Effect of Eucommia ulmoides Leaf Extract on Chronic Dextran Sodium Sulfate-Induced Colitis in Mice.

Ulcerative colitis (UC) is a refractory disease that causes chronic inflammation or ulceration in the mucosa of the large intestine with multiple relapses. Although several drugs, including 5-aminosalicylic acid, steroids, immunosuppressants, and infliximab, are used for UC therapy, patients suffer from side effects of these drugs, and a new safer therapeutic agent is desired. Eucommia ulmoides OLIV. leaf extract (ELE) has an anti-inflammatory effect. Therefore, we examined the effect of ELE on UC using a chronic dextran sulfate sodium (DSS)-induced colitis model in mice. Chronic DSS-induced colitis was triggered by alternately repeating 5 days' DSS and 7 days' water administration in mice for 29 d. The severity of DSS-induced colitis was evaluated by daily body weight and bloody stool score, and colon length and myeloperoxidase (MPO) activity in colon tissue on day 29. ELE (3 or 9%) was administered in combination by feeding for 29 d, and the effect on colitis was evaluated. The mice given DSS exhibited chronic colitis symptoms with body weight loss, increased bloody stool score and MPO activity, and shortened colon length. Administration of 3 or 9% ELE suppressed the body weight loss, bloody stool score, colon shortening, and MPO activity in a dose-dependent manner. Histological analysis showed that the ELE-treated mice had less damages and leukocyte infiltration in the mucosal layer of the large intestine compared to DSS alone group. These results suggested that ELE has the potential to prevent the development of DSS-induced colitis and a therapeutic effect on UC in a safe manner.

Risk factors for discontinuation of s-1 adjuvant chemotherapy for gastric cancer.

PURPOSE: The aim of this study was to clarify the risk factors for discontinuing tegafur/gimeracil/oteracil potassium (S-1) adjuvant chemotherapy following gastrectomy in patients with gastric cancer. METHODS: We retrospectively investigated patients with curatively-resected gastric cancer who received S-1 adjuvant chemotherapy. S-1 was administered orally at 80-120 mg/day, depending on body surface area, on days 1-28 every 6 weeks for 1 year. The dose and treatment schedule were modified at the clinicians' discretion, according to toxicity. RESULTS: Seventy-one patients were included in the study, 26 of whom discontinued S-1 therapy. The relapse-free survival rates in the S-1-completed and S-1-discontinuation groups at 5 years post-surgery were 88.1% and 55.8%, respectively. The overall survival rates in the S-1-completed and S-1-discontinuation groups at 5 years post-surgery were 89.4% and 59.8%, respectively. The hazard ratios for relapse and death were significantly lower in the S-1-completed group compared with those in the S-1-discontinuation group (0.18; p<0.001 and 0.19; p=0.002, respectively). Multivariate logistic regression analysis revealed that S-1 discontinuation was significantly associated with an initial overdose of S-1, having stage I cancer, creatinine clearance <66 mL/min, and a side effect of nausea. CONCLUSIONS: These results suggest that assessing renal function to avoid initial overdose of S-1, together with the early management of side effects, may support the continuation of S-1 adjuvant chemotherapy in patients with gastric cancer.

A new method for evaluation of motivational effects of drugs.

Motivation is a process that continuously changes behavior to achieve a goal and can be conceptualized as a series of steps relating to that process. Intracranial self-stimulation (ICSS) behavior is considered to consist of reward and motivational effects. Moreover, priming stimulation of ICSS behavior is known to promote motivational effects. Using the runway method and priming stimulation, rewards and motivational effects of ICSS behavior can be differentiated. We investigated whether the runway method and priming stimulation of ICSS behavior could be used to evaluate motivational effects of a drug. In the ICSS runway model, running speed was considered as a reference of motivational effect. An assessment of pharmacological drugs known to influence motivational states was also undertaken. Using our experimental methods, prominent changes were observed in running speed when animals were administered methamphetamine and nicotine. Based on our results, we conclude that the runway method may be useful for the evaluation of substances that affect motivation. This review introduces 4 types of neuronal processes involved in motivation, reward mechanisms, outlines evaluation methods, and describes motivational properties of psychoactive drugs.

Identification of antidepressant-like ingredients in ginseng root (Panax ginseng C.A. Meyer) using a menopausal depressive-like state in female mice: participation of 5-HT2A receptors.

RATIONALE: After reports of adverse effects with hormone replacement therapy, such as reproductive and breast cancer and coronary heart disease, much attention has been given to the development of new remedies to alleviate menopausal depression in women, but methods for their preclinical evaluation have not been clarified. We previously developed a procedure to predict the drug effect on the menopausal depressive-like state in female mice. OBJECTIVES: We attempted to identify psychoactive components from ginseng root, one of the earliest known materials for menopausal disorder, and to clarify the possible mechanism involved. METHODS: As an index of a depressive-like state, we used the prolongation of immobility time induced by an ovariectomy during the forced swimming test. Chronic treatment with the candidate substance began the day after ovariectomy and continued for 14 days. To examine whether the 5-HT(2A) receptor antagonist ritanserin antagonized the antidepressant-like effect of ginsenoside Rb(1), ritanserin was given as pretreatment 15 min before the daily administration of ginsenoside Rb(1) and the antagonistic effect was compared with ginsenoside Rb(1) alone. RESULTS: Ginsenoside Rb(1) and compound K were active ingredients that dose-dependently prevented the prolongation of immobility time induced by ovariectomy. Co-administration of ritanserin, a 5-HT(2A)-receptor antagonist, antagonized the effect of ginsenoside Rb(1). CONCLUSIONS: We suggest that ginsenoside Rb(1) and its metabolite, compound K, are antidepressant-like components of the ginseng root, and that 5-HT(2A) receptors may play an important role in mediating the antidepressant-like effect of ginsenoside Rb(1).

Ameliorating effects of tropisetron on dopaminergic disruption of prepulse inhibition via the alpha(7) nicotinic acetylcholine receptor in Wistar rats.

Nicotine has ameliorating effects on sensorimotor gating deficits in schizophrenia. We have shown that nicotine ameliorated disruption of prepulse inhibition (PPI) via the alpha(7) nicotinic acetylcholine receptor (nAChR) in Wistar rats. The 5-HT(3) receptor antagonist tropisetron was recently found to be an alpha(7) nAChR partial agonist. We initially investigated the effects of tropisetron on disruption of PPI induced by phencyclidine (PCP) (2mg/kg) or apomorphine (1mg/kg). Tropisetron had no effect on the disruption of PPI induced by PCP, but ameliorated the disruption by apomorphine. The ameliorating effect of tropisetron was antagonized by methyllycaconitine (2 or 5mg/kg), a partially selective alpha(7) nAChR antagonist. Next, to find the action site of tropisetron, we examined c-Fos protein expression in the nucleus accumbens (NAc), dorsolateral striatum (DLst) and ventral tegmental area (VTA). Tropisetron alone did not change the number of c-Fos-positive cells, whereas apomorphine increased the number of positive cells in the NAc and DLst. Tropisetron administration followed by apomorphine administration decreased the number of positive cells in the VTA compared with the apomorphine-alone group. These results suggest that tropisetron has an ameliorating effect on the sensorimotor gating deficits via the alpha(7) nAChR, and that one possible site of its action is the VTA.

The effect of aripiprazole on prepulse inhibition of the startle response in normal and hyperdopaminergic states in rats.

This study compared the D(2) partial agonists, aripiprazole, (R(+)-terguride; S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [S(-)-3-PPP]; 7-[3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy]-2(1H)-quinolinone [OPC-4392]) and D(2) antagonists (haloperidol, olanzapine, clozapine, risperidone, and quetiapine) on prepulse inhibition (PPI) of the startle response, and the ability to reverse apomorphine-induced deficits in the PPI response. Aripiprazole did not essentially affect PPI in naïve rats but dose-dependently restored apomorphine-induced PPI disruption. R(+)-terguride restored PPI disruption but suppressed PPI significantly in naïve rats, S(-)-3-PPP partially restored whereas OPC-4392 did not restore PPI disruption. Haloperidol and risperidone restored PPI disruption whereas olanzapine and quetiapine partially restored PPI disruption and clozapine had no restorative effect. In conclusion, aripiprazole, unlike other antipsychotic agents, failed to suppress PPI significantly and restored PPI disruption.

Evaluation of topical external medicine for 5-fluorouracil-induced oral mucositis in hamsters.

Oral ulcerative mucositis is a common and painful toxicity associated with chemotherapy for cancer. Current treatment for chemotherapy-induced oral mucositis is largely palliative, and no adequate treatment with conclusive evidence exists. The purpose of this study was to evaluate the potential effectiveness of the topical external medicines used in clinical settings, and the authors investigated the effects of 1% azulene ointment, 0.12% dexamethasone ointment, and polaprezinc-sodium alginate suspension on an animal model for oral mucositis induced by chemotherapy. Oral mucositis was induced in hamsters through a combination treatment of 5-fluorouracil and mild abrasion of the cheek pouch. Each drug was administered topically to the oral mucosa of hamsters, and the process of healing of damaged oral mucositis was examined by measuring the size of the mucositis. Azulene ointment did not reduce the size of the mucositis compared with the vaseline-treated control group. Polaprezinc-sodium alginate suspension significantly improved the recovery from 5-fluorouracil-induced damage. In contrast, local treatment with dexamethasone exacerbated the mucositis markedly. These results suggested the healing effect of polaprezinc-sodium alginate suspension and the risk of steroids to severe oral mucositis induced by chemotherapy.

Nicotine blocks apomorphine-induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic alpha7 receptors.

Nicotine has been reported to normalize deficits in auditory sensory gating in the cases of schizophrenia, suggesting an involvement of nicotinic acetylcholine receptors in attentional abnormalities. However, the mechanism remains unclear. The present study investigated the effects of nicotine on the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine or phencyclidine in rats. Over the dose range tested, nicotine (0.05-1 mg kg(-1), s.c.) did not disrupt PPI. Neither methyllycaconitine (0.5-5 mg kg(-1), s.c.), an alpha(7) nicotinic receptor antagonist, nor dihydro-beta-erythroidine (0.5-2 mg kg(-1), s.c.), an alpha(4)beta(2) nicotinic receptor antagonist, had any effect on PPI. Nicotine (0.01-0.2 mg kg(-1), s.c.) dose-dependently reversed the disruption of PPI induced by apomorphine (1 mg kg(-1), s.c.), but had no effect on the disruption of PPI induced by phencyclidine (2 mg kg(-1), s.c.). The reversal of apomorphine-induced PPI disruption by nicotine (0.2 mg kg(-1)) was eliminated by mecamylamine (1 mg kg(-1), i.p.), but not by hexamethonium (10 mg kg(-1), i.p.), indicating the involvement of central nicotinic receptors. The antagonistic action of nicotine on apomorphine-induced PPI disruption was dose-dependently blocked by methyllycaconitine (1 and 2 mg kg(-1), s.c.). However, dihydro-beta-erythroidine (1 and 2 mg kg(-1), s.c.) had no effect. These results suggest that nicotine reverses the disruption of apomorphine-induced PPI through central alpha(7) nicotinic receptors.