Effect of quercetin and role of nitric oxide pathway in chloroquine-induced scratching

Abstract Nitric oxide (NO) is an abundant mediator which is demonstrated to be involved in pruritus. Assuming that the increased NO also mediates chloroquine-induced pruritus, which is a frequent complication seen in the chronic chloroquine treatment, the current study aimed to investigate the effect of quercetin and the role of NO in chloroquine-induced pruritus in C57BL/6 mice. Model was created with subcutaneous chloroquine (400µg/site) injection to the nape of the mice. Effect of quercetin and role of NO were investigated with administration of quercetin, and co-administration with L-NAME, 7-NI and L-arginine before chloroquine injection. Locomotor activity was assessed by activity cage and number of the scratching bouts after chloroquine injection was recorded for 30 minutes. Our results show that quercetin significantly reduced scratching bouts at the doses of 10, 20, 40 and 80 mg/kg. Locomotor activity was decreased at the 40 and 80 mg/kg doses of quercetin. Additionally, decrease of the number of scratching bouts by quercetin prevented by L-arginine treatment, while L-NAME and 7-NI enhanced the anti-pruritic effect of sub-effective doses of quercetin. Therefore, our study demonstrated that acute injection of quercetin significantly diminished chloroquine-induced scratching behavior, and this effect is partly mediated by inhibition of neuronal nitric oxide synthase enzyme.

Asiatic acid exerts an anti-psoriatic effect in the imiquimod-induced psoriasis model in mice.

Background: Psoriasis is a common skin disorder related to inflammation and immune response. However, many treatment modalities are present in the clinics, and drug conformity halts chronic treatment. Therefore, novel treatment options are still needed. In this study, the possible protective effect of asiatic acid is one of the active compounds present in Centella Asiatica, was investigated in the imiquimod-induced psoriasis murine model.Methods:Imiquimod (62.5 mg) was administered dorsal skin of the mice for 6 days. Animals were co-treated with low-dose (25 mg/kg, p.o.) and high-dose (100 mg/kg, p.o.) asiatic acid. The dorsal skin of the animals was daily scored for erythema, thickness, and scaling. At the end of the treatments, serum levels of IL-17A and IL-23 were determined by ELISA. Additionally, the dorsal skins of animals were histopathologically evaluated.Results: Asiatic acid (high-dose) prevented imiquimod-induced skin lesions and protected dermal integrity in addition decreasing mast cell infiltration due to the imiquimod. Furthermore, asiatic acid (high-dose) suppressed the imiquimod-induced increase in serum levels of IL-17A and IL-23.Conclusion: These results indicate that asiatic acid showed an anti-psoriatic effect in the imiquimod-induced psoriasis model via mediating IL-17A and IL-23 pathways. Because wound healing properties of asiatic acid are described, further investigations should be carried out to understand deeper mechanisms and possible use in dermatological pathologies such as psoriasis.

Atorvastatin reduces alloxan-induced impairment of aversive stimulus memory in mice.

Background: An association between dysregulated glucose levels in patients with diabetes mellitus and detrimental effects on the central nervous system, particularly in Alzheimer disease, has been recognized. Atorvastatin treatment has improved memory and cognition in some patients with diabetes mellitus and Alzheimer disease. Objectives: To determine possible neuroprotective effects of atorvastatin on memory and cognition by measuring changes in an adverse stimulus avoidance learning deficit induced by alloxan in a murine model of diabetes mellitus and impaired memory and cognition. Methods: We administered 150 mg/kg and 100 mg/kg alloxan in saline (intraperitoneally, i.p.) at a 48 h interval to produce a model of diabetes mellitus in male BALB/c mice. An oral glucose tolerance test (OGTT) was used to assess blood glucose regulation. After demonstrating hyperglycemia in mice (n = 7 per group) we administered vehicle (saline, i.p.), atorvastatin (10 mg/kg, i.p.), or liraglutide (200 µg/kg, i.p.) for 28 d except for those in a negative control group, which were given saline instead of alloxan, and a group administered atorvastatin alone, which were given saline instead of alloxan followed by atorvastatin (10 mg/kg, i.p.) for 28 d. Locomotor activity was measured 24 h after the final drug treatments, and subsequently their learned behavioral response to an adverse electrical stimulus to their plantar paw surface in a dark compartment was measured using a passive avoidance apparatus (Ugo Basile) in a model of impaired memory and cognition associated with Alzheimer disease. To determine any deficit in their learned avoidance of the adverse stimulus, we measured the initial latency or time mice spent in an illuminated white compartment before entering the dark compartment in the learning trial, and on the day after learning to avoid the adverse stimulus, the retention period latency in the light compartment and time spent in the dark compartment. Results: Atorvastatin alone produced no significant change in blood glucose levels (F4,10 = 0.80, P = 0.55) within 2 h. Liraglutide decreased blood glucose levels after 0.5 h (F4,10 = 11.7, P < 0.001). We found no significant change in locomotor activity in any group. In mice with alloxan-induced diabetes, atorvastatin significantly attenuated the decreased avoidance associated with the diabetes (F4,30 = 38.0, P = 0.02) and liraglutide also significantly attenuated the decreased avoidance (F4,30 = 38.0, P < 0.001). Atorvastatin alone had no significant effect on the adversive learned response compared with vehicle treatment (F4,30 = 38.0, P > 0.05). Atorvastatin significantly decreased the time mice with alloxan-induced diabetes spent in the dark compartment compared with mice in the diabetes group without atorvastatin treatment (F4,30 = 53.9, P = 0.046). Liraglutide also significantly reduced the time mice with alloxan-induced diabetes spent in the dark compartment compared with vehicle-treated mice with alloxan-induced diabetes (F4,30 = 53.9, P < 0.001). Atorvastatin treatment alone had no significant effect on the time mice spent in dark compartment compared with the control group (F4,30 = 53.9, P > 0.05). Conclusion: Atorvastatin significantly attenuated the adverse stimulus avoidance learning deficit in the alloxan-induced murine model of diabetes suggesting decreased impairment of memory and cognition.

Role of TRPV1 channels on glycogen synthase kinase-3ß and oxidative stress in ouabain-induced bipolar disease.

Bipolar disorder (BD) is a multifactorial chronic and refractory disease characterized by manic, depressive, and mixed mood episodes. Although epidemiological, and pathophysiological studies demonstrated a strong correlation between bipolar disorder and oxidative stress, precise etiology is still missing. Recent studies suggested the possible role of transient receptor potential channels (TRP) in the BD but, current knowledge is limited. Therefore, the current study investigates the possible role of TRPV1 in the ouabain-induced model of BD. The model was created with intracerebroventricular single dose ouabain (10-3 M) administration. Animals were treated with capsaicin, capsazepine, and lithium for seven days. Mania and depressive-like states were investigated with open-field, sucrose preference, and elevated plus maze tests. Oxidative stress was assessed by measuring total antioxidant and oxidant states, spectrophotometrically. The phosphorylation Glycogen synthase kinase-3ß (GSK-3ß) evaluated by western blotting. Our results demonstrated that capsaicin dose-dependently inhibited the ouabain-induced hyperlocomotion and depression. Although capsazepine exacerbated behavioral impairment, it did not show a significant effect on the antioxidant and oxidant states, and the effects of capsazepine on behaviors were abolished by combination with capsaicin. Additionally, capsaicin potently prevented the ouabain-induced decrease in GSK-3ß phosphorylation. In contrast, capsazepine potentiated ouabain-induced decrease in GSK-3ß phosphorylation and combination with capsaicin, suppressed the effect of capsazepine on GSK-3ß phosphorylation. The effects of TRPV1 activation on oxidative stress and mania-like behaviors in the ouabain-induced BD model might be regulated by GSK-3ß phosphorylation.

The effect of hippophae rhamnoides extract on oral mucositis induced in rats with methotrexate.

OBJECTIVE:: To investigate the effect of HRE (Hippophae rhamnoides extract) on oral mucositis induced in rats with MTX. MATERIAL AND METHODS:: Experimental animals were divided into groups as healthy (HG), HRE+MTX (HMTX), and control group, which received MTX (MTXC). HMTX group received 50 mg/kg HRE while MTXC and HG groups received equivolume distilled water with gavage once a day. After one hour of HRE and distilled water administration, HMTX and MTXC groups received a single dose of oral MTX 5 mg/ kg. This procedure was repeated for one month. RESULTS:: The levels of MDA, IL-1ß, and TNF-α were found to be significantly higher in the cheek, lower lip, and tongue tissue of the animals receiving MTX, compared with HG and HMTX groups; however, these parameters were lower in the cheek and low lip tissue, and a milder damage ocurred in these tissues, compared with the tongue tissue in MTXC group. No histopathologic damage was observed in the cheek, lower lip, and tongue tissues of the rats treated with HRE. CONCLUSION:: This findings indicate that HRE as a natural product is an important advantage compared with synthetic drugs for prophylaxis of oral mucositis developed due to MTX.

The effect of hippophae rhamnoides extract on oral mucositis induced in rats with methotrexate

ABSTRACT Objective: To investigate the effect of HRE (Hippophae rhamnoides extract) on oral mucositis induced in rats with MTX. Material and Methods: Experimental animals were divided into groups as healthy (HG), HRE+MTX (HMTX), and control group, which received MTX (MTXC). HMTX group received 50 mg/kg HRE while MTXC and HG groups received equivolume distilled water with gavage once a day. After one hour of HRE and distilled water administration, HMTX and MTXC groups received a single dose of oral MTX 5 mg/ kg. This procedure was repeated for one month. Results: The levels of MDA, IL-1β, and TNF-α were found to be significantly higher in the cheek, lower lip, and tongue tissue of the animals receiving MTX, compared with HG and HMTX groups; however, these parameters were lower in the cheek and low lip tissue, and a milder damage ocurred in these tissues, compared with the tongue tissue in MTXC group. No histopathologic damage was observed in the cheek, lower lip, and tongue tissues of the rats treated with HRE. Conclusion: This findings indicate that HRE as a natural product is an important advantage compared with synthetic drugs for prophylaxis of oral mucositis developed due to MTX.

Effect of thiamine pyrophosphate on retinopathy induced by hyperglycemia in rats: A biochemical and pathological evaluation.

PURPOSE: Information is lacking on the protective effects of thiamine pyrophosphate (TPP) against hyperglycemia-induced retinopathy in rats. This study investigated the biochemical and histopathological aspects of the effect of TPP on hyperglycemia-induced retinopathy induced by alloxan in rats. MATERIALS AND METHODS: The rats were separated into a diabetic TPP-administered group (DTPG), a diabetes control group (DCG) and a healthy group (HG). While the DTPG was given TPP, the DCG and HG were administered distilled water as a solvent at the same concentrations. This procedure was repeated daily for 3 months. At the end of this period, all of the rats were euthanized under thiopental sodium anesthesia, and biochemical and histopathological analyses of the ocular retinal tissues were performed. The results of the DTPG were compared with those of the DCG and HG. RESULTS: TPP prevented hyperglycemia by increasing the amount of malondialdehyde and decreasing endogen antioxidants, including total glutathione, glutathione reductase, glutathione S-transferase and superoxide dismutase. In addition, the amounts of the DNA oxidation product 8-hydroxyguanine were significantly lower in the retinas of the DTPG compared to the DCG. In the retinas of the DCG, there was a marked increase in vascular structures and congestion, in addition to edema. In contrast, little vascularization and edema were observed in the DTPG, and there was no congestion. The results suggest that TPP significantly reduced the degree of hyperglycemia-induced retinopathy. CONCLUSIONS: The results of this study indicate that TPP may be useful for prophylaxis against diabetic retinopathy.

The Effect of Etoricoxib on Hepatic Ischemia-Reperfusion Injury in Rats.

UNLABELLED: Ischemia-reperfusion (I/R) damage is known to be a pathological process which continues with the increase of oxidants and expands with the inflammatory response. There is not any study about protective effect of etoricoxib on the liver I/R damage in literature. OBJECTIVE: This study investigates the effect of etoricoxib on oxidative stress induced by I/R of the rat liver. MATERIAL AND METHODS: Experimental animals were divided into four groups as liver I/R control (LIRC), 50 mg/kg etoricoxib + liver I/R (ETO-50), 100 mg/kg etoricoxib + liver I/R (ETO-100), and healthy group (HG). ETO-50 and ETO-100 groups were administered etoricoxib, while LIRC and HG groups were orally given distilled water by gavage. Hepatic artery was clamped for one hour to provide ischemia, and then reperfusion was provided for 6 hours. Oxidant, antioxidant, and COX-2 gene expressions were studied in the liver tissues. ALT and AST were measured. RESULTS: Etoricoxib in 50 and 100 mg/kg doses changed the levels of oxidant/antioxidant parameters such as MDA, MPO, tGSH, GSHRd, GST, SOD, NO, and 8-OH/Gua in favour of antioxidants. Furthermore, etoricoxib prevented increase of COX-2 gene expression and ALT and AST levels. This important protective effect of etoricoxib on the rat liver I/R can be tested in the clinical setting.

Effects of female sex hormones on caffeine-induced epileptiform activity in rats.

Research on female sex hormones has demonstrated that estrogen aggravates epileptogenesis. Theoretically, this means that the frequency of epileptic attacks should be decreased in epileptic women during menopause. However, although epilepsy attacks are reported to decrease in some women during menopause, they may not change in others. Increases in attack frequency have even been reported during menopause in some epileptic women. This study has investigated the effects of estrogen, progesterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) on caffeine-induced epileptiform activity in rats. Estrogen was found to increase epileptiform activity in a dose-dependent manner via its own receptors. In contrast, progesterone had no effect on epileptiform activity. FSH and LH suppressed epileptiform activity at low doses; however, at high doses they enhanced it. In conclusion, we suggest that the occurrence or aggravation of epilepsy, despite estrogen deficiency in the menopausal or post-menopausal period, is related to excessive accumulation of FSH and LH.

Gastroprotective and antioxidant effects of opipramol on indomethacin-induced ulcers in rats.

Tricyclic antidepressants are particularly useful in the treatment of endogenous depression. Since the 1950s, tricyclic antidepressants (TCAs) have also been used for the treatment of gastric ulcer disease. Many TCAs have been evaluated for their antiulcer effects, but there are presently no data in the literature specifically concerning the antidepressant opipramol. This study aimed to investigate the antiulcer effects of opipramol and to determine its potential relationship with oxidant and antioxidant systems. The antiulcer activities of 25, 50 and 100 mg/kg opipramol have been investigated on indomethacin-induced ulcers in rats. Compared with a control group (indomethacin alone), opipramol decreased indomethacin-induced ulcers significantly at all doses used (52%, 71% and 76% respectively). Opipramol also significantly increased the glutathione (GSH), superoxide dismutase (SOD) and nitric oxide (NO) levels in the stomach tissue, all of which were decreased in the control group given only indomethacin. All doses of opipramol also significantly decreased myeloperoxidase (MPO), malondialdehyde (MDA) and catalase (CAT) levels in stomach tissue compared to the control. In conclusion, the activation of enzymatic and non-enzymatic antioxidant mechanisms, as well as the inhibition of some toxic oxidant mechanisms, appear to play a role in the antiulcer effect of opipramol. This new indication for opipramol prompts a rethinking about the possible clinical application of opipramol, particularly for peptic ulcer patients also presenting depression.

Effect of sildenafil on anxiety in the plus-maze test in mice.

Several studies have shown a role of nitric oxide/cyclic guanosine monophosphate signaling pathway in the regulation of anxiety. The effects of the phosphodiesterase (PDE) 5 inhibitors on anxiety are not fully understood. The aim of present study was to investigate the possible role of sildenafil, an inhibitor of cyclic GMP-specific phosphodiesterase, on anxiety in the plus-maze test in mice. Sildenafil at a dose of 0.5 mg/kg had no significant effect on the behavior in the plus-maze test but at doses of 1 and 3 mg/kg induced an anxiogenic effect. The combination of sildenafil (1 mg/kg, i.p.) and methylene blue (1 mg/kg, i.p.) abolished the anxiogenic-like effect of sildenafil. The combination of sildenafil (1 mg/kg, i.p.) and L-arginine (50 mg/kg, i.p.) decreased the percentage of time spent in open arms compared to saline-treated group. Diazepam at a dose of 2 mg/kg significantly increased the percentage of time spent in open arms (p < 0.05). Sildenafil at a dose of 3 mg/kg and the combination of L-arginine (50 mg/kg, i.p.) and sildenafil (1 mg/kg, i.p.) significantly decreased the locomotor activity (p < 0.05). These results suggest that a nitric oxide-cGMP pathway seems to play an important role in sildenafil-induced anxiogenic-like effect.

Anxiolytic-like profile of propofol, a general anesthetic, in the plus-maze test in mice.

The present study was performed to investigate the effect of propofol on anxiety using the elevated plus-maze test. Groups of mice received propofol (20, 40, 60 mg/kg) or diazepam (2 mg/kg), caffeine (30 mg/kg), L-arginine (100 mg/kg), m-chlorophenylpiperazine (m-CPP, 2.5 mg/kg) and then were placed in an elevated plus-maze that was composed of two opposite closed arms and two opposite open arms. Propofol (20, 40, 60 mg/kg) and diazepam (2 mg/kg) significantly increased the percentage of time spent in the open arms compared to control. Caffeine (30 mg/kg) and m-CPP (2.5 mg/kg) decreased the percentage of time spent in the open arms and these effects were antagonized when propofol (40 mg/kg) was administered before the test. L-arginine (100 mg/kg) has also produced anxiogenic effect and this effect was not prevented by propofol. All drugs used in this study did not significantly change locomotor activity. These results suggest that propofol has anxiolytic effect in plus-maze test.