Journal of Experimental Pharmacology最新文献

Background: The root bark of Carissa spinarum Linn. (Apocynaceae) is claimed to be used for the management of depression in Ethiopian folkloric medicine, and the crude extract has been reported to possess antidepressant-like activity in rodents.

Objective: This study aimed to evaluate the antidepressant-like effect of different fractions of the root bark in rodents and the possible underlying mechanisms in rats.

Methods: A 70% ethanol extract of the root bark was successively fractionated with n-butanol, ethyl acetate, and water. Animals of both sexes received 2% Tween 80, imipramine (30 mg/kg), or various doses (50, 100, 200 mg/kg) of the fractions. Duration of immobility was determined using the tail suspension test and the forced swim test. Locomotor activity was evaluated in the open field test. Serum corticosterone levels, total phenols, flavonoids, and alkaloids were determined. Preliminary mechanistic studies were also performed to explore possible mechanisms of action of the active fraction.

Results: All fractions but the aqueous fraction significantly (p<0.001) decreased the duration of immobility in both tests, with the ethyl acetate fraction being the most active. The locomotor test revealed that the activity was not due to non-specific psycho-stimulant effects. Serum corticosterone levels were reduced by both fractions, with the ethyl acetate fraction again being the most effective. Mechanistic studies showed the involvement of multiple neurotransmission systems, including adrenergic, dopaminergic and cholinergic as well as L-Arginine-NO-cGMP pathway. Higher contents of phenols (42.42 vs 29.8 mgGAE/g), flavonoids (12.43 vs 2.07 mgQE/g), and alkaloids (0.17 vs 0.07 mgATE/g) were found in the ethyl acetate than in the n-butanol fraction.

Conclusion: The present findings collectively indicate that the ethyl acetate and n-butanol fractions are endowed with antidepressant-like activity due to the presence of phenols, flavonoids, and alkaloids, which are medium polar in nature.

Introduction: Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ) are successfully deployed for different diseases beyond the prophylaxis and treatment of malaria. Both substances exhibit antiviral properties and have been proposed for prophylaxis and treatment of COVID-19 caused by SARS-CoV-2. CQ and HCQ cause similar adverse events including life-threatening cardiac arrhythmia generally based on QT-prolongation, which is one of the most reported adverse events for both agents associated with the treatment of COVID-19. Various drugs known to induce QT-prolongation have been proven to exert local anesthetic (LA)-like properties regarding their impact on the cardiac Na⁺ channel Nav1.5. Inhibition of Nav1.5 is considered as the primary mechanism of cardiotoxicity caused by LAs. However, the mechanism of the arrhythmogenic effects of CQ and HCQ related to Nav1.5 has not yet been fully investigated. Therefore, the exact mechanism of how CQ and HCQ affect the sodium currents generated by Nav1.5 need to be further elucidated.

Objective: This in vitro study aims to investigate the effects of CQ and HCQ on Nav1.5-generated sodium currents to identify possible LA-like mechanisms that might contribute to their arrhythmogenic properties.

Methods: The effects of CQ and HCQ on Nav1.5-generated sodium currents by HEK-293 cells expressing either wild-type human Nav1.5 or mutant Nav1.5 F1760A are measured using the whole-cell patch-clamp technique.

Results: Both agents induce a state-dependent inhibition of Nav1.5. Furthermore, CQ and HCQ produce a use-dependent block of Nav1.5 and a shift of fast and slow inactivation. Results of experiments investigating the effect on the LA-insensitive mutant Nav1.5-F1760A indicate that both agents at least in part employ the proposed LA-binding site of Nav1.5 to induce inhibition.

Conclusion: This study demonstrated that CQ and HCQ exert LA-typical effects on Nav1.5 involving the proposed LA binding site, thus contributing to their arrhythmogenic properties.

Alzheimer disease (AD) is the most common neurodegenerative disease and typically affects patients older than age 65. Around this age, the number of neurons begins to gradually decrease in healthy brains, but brains of patients with AD show a marked increase in neuron death, often resulting in a significant loss of cognitive abilities. Cognitive skills affected include information retention, recognition capabilities, and language skills. At present, AD can be definitively diagnosed only through postmortem brain biopsies via the detection of extracellular amyloid beta (Aβ) plaques and intracellular hyperphosphorylated tau neurofibrillary tangles. Because the levels of both Aβ plaques and tau tangles are increased, these 2 proteins are thought to be related to disease progression. Although relatively little is known about the cause of AD and its exact pathobiological development, many forms of treatment have been investigated to determine an effective method for managing AD symptoms by targeting Aβ. These treatments include but are not limited to using small molecules to alter the interactions of Aβ monomers, reducing hyperactivation of neuronal circuits altering Aβ's molecular pathway of synthesis, improving degradation of Aβ, employing passive immunity approaches, and stimulating patients' active immunity to target Aβ. This review summarizes the current therapeutic interventions in Phase II/III of clinical development or higher that are capable of reducing abnormal brain Aβ levels to determine which treatments show the greatest likelihood of clinical efficacy. We conclude that, in the near future, the most promising therapeutic interventions for brain Aβ pathology will likely be passive immunotherapies, with aducanumab and donanemab leading the way, and that these drugs may be combined with antidepressants and acetylcholine esterase inhibitors, which can modulate Aβ synthesis.

Background: Diabetes mellitus has become a huge global public health and economic issue. The shortcomings of current medicines, as well as their serious side effects, prompted a focused quest for natural medicinal agents. In Ethiopia, the leaf of Discopodium penninervum Hoschst has been utilized in the traditional health system to treat diabetes. The goal of this study was to confirm the anti-diabetic, anti-dyslipidemia, and anti-oxidant activity of Discopodium penninervum Hoschst leaf in both in vitro and in vivo.

Methods: In the normoglycemic, glucose-loaded, and streptozotocin-induced diabetic mouse models, the blood glucose-lowering effects of extract and solvent fractions of the leaf of Discopodium penninervum Hoschst were tested. The weight and lipid profile of streptozotocin-induced diabetic mice were assessed after treatment with leaf extract and solvent fractions for 14 days. The DPPH test was used to assess the antioxidant activity of the plant leaf extract.

Results: In the normoglycemic model and glucose loaded test, the leaf extract of Discopodium penninervum Hoschst demonstrated significant blood glucose decrease (34.1%, p<0.001) and 44.5%, p<0.001, respectively, when compared to the normal control. When compared to a diabetic control group, extract and solvent fractions significantly (p<0.001) reduced blood glucose levels on the 14th day in the streptozotocin-induced diabetic model. In addition, serum TC, STG, TG, LDL, and VLDL levels were reduced significantly (p<0.001). IC50 values of leaf extract and a standard medication (ascorbic acid) in the antioxidant activity test were 4.1g/mL and 10.23g/mL, respectively.

Conclusion: The hydro-alcoholic leaf extract and solvent fractions of Discopodium penninervum Hoschst leaves have demonstrated blood glucose-lowering effect, which justify ethnobotanical use, and can therefore be used as a good insight for new anti-diabetic medication source with a call for additional studies.

Objective: The aim of this study was to estimate the platelet count and bleeding time on peripheral blood smear of mice tail wound using Musa paradisiaca var. sapientum (L.) Kuntze (ambonese banana stem extract).

Design: Randomized post-test-only control group design.

Materials and methods: Twenty-four male mice (Mus Musculus) were randomly divided into 4 groups. A negative control group was treated with carboxymethyl cellulose (CMC), a positive control group (K+) treated aspirin 100 mg/kg body weight, group P1 treated with aspirin 100 mg/kg body weight and tranexamic acid 50 mg/kg body weight, and group P2 treated with 30% of ambonese banana stem extract (ABSE). The mean and standard deviation data of platelet counts and bleeding time were analyzed by one-way ANOVA statistical software.

Results and discussion: Tranexamic acid had no significant effect on platelets count compared to CMC group (p = 0.871), but administration of aspirin resulted in low platelets count significantly (p = 0.003). The platelet counts of ABSE and CMC groups were not significant different (p = 0.937). Aspirin has significantly shown prolonged bleeding time than CMC, tranexamic acid, and ABSE groups. However, there was no difference between the tranexamic acid and ABSE groups (p=0.934). The bleeding time of tranexamic acid and ABSE groups was similar, although the platelet count in the ABSE group was lower than in the CMC group.

Conclusion: This study proved that ambonese banana stem extract has a potency to shorten the bleeding time in mice tail wound without interfering to platelet count.

Background: Moringa stenopetala is a traditionally used medicinal plant that has been used for the management of different disorders including diabetes in Ethiopia. This study was aimed to assess the antidiabetic activity of hot tea infusion of leaves of Moringa stenopetala in streptozotocin-induced diabetic rats.

Methods: Experimental animals were Wistar male rats aged 4-6 weeks weighing 200-250 gram. The animals were maintained in equal light/dark series of laboratory conditions, and the average ambient temperature was 23±2 °C. The hot tea infusion of Moringa stenopetala leaves of different concentrations (as fine and coarse powder decoction), distilled water (10 mL/kg), and 150 mg/kg body weight of metformin were administered to diabetic rats as test, negative control, and positive standard drugs, respectively. Sucrose oral challenge test was also carried out to assess the effect of Moringa stenopetala hot tea infusion on postprandial glucose level. Blood glucose level was measured at 0, 30, 60, 90, and 180 minutes. Statistical analysis was conducted by SPSS package version 23, and the p-value less than 0.05 was declared as level of statistical significance.

Results: The phytoconstituents that tested positive in hot tea infusion of Moringa stenopetala leaves were alkaloids, tannins, flavonoids, saponins, and terpenoids. Different experimental groups treated with the hot tea infusion of Moringa stenopetala leaves showed significant reduction of blood glucose level after 30 minutes of hot tea infusion administration. In addition, the hot tea infusion at a different concentration for both fine and coarse powders reduced significantly raised blood glucose level. The present findings revealed that the hot tea infusion has blood glucose-lowering and antioxidant effects with wide safety margin.

Conclusion: The findings indicated that the hot tea infusion of the leaves of Moringa stenopetala shows a credible reduction in blood glucose level in rats.

Purpose: The recent increase in aluminum exposure and its effect on the development of the brain call for serious attention. The study investigated the behavioral and immunohistochemical changes in the cerebral cortex of Wistar rats following prenatal co-administration of ethyl acetate leaf fraction of Tamarindus indica (EATI) and aluminum chloride (AlCl₃).

Methods: Pregnant Wistar rats were divided into 5 groups (n=4). Group I (negative control), Group II-V were experimental groups treated with 200 mg/kg of AlCl₃ s/c. Group III and IV received an additional 400 mg/kg and 800 mg/kg of EATI respectively, while Group V received an additional 300 mg/kg of Vitamin E for 14 days (prenatal days 7-21) via the oral route. The pups were then exposed to cliff avoidance, negative geotaxis, and elevated plus maze (EPM) test on the post-natal day (PoND) 4-6, 7-10, and 18 respectively. On PoND 21 pups were sacrificed, and the skull dissected to remove the brain. The harvested brain tissues were processed for Cresyl fast (CF) and glial fibrillary acid protein (GFAP).

Results: The study showed that EATI administration during AlCl₃ exposure was associated with significant improvement in sensory-motor development. The EPM, CF, and GFAP results revealed significant improvement in anxiety-like behavior, motor activities, GFAP expression, pyramidal cell count, and Nissl staining following prenatal EATI administration during AlCl₃ exposure.

Conclusion: The present study concludes that EATI was associated with some protective potential during prenatal AlCl₃ exposure in Wistar rats.

Background: Scientists and researchers continue to focus on medicinal plants as a potential source of lead chemicals in the search for and development of new antiepileptic medicines. Biophytum umbraculum Welw. Syn is used to treat epilepsy in Ethiopian traditional medicine. The anticonvulsant effect of Biophytum umbraculum Welw. Syn hydroalcoholic extract and solvent fractions was evaluated in this study since the claim has not been thoroughly explored.

Methods: The plant's root was extracted using the maceration procedure, with aqueous, butanol, and chloroform as solvents. The maximum electroshock and pentylenetetrazol model tests were used to assess anticonvulsant activity. Mice were divided into five groups (n = 6) at random. The test groups received 100, 200, and 400 mg/kg of hydroalcoholic extract and solvent fraction, respectively. For the maximum electric shock test, the positive control groups received 25 mg/kg phenytoin and 200 mg/kg valproate for the pentylenetetrazol test. The negative control was given 10 mL/kg of pure water or 2% Tween 80.

Results: There were no signs of toxicity in the hydroalcoholic extract or solvent extraction. When compared to the negative control, the hydro-alcoholic extract had a significant anticonvulsant effect in both the maximum electric shock test and the pentylenetetrazol test. In both cases, the butanol component had a comparable impact. In the pentylenetetrazol test, the chloroform fraction had a significant anticonvulsant effect when compared to the control at dosages of MB200 and MB400. Flavonoids, phenols, tannins, steroids, terpenoids, and saponins were found in both the hydroalcoholic and solvent fractions of the plant extract.

Conclusion: The plant appears to have promising anticonvulsant properties, and it might be used to generate novel anti-epileptic drugs, according to this study.

Background: The root of Stephania abyssinica (Dill. and A. Rich.) Walp. (Menispermaceae) is traditionally used to treat wounds. Despite the fact that there have been in vitro studies and claims supporting wound healing, there has been no scientific data on the in vivo wound healing activities of the root of S. Abyssinica.

Objective: The aim of the study was to evaluate the wound healing activity of 80% methanol root extract and solvent fractions of S. Abyssinica in mice.

Methods: The roots of S. Abyssinica were air dried, ground and macerated by 80% methanol three times successively. The crude extract was fractionated by water, hexane and ethyl acetate separately. The acute dermal toxicity test was done by applying 2000 mg/kg of the 10% w/w crude extract. Wound healing activity of crude extract was evaluated on excision, incision and burn wound models, while the fractions were evaluated on excision wound model only.

Results: In mice, an acute dermal toxicity test of 2000 mg/kg of the 10% w/w crude extract was found to be safe. The 10% w/w crude extract ointment (CEO) produced significant (p < 0.001) wound contraction from 4th to 16th post wounding days, and the 5% w/w CEO were significant (p < 0.01) wound contraction on 10th post wounding day as compared to simple ointment (SO) treated group on excision wound. On burn wound models, the CEO showed highly significant (p < 0.001) from the 6th post wounding days onwards. The tensile strength was increased significantly (p < 0.001) by the CEO treated mice as compared to the untreated group and SO group.

Conclusion: The data obtained from this study showed 80% methanol crude extract, the aqueous and the 10% w/w ethyl acetate fraction possessed better wound healing activities, and decreased period of epithelialization.

Introduction: A combination of chemotherapy agents is the best choice in breast cancer treatment to increase the patient survival rate. 5-fluorouracil (5-FU) is one of the drugs applied in combination with other drugs to control and delay development of cancer cells. Nevertheless, the occurrence of multidrug resistance and dose-limiting cytotoxicity have limited the efficacy of 5-FU treatment. Therefore, the discovery of new anti-breast cancer drugs should be pursued.

Objective: To study potency of a promising naturally derived compound, caffeic acid phenethyl ester (CAPE), for breast cancer treatment in single and combination with 5-FU.

Methods: Cytotoxicity of CAPE, 5-FU, and 5-FU+CAPE was studied by in vitro MTT experiment in MCF-7 cell line, and RT-PCR analysis was used to evaluate the change in gene expression due to the treatment. Moreover, an enzymatic assay and molecular docking analysis were applied to evaluate the possible mechanism of substance-induced apoptosis.

Results: The study revealed that a single treatment of CAPE showed cytotoxicity with IC₅₀ 6.6 ± 1.0 µM and 6.5 ± 2.9 µM at 24 h and 48 h, respectively. Meanwhile, 5-FU showed cytostatic activity. The 5-FU + CAPE has a synergistic effect at 24 h treatment with a CI = 0.5 and an additive effect at 48 h treatment with CI = 1.0. CAPE was also found to enhances the mRNA expression of caspase-8 and BAX within 6 hours in combination with 5-FU compared to 5-FU treatment alone. Our study reveals a new mechanism of CAPE which is related to the inhibition of human dihydroorotate dehydrogenase (HsDHODH) with an IC₅₀ of 120.7 ± 6.8 µM, by bound to the ubiquinone-binding site of the enzyme and could be responsible for inducing extrinsic and intrinsic apoptosis.

Conclusion: This study demonstrated the cytotoxicity of CAPE potential to induce apoptosis of breast cancer MCF-7 cell line single and cytotoxic-cytostatic combination with 5-FU. Therefore, further studies to develop CAPE and its derivatives will be required to discover new candidates for breast cancer agents.