, CCK-8 assay, Hoechst staining and flow cytometry were used to evaluate the apoptotic effect of an A. echinocaulis ethanol extract (AEE) on AA FLS. Western blotting analysis was performed to measure the protein expression levels of Bcl-2, Bax, cleaved caspase-3, Akt, p-Akt, and Hif-1α. The results revealed that AEE could inhibit FLS proliferation in a dose and time-dependent manner. After treatment with AEE, AA FLS displayed the classical apoptotic morphology, and the apoptosis rates were significantly increased. Furthermore, we found that AEE increased the protein levels of Bax, cleaved caspase 3, and decreased the protein levels of Bcl-2, Hif-1α and p-Akt, without affecting total Akt levels. Collectively, these results suggested that the apoptosis inducing effect of AEE on AA FLS was related to the regulation of the expression of apoptosis-related proteins and the inhibition of the Akt/Hif-1α signaling pathway.     

Experimental study of icariin on improvement of the learning and memory in AD rats induced by Aβ25 -35

Aim： To examine the protective effects of icariin （ICA） on the learning and memory deficits of Alzheimer＇s disease （AD） model rats induced by Aβ25 -35 and its potential mechanisms. Methods： The rats were randomized and divided into six groups of sixteen animals each. They were sham, Normal saline, model, ICA 30 mg. kg - 1, ICA 60 mg. kg - 1 and ICA 120 mg. kg -1. Wistar rats were microinjected beta-amyloid peptide segment 25 -35 （AI325 -35） into hippocampus. ICA （30 - 120 mg.kg - 1, ig. ） had been administered for fourteen days. The ability of spatial learning and memory was tested by Morris water maze ; Brain tissues were made into paraffin section of 6μm thickness and were stained with Hematoxylin- eosin and Congo red to observe with optical microscope.     

Effect of Urena lobataleaves extract on glucagon like peptide-1 serum level by inhibition of dipeptidyl peptidase-Ⅳ on diabetic rats

OBJECTIVE To investigate effect of Urenalobataleaves extract on glucagon like peptide-1(GLP-1)serum level by inhibition of dipeptidyl peptidase-Ⅳ(DPP-Ⅳ)on diabetic rat. METHODS This study uses control group post test only with male spraque dawley rats.Diabetic rats was induced by High Fructose Diet(HFD)and single dose streptozotocin 25mg·kg-1 bw intra peritoneal.The rat was administrated orally with ethanolic extract of U.lobataleaves in dose of 250,500 and 1000mg·kg-1 for 4weeks.Blood sample were collected from the tail vein at 15 min after oral glucose administration and then DPP-Ⅳserum level and GLP-1were examined using a rat elisa kits of DPP-Ⅳ and GLP-1.The data was analyzed using ANOVA test continued with LSD test(P<0.05).RESULTS The oral administration of U.lobataleaves extract at dose of 250,500 and 1000mg·kg-1 bw were able to prolong GLP-1 bioavaibility approximately 5,2and 2.5-fold respectively compared to diabetic group(P<0.05),while the DPP-Ⅳ serum level was decreased by 60%,50% and 40%(P<0.05),respectively.In diabetic groups,DPP-Ⅳ serum level was increased more and less 4-fold compared to normal group(P<0.05)while the GLP level were decreased by 8-fold(P<0.05).CONCLUSION U.lobataleaves extract could prolong GLP-1 bioavaibility by reducing of DPP-Ⅳserum level.This effect may be related to active compounds that act as an DPP-Ⅳinhibitor in U.lobata extract.     

Effect of 17β-oestradiol and ginsenoside on osteoporosis in ovariectomised rats

To study the anti-osteoporosis effects and mechanism of action of oestradiol (E₂) and ginsenoside (tR), we measured the bone mineral densities (BMD) of lumbar vertebra and tibia and analysed the tibia histological morphological data, as well observed the activity and the number of osteoblasts and the activity of alkaline phosphatase (ALP) and the concentration of cAMP. Results showed that E₂ (400 μg kg^? 1 week^? 1) and tR (10, 20, 30 mg kg^? 1 day^? 1) were able to countervail the decreasing in BMDs of lumbar vertebra and tibia induced by OVX in rats (P < 0.05); E₂ (0.1 μmol l^? 1) and ginsenoside Rg₁ (1 μmol l^? 1 and 10 μmol l^? 1) were able to increase the number of osteoblasts, the activity of ALP and the concentration of intercellular cAMP in cultured osteoblast cells. The present findings suggest that E₂ and tR have an anti-osteoporosis effect in ovariectomised rats.     

Effect of pioglitazone on altered expression of Aβ metabolism-associated molecules in the brain of fructose-drinking rats, a rodent model of insulin resistance

Accumulation of β-amyloid (Aβ) peptide in the brain is a major hallmark of Alzheimer's disease. An optimal brain insulin level promotes Aβ clearance, which may play protective roles against Alzheimer's disease. In this study we examined the role of dietary conditions leading to insulin resistance on amyloidosis in fructose-drinking rats. Further investigations tested pioglitazone, an insulin sensitizer, intervention on the altered amyloidosis in this rodent model of insulin resistance. Six-week-old male Wistar rats were fed a standard commercial diet and water without (control) or with 10% fructose for 16 weeks. The animals were randomly divided into 4 groups (n=10): non-treated and water-drinking rats (control group); pioglitazone treated and water-drinking (control treatment group); non-treated and fructose-drinking rats (fructose group) and pioglitazone-treated and fructose-drinking rats (fructose treatment group). Pioglitazone was given at the dose of 10mg/kgd by gavage for the last 12 weeks of the 16-week period. We found that diet-induced insulin resistance induced Aβ overproduction with altered expression of Aβ metabolism-associated molecules, which corresponded with increased β-secretase-1 (BACE1), γ-secretase (PS-1) activities and decreased insulin degrading enzyme (IDE) activities, but not neprilysin in the cortex and hippocampus. Additionally, pioglitazone treatment prevented all these observed abnormalities. This study indicates that insulin resistance induced by fructose-drinking affects the expression of Aβ metabolism-associated molecules that are responsible for Aβ deposition and pioglitazone treatment negatively modulate amyloidogenesis.     

Lariciresinol protects rats from complete Freund's adjuvant induced arthritis in rats via modulation of transforming growth factor-β and nuclear factor kappa B pathway: An in vivo and in silico study

Rheumatoid arthritis (RA) is a severe inflammatory auto-immune disorder affecting millions of people across the globe. The current therapeutic options are not adequate to address the complications of RA. Therefore, the present study was conducted to elucidate the protective effect of lariciresinol, a lignan, against Complete Freund's adjuvant (CFA)-induced arthritis in rats. The results of the study showed that lariciresinol improves paw swelling and arthritic scores in rats as compared to CFA rats. Lariciresinol also showed a significant reduction in rheumatoid factor, C-reactive protein, tumor necrosis factor-α, interleukin (IL)-17, and tissue inhibitor of metalloproteinases-3 level with a simultaneous increase in IL-4 level. The burden of oxidative stress was also reduced in CFA rats, as shown by reduced MDA levels and increased SOD and GPx after the administration of lariciresinol. In a Western blot analysis, lariciresinol showed a significant reduction of transforming growth factor-β and nuclear factor-κB (NF-κB) protein levels in CFA rats. To understand the binding characteristic of lariciresinol with NF-κB, molecular docking analysis was conducted, which showed Larciresinol interacted with the active site of NF-κB. Our study demonstrated the significant protective effect of lariciresinol against RA via multi-target action.     

Effect of maternal feed restriction on prenatal development in rats and rabbits – A review of published data

With respect to hazard classification for developmental toxicity under the CLP Regulation it is important to consider the possible influence of maternal toxicity. The aim of the present review was to characterize to which extent developmental effects could be caused by non-specific maternal toxicity. Such effects would not be relevant for classification. In prenatal developmental toxicity studies, the administration of high doses is given in the guideline. The associated non-specific systemic toxicity often affects the maternal body weight. Therefore, published results of studies in rats and rabbits, where maternal weight gain during gestation was inhibited by restricted feeding, were examined regarding developmental effects. In summary, maternal feed restriction resulted in a reduction of fetal body weight that was sometimes accompanied by delayed ossification in both species. Considering their magnitude these effects could be interpreted as secondary non-specific (i.e. not caused by a developmental toxicant) effects. Based on the limited number of available publications in total no further consequences on prenatal development by maternal feed restriction were observed.     

Effect of the AT₁ receptor antagonist losartan on diurnal variation in pain threshold in spontaneously hypertensive rats

Angiotensin (AT) II plays a key role in the regulation of blood pressure and water-salt balance and modulates nociception. Peptides based on AT influence central functions through the activation of AT?, AT? or AT? receptors. The aim of this study was to elucidate the role of AT? receptors in diurnal variation in nociception in spontaneously hypertensive rats (SHR). Male Wistar rats (16 weeks old) and SHR were caged individually and exposed to light from 08:00 to 20:00 h. The tail cuff method for noninvasive measurement of arterial blood pressure (ABP), paw pressure test for the determination of pain threshold and rotarod test to study motor coordination were used. Chronic treatment was administered to the SHR with the AT? receptor antagonist losartan (10 mg/kg/day, s.c.) for 14 days. Spontaneously hypertensive rats showed lower pain threshold and smaller day-night variations of nociception as compared to Wistar rats. Chronic losartan decreased the ABP and produced an inverted diurnal pattern of nociception in SHR, increasing the pain threshold at 03:00 h. Neither strain differences nor changes in motor coordination after losartan treatment were observed in SHR. Our results suggest that SHR have disturbances in diurnal variation in nociception and that the AT? receptor plays a role in the regulation of the circadian rhythm of mechanical pain threshold in SHR.