Background&Objective: It has been reported that, the â-carboline alkaloids of peganum harmala seeds have a stimulatory action on serotonin and catecholamines releases in different brain regions. In addition, one of the most important pharmacological effects demonstrated for â- carbolines is a revesible inhibitory action on MAO-A. These findings suggest that â-carbolines, should alleviate at least some of the signs of depression. The purpose of present study is to determine the antidepressant activity of â-carbolines harmane, norharmane and HARMINE. Materials&Methods: All experiments were carried out on male Swiss-Webster mice (25-30g). The antidepressant activities of the â-carbolines were assessed using the forced swim test. This test is the most widely used tool for antidepressant activity preclinically. In this test, mice were placed into a cylinderical glass (25 cm height, 12 cm in diameter) containing a column of 15 cm of water at 25 ±1 °C. After 30 min of the â-carbolines injections, the mice were subjected to forced swimming test for 8 min and their immobility time was recorded. Results: Intrperitoneal (i.p.) injections of harmane (5-15 mg/kg), norharmane (2.5-10 mg/kg) and HARMINE (5-15 mg/kg) significantly decreased the immobility time in the mouse forced swim test. The inhibitory effects of harmane, norharmane and HARMINE were antagonized by flumazenil (5 mg/kg, i.p.) but not by reserpine (5 mg/kg, i.p., 18 h before test). Conclusion: The results suggest that the antidepressant activities of harmane, norharmane and HARMINE may be mediated through an inverse agonistic mechanism.

Background: The nicotine content of cigarettes plays a key role in the pathogenesis of kidney disease. HARMINE is a harmal‑ derived alkaloid with antioxidant properties. This study was designed to evaluate the effects of HARMINE against nicotine‑ induced damage to the kidneys of mice. Methods: In this study, 64 male mice were randomly assigned to eight groups: saline and nicotine‑ treated groups (2. 5 mg/kg), HARMINE groups (5, 10, and 15 mg/kg), and nicotine (2. 5 mg/ kg) + HARMINE‑ treated groups (5, 10, and 15 mg/kg). Treatments were administered intraperitoneally daily for 28 days. The weights of the mice and their kidneys, kidney index, glomeruli characteristics, thiobarbituric acid reactive species, antioxidant capacity, kidney function indicators, and serum nitrite oxide levels were investigated. Results: Nicotine administration significantly improved kidney malondialdehyde (MDA) level, blood urea nitrogen (BUN), creatinine, and nitrite oxide levels and decreased glomeruli number and tissue ferric reducing/antioxidant power (FRAP) level compared to the saline group (P < 0. 05). The HARMINE and HARMINE + nicotine treatments at all doses significantly reduced BUN, kidney MDA level, creatinine, glomerular diameter, and nitrite oxide levels and increased the glomeruli number and tissue FRAP level compared to the nicotine group (P < 0. 05). Conclusions: It seems that HARMINE administration improved kidney injury induced by nicotine in mice.

In vitro maturation of oocytes is the technique that can reduce costs and eliminate the side effects of the use of gonadotropins for in vitro fertilization. Conducting research on the development and improvement of in vitro culture conditions for human oocyte maturation is very difficuly. The use domestic animals has provided the most advanced and best system to study the maturation of immature follicles in the laboratory. Due to the active ingredient in the HARMINE alkaloid with multiple pharmacological effects including anti-free radical, anti-inflammation and immune system, etc., the present study assesses the effects of HARMINE alkaloid on bovine oocyte maturation. In this study, at least three layers of cumulus oocytes aspirated from 2-8 mm follicles obtained from bovine ovaries from slaughterhouses after three washes in the washing environment were incubated for 22-24 hours in maturation environments with different concentrations of 0. 5, 1, 2. 5, and 5 µ g/ml of the alkaloid HARMINE at a temperature of 38. 5 ° C with 5% carbon dioxide. After a while, the cumulus incubation was removed from surrounding eggs were removed and the release of polar corpuscle (maturity) was assessed. Results were evaluated using SPSS and ANOVA. Research results showed the positive impact of the alkaloid HARMINE at 1 µ g/ml (p <0. 05) such that the maturity of the groups treated with doses of 0. 5, 1, 2. 5 and 5 micrograms per milliliter were 59. 85, 72. 65, 64. 34, and 37. 22 percent, respectively, which was 56. 93 percent in the control group. Adding 1 µ g/ml of alkaloids HARMINE led to the maturity environment increased the maturation of the bovine oocytes, which can be used as a supplement in oocyte maturation environments.

Background and purpose: b-carboline alkaloids, also known as harmala's alkaloids have a wide spectrum of pharmacological actions including a stimulatory action on release of dopamine and other catecholamines in several brain regions and an inhibitory action on monoamine oxidase (MAO). These findings suggest that b-carbolines should alleviate at least some of the dopaminergic stereotyped behaviors. The purpose of present study is to determine the effects of b-carbolines harmane, norharmane and HARMINE on apomorphine-induced pecking behavior in chick.Materials and methods: All experiments were carried out on male/female chicks (40-60 g). The modulatory effects of b-Carbolines on stereotyped behavior were assessed using the pecking behavior induced by apomorphine. Subcutaneous (s.c.) injection of apomorphaine (0.025 mg/kg, mixed agonist of dopamine D1/D2 receptors) induced pecking. The pecking response was counted by direct observation and recorded for a 40-minute period.Results: S.C. injection of harmane (2.5-10 mg/kg) and HARMINE (1.25-5 mg/kg) significantly decreased the pecking behavior induced by apomorphine (0.25 mg/kg). The norharmane (2.5-15 mg/kg, i.p.) response was biphasic. The inhibitory effects of harmane, norharmane and HARMINE were blocked by flumazenil (5 mg/kg, i.e., 30 minutes before the test) or reserpine (5 mg/kg, i.e., 18 hours before the test).Conclusion: Results suggest that the modulatory effect of harmane, norharmane and HARMINE on the pecking behavior may be mediated through an inverse agonistic/monoaminergic mechanism.

Background: Glioblastoma multiforme (GBM) is considered the deadliest human cancer. Temozolomide is now a part of postresection standard chemotherapy for this type of cancer. Unfortunately, resistance to temozolomide is a major obstacle to treatment success. Combination therapy with natural anticancer agents increases the activity of temozolomide against cancer cells. Objectives: This study aimed to assess the effects of temozolomide in combination with HARMINE against GBM cells. Methods: Cancer cells were treated with temozolomide and/or HARMINE. After 24, 48, 72, and 96 h, the viability of the cells was assessed by theMTT test. The combination indexanddose reduction index were determined byCompuSynsoftware. Tumorinvasion potential was investigated by evaluating cell migration, invasion, and adhesion. The real-time PCR technique was done to study the expression pattern of two genes involved in cancer cell invasion. Statistical analysis was performed using one-way analysis of variance and Tukey’, s post-hoc test, and differences were considered non-significant at P > 0. 05. Results: After treatment with temozolomide, cell viabilityshoweda concentration-and time-dependent decrease, and the cells’,survival rate decreased. The combination of temozolomide and HARMINE had a synergistic effect. Also, temozolomide and/or HARMINE treatment decreased cancer cells’,migration, invasion, and adhesion potentials, as well as the expression of metalloproteinases 2 and 9 in T98G cells. Conclusions: The combination of temozolomide and HARMINE can be promising for the successful treatment of GBM.

Background and objective: The mercury-induced liver pathogenesis is mainly mediated by oxidative stress. The aim of the current study was to evaluate the possible ameliorative effect of HARMINE, a natural compound, on liver toxicity induced by mercury chloride (HgCl2). Methods: Forty-two male Balb/c mice were randomly divided into six groups (n = 7): Control, HgCl2 (0. 5 mg/kg), HARMINE (20 mg/kg), and HgCl2 (0. 5 mg/kg) + HARMINE (5, 10, or 20 mg/kg). The mice received treatments once per day for two weeks. After this period, the blood and tissue samples were collected for analyses. Results: HgCl2 caused a significant increase in levels of hepatic enzymes alanine aminotransferase, aspartate transaminase, and alkaline phosphatase; while HARMINE ameliorated these effects. HARMINE in HgCl2-intoxicated mice, showed protective effects as evidenced by the increase in liver relative weight to body as well as the diameter of central vein in the co-treated group. Serum levels of malondialdehyde and nitric oxide increased in HgCl2, while they were declined in HARMINE co-treated groups compared to HgCl2 group. The serum level of superoxide dismutase and total antioxidant capacity improved following HARMINE treatment in the co-administrated group compared to HgCl2 group. Moreover, gene expression analysis demonstrated that HARMINE treatment improved the HgCl2induced decreasing of Ho-1, Nrf2, Hqo1, and Trx1. The histopathological examination confirmed the protective effects of HARMINE. Conclusion: Mercury can induce toxicity by elevation of oxidative stress in the liver and HARMINE attenuates hepatic injury induced by HgCl2, at least in part, through its antioxidant activities.

Aim and Background: The ability to secrete insulin from the islets of Langerhans on the one hand and suppress the factors that increase serum glucose concentrations on the other; It is very important in patients with metabolic disorders such as diabetes. The aim of this study was to compare the effects of HARMINE with ghrelin agonist (as a suppressor of insulin secretion) on insulin secretion and c-peptide in PANC-1 cell line and intracellular glucose concentration in HT1080 cell line. Materials and Methods: To do this, cell lines were purchased from the Iranian Genetic Resources Center and after cell passage and preparation, were treated with doses of 0/01, 0/1, 1, 10 and 100 μ g /ml harmin and ghrelin agonists with doses of 0/05, 0/5, 5, 50 and 500 μ g / ml. While performing MTT test, insulin secretion and c-peptide were measured by ELISA. Results: The results showed that HARMINE dose-dependently increased insulin and c-peptide secretion as well as increased intracellular glucose and had the opposite effect of ghrelin agonist. Conclusion: HARMINE analogues could be a unique therapeutic promise for human diabetes and possibly serve as inhibitors of ghrelin agonists.

Introduction: The b-carbolines harmane, HARMINE and norharmane are the members of Harmala,s alkaloids group (Peganum harmala, Zygophillaceae). The b-carboline alkaloids adjoined to benzodiazepine site of the g-aminobutyric acid type A (GABAA). These alkaloids also inhibited cyclooxygenase and lipoxygenase activities. These findings showed that the b-carbolines should be able to reduce writhing nociceptio induced by acetic acid- in mice. Objective: To assess the effects of acute treatment with harmane, norharmane and HARMINE on the writhing induced by acetic acid in mice.Materials and Methods: The experiments were carried out on male BALB/C mice (20-25g). Intraperitoneal (I.p) injection of acetic acid (0.6%) was performed in order to cause writhing behavior. This behavior was recorded by direct observation for a 30-minutes period. Decrease of writhing count is indicative of an anti-nociception. In order to avoid the possibility of a physicochemical interaction between them, Drugs were administered on opposite sides of peritoned.Results: Intraperitoneal (I.p) injection of Harmane (5-20mg/kg) on 6-9 mice, norharmane (5-15mg/kg) on 8-9 mice and HARMINE (10-15mg/kg) on 8-9 mice in per group decreased the writhing behavior significantly (P<0.0001, P<0.0003 and P<0.0016, respectively). The inhibitory effects of the mentioned drugs were antagonized by flumazenil (2 mg/kg).Conclusion: Effects of harmane, norharmane and HARMINE on writhing response may be mediated through an inverse agonistic mechanism located in the benzodiazepine receptors.