|
1
|
Khezri MR, Varzandeh R, Ghasemnejad-Berenji M. Concomitant Effects of Metformin and Vitamin C on Indomethacin-Induced Gastric Ulcer in Rats: Biochemical and Histopathological Approach. Drug Res (Stuttg) 2024; 74:280-289. [PMID: 38968951 DOI: 10.1055/a-2317-7578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/07/2024]
Abstract
INTRODUCTION Gastric ulcer is one of the most common and serious conditions in the gastrointestinal tract. One of the main causes of gastric ulcers is using of non-steroidal anti-inflammatory drugs (NSAIDs) which have limited their use in clinical practice. Several studies have revealed that metformin and Vitamin C (Vit C) exhibit protective effects against gastric mucosal damage in different animal models. However, no studies indicate their combination's effect on gastric ulcer models. Therefore, this study aims to investigate the protective effects of metformin and Vit C combination on indomethacin-induced gastric ulcers. MATERIAL AND METHODS In total, thirty rats were divided into six groups, including the control group, rats received indomethacin (50 mg/kg, i.p.), rats received indomethacin and pretreated with ranitidine (100 mg/kg), metformin (100 mg/kg, i.p.), Vit C (100 mg/kg), or metformin combined with Vit C. Four hours after indomethacin administration, rats were euthanized, and gastric tissues were removed for macroscopic, histopathologic, and biochemical examinations. RESULTS All therapeutics used in this study were found to alleviate gastric mucosal injury caused by indomethacin, as observed in histopathologic and macroscopic evaluations. Both Vit C and metformin were observed to significantly decrease lipid peroxidation and enhance the activity of anti-oxidative enzymes, SOD, GPx, and catalase. However, a more significant effectiveness was observed in catalase and GPx activities when Vit C was co-administered with metformin. CONCLUSIONS In conclusion, the present study revealed that metformin and Vit C combination therapy could potentially treat gastric ulcers associated with indomethacin.
Collapse
Affiliation(s)
| | - Reza Varzandeh
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Morteza Ghasemnejad-Berenji
- Experimental & Applied Pharmaceutical Sciences Research Center, Urmia University of Medical Sciences, Urmia, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences,Urmia, Iran
| |
Collapse
|
|
2
|
Pineda-Peña EA, Orona-Ortiz A, Velázquez-Moyado JA, Tavares-Carvalho JC, Chávez-Piña AE, Balderas-López JL, Navarrete A. Anti-inflammatory, antioxidant, and gaso-protective mechanism of 3α-hydroxymasticadienoic acid and diligustilide combination on indomethacin gastric damage. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:1501-1513. [PMID: 32242245 DOI: 10.1007/s00210-020-01857-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 03/19/2020] [Indexed: 02/07/2023]
Abstract
The co-administration of 3α-hydroxymasticadienoic acid (3α-OH MDA) and diligustilide (DLG) generates a synergist gastroprotective effect on indomethacin-induced gastric damage. However, the related protective activities of the compounds alone (or in combination) remain unclear. In the present study, we evaluated the anti-inflammatory and antioxidative activities, as well as the potential modulation of important gasotransmitters of each compound individually and in combination using the indomethacin-induced gastric damage model. Male Wistar rats were treated orally with the 3α-OH MDA, DLG, or their combination (at a fixed ratio of 1:1, 1:3, and 3:1) 30 min before the generation of gastric mucosal lesions with indomethacin (30 mg/kg, p.o.). Three hours later, the gastric injury (mm2) was determined. Results from these experiments indicate, in addition to maintaining basal levels of PGE2, the gastroprotective effect of the pre-treatment with 3α-OH MDA (70%), DLG (81%), and their combination (72%) which was accompanied by significant decreases in leukocyte recruitment, as well as decreases in TNF-α and LTB4 gastric levels (p < 0.05). We also found that the pre-treatment maintains the basal antioxidant enzyme activities (SOD) and gastric NO and H2S production even in the presence of indomethacin (p < 0.05). In conclusion, when 3α-OH MDA-DLG is given at a 1:1 combination ratio, the gastroprotective effect and the inflammatory, antioxidant, and gaso-modulation properties are not different from those of treatments using the maximum doses of each compound, revealing that this combination produces promising results for the treatment of gastric ulcers.
Collapse
Affiliation(s)
- Elizabeth Arlen Pineda-Peña
- Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, 04510, Ciudad de México, Mexico
| | - Alejandra Orona-Ortiz
- Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, 04510, Ciudad de México, Mexico
| | - Josué Arturo Velázquez-Moyado
- Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, 04510, Ciudad de México, Mexico
| | - José Carlos Tavares-Carvalho
- Laboratório de Pesquisa em Fármacos, Curso de Farmácia, Departamento de Ciências Biológicas e da Saúde, Universidade Federal do Amapá, Macapá, Amapá, Brazil
| | - Aracely Evangelina Chávez-Piña
- Laboratorio de Farmacología, Programa Institucional en Biomedicina Molecular, Doctorado en Ciencias en Biotecnología, Escuela Nacional de Medicina y Homeopatía del Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - José Luis Balderas-López
- Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, 04510, Ciudad de México, Mexico
| | - Andrés Navarrete
- Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, 04510, Ciudad de México, Mexico.
| |
Collapse
|
|
3
|
Lim JM, Song CH, Park SJ, Park DC, Jung GW, Cho HR, Bashir KMI, Ku SK, Choi JS. Protective effects of triple fermented barley extract (FBe) on indomethacin-induced gastric mucosal damage in rats. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 19:49. [PMID: 30786935 PMCID: PMC6383278 DOI: 10.1186/s12906-019-2457-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 02/12/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Hordeum vulgare L (barley) contains numerous phenolic substances with proven anticancer, antioxidant and gastroprotective activities. Saccharification increases the functionality and bioavailability of these compounds thus can aid in the development of a natural product based medicine. This study aimed to investigate the possible gastroprotective effects of saccharification on the indomethacin (IND)-induced gastric ulcers in rats using Weissella cibaria- and Saccharomyces cerevisiae-triple fermented H. vulgare extract (FBe). METHODS In total, 60 healthy male 6-week old Sprague-Dawley SD (SPF/VAF Outbred CrljOri:CD1) rats were commercially purchased. The FBe extract (100, 200, and 300 mg kg- 1) was orally administered 30 min before an oral treatment of IND (25 mg kg- 1). Six hours after IND treatment, variations in the histopathology, myeloperoxidase (MPO) activity, gross lesion scores, lipid peroxidation, and antioxidant defense system component (superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH)) levels were measured. RESULTS FBe treatment showed significant (p < 0.01 or p < 0.05) and dose-dependent decrease in gastric mucosal damage. In the present study hemorrhagic gross lesions, gastric MPO activity, and histopathological gastric ulcerative lesions were observed in IND-treated rats compared to the IND control rats. In particular, FBe, in a dose-dependent manner, strengthened the antioxidant defense systems, decreased lipid peroxidation and CAT activity by increasing the GSH levels and SOD activity, respectively. The 200 mg kg- 1 dose of FBe was similarly gastroprotective as the 10 mg kg- 1 dose of omeprazole in rats with IND-induced gastric mucosal damage. CONCLUSIONS The findings of the present study show that an oral administration of FBe had positive gastroprotective effects through strengthening the body antioxidant defense system and anti-inflammatory effects.
Collapse
|
|
4
|
Chindo BA, Schröder H, Koeberle A, Werz O, Becker A. Analgesic potential of standardized methanol stem bark extract of Ficus platyphylla in mice: Mechanisms of action. JOURNAL OF ETHNOPHARMACOLOGY 2016; 184:101-106. [PMID: 26945978 DOI: 10.1016/j.jep.2016.03.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 02/24/2016] [Accepted: 03/01/2016] [Indexed: 06/05/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Extracts of the stem bark of Ficus platyphylla (FP) have been used in traditional the Nigerian medicine to treat psychoses, depression, epilepsy, pain and inflammation. Previous studies have revealed the analgesic and anti-inflammatory effects of FP in different assays including acetic acid-induced writhing, formalin-induced nociception, and albumin-induced oedema. PURPOSE/METHODS In this study, we assessed the effects of the standardised extract of FP on hot plate nociceptive threshold and vocalisation threshold in response to electrical stimulation of the tail root in order to confirm its acclaimed analgesic properties. We also investigated the molecular mechanisms underlying these effects, with the focus on opiate receptor binding and the key enzymes of eicosanoid biosynthesis, namely cyclooxygenase (COX) and 5-lipoxygenase (5-LO). RESULTS FP (i) increased the hot plate nociceptive threshold and vocalisation threshold. The increase in hot plate nociceptive threshold was detectable over a period of 30min whereas the increase in vocalisation threshold persisted over a period of 90min. (ii) FP showed an affinity for µ opiate receptors but not for δ or κ opiate receptors, and (iii) FP inhibited the activities of COX-2 and 5-LO but not of COX-1. CONCLUSIONS We provided evidence supporting the use of FP in Nigerian folk medicine for the treatment of different types of pain, and identified opioid and non-opioid targets. It is interesting to note that the dual inhibition of COX-2 and 5-LO appears favourable in terms of both efficacy and side effect profile.
Collapse
Affiliation(s)
- Ben A Chindo
- Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, Kaduna State University, Kaduna, Nigeria; Institute of Pharmacology and Toxicology, Faculty of Medicine, Otto-von-Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany; Department of Pharmacology and Toxicology, National Institute for Pharmaceutical Research and Development, P. M. B. 21, Abuja, Nigeria
| | - Helmut Schröder
- Institute of Pharmacology and Toxicology, Faculty of Medicine, Otto-von-Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Andreas Koeberle
- Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, 07743 Jena, Germany
| | - Oliver Werz
- Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, 07743 Jena, Germany
| | - Axel Becker
- Institute of Pharmacology and Toxicology, Faculty of Medicine, Otto-von-Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.
| |
Collapse
|
|
5
|
Niranjan R, Manik R, Srivastava A, Palit G, Natu S. Cardiovascular Side Effect Remotely Related to NSAIDs: A Comparative Experimental Study on Albino Rats. J ANAT SOC INDIA 2011. [DOI: 10.1016/s0003-2778(11)80016-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
|
|
6
|
Nahman S, Belmaker RH, Azab AN. Effects of lithium on lipopolysaccharide-induced inflammation in rat primary glia cells. Innate Immun 2011; 18:447-58. [DOI: 10.1177/1753425911421512] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Lithium is the gold-standard treatment for bipolar disorder, a severe mental illness. A large body of evidence suggests that inflammation plays a role in the pathogenesis of bipolar disorder and that mood stabilizers exhibit anti-inflammatory properties. However, contradicting findings have also been reported. In this study, we examined the effects of lithium on LPS-induced inflammation in rat primary glia cells. Cells were pre-treated with lithium (1 or 10 mM) for 6 or 24 h, after which, inflammation was induced by the addition of LPS (for another 18 h) to the culture medium. Thereafter, medium was collected and cells were harvested for further analyses. Levels of TNF-α, IL1-β and PGE2 were determined by ELISA and NO levels by the Griess reaction assay. Expression levels of cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) were examined by Western blot analysis. We found that pre-treatment with lithium 10 mM (but not 1 mM) significantly reduced LPS-induced secretion of TNF-α, IL1-β, PGE2 and NO. In addition, lithium significantly reduced the expression of COX-2 and iNOS. These findings indicate that lithium exhibits a potent anti-inflammatory effect. However, it’s important to emphasize that this effect was obtained mainly under treatment with an extra-therapeutic concentration of the drug.
Collapse
Affiliation(s)
- Sigalit Nahman
- Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-sheva, Israel
- Psychiatry Research Unit and Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-sheva, Israel
| | - RH Belmaker
- Psychiatry Research Unit and Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-sheva, Israel
| | - Abed N Azab
- Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-sheva, Israel
- School for Community Health Professions, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-sheva, Israel
| |
Collapse
|
|
7
|
Giraudel JM, Toutain PL, King JN, Lees P. Differential inhibition of cyclooxygenase isoenzymes in the cat by the NSAID robenacoxib. J Vet Pharmacol Ther 2009; 32:31-40. [PMID: 19161453 DOI: 10.1111/j.1365-2885.2008.01031.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Robenacoxib is a new nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animal medicine. The objectives of this study were: to quantify the inhibitory actions of robenacoxib on cyclooxygenase (COX) isoenzymes in feline whole blood assays; to establish blood concentration-time profiles of robenacoxib after intravenous and subcutaneous dosing in the cat and; to predict the time courses of inhibition of COX isoforms by robenacoxib. COX-1 and COX-2 activities in heparinized feline whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. Inhibition of thromboxane B2 provided a marker of both COX-1 and COX-2 activities and a nonlinear parametric mixed effects modelling approach was used to establish the pharmacodynamic parameters describing this inhibition. Mean values (and prediction intervals) of IC50 were 28.9 (16.4-51.1) microM (COX-1) and 0.058 (0.010-0.340) microM (COX-2). These parameters were used to compute several selectivity indices. Selectivity IC ratios (COX-1:COX-2) were 502.3 (IC50/IC50), 451.6 (IC95/IC95) and 17.05 (IC20/IC80). Based on a clinically recommended dosage regimen of 2 mg/kg, it was predicted that the corresponding mean robenacoxib blood concentration over the first 12 h after drug administration corresponded to 5% inhibition of COX-1 and 90% inhibition of COX-2.
Collapse
Affiliation(s)
- J M Giraudel
- Department of Veterinary Basic Sciences, Royal Veterinary College, Hertfordshire, UK
| | | | | | | |
Collapse
|
|
8
|
Combination Therapy of PPARgamma Ligands and Inhibitors of Arachidonic Acid in Lung Cancer. PPAR Res 2009; 2008:750238. [PMID: 19277204 PMCID: PMC2652614 DOI: 10.1155/2008/750238] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2008] [Revised: 11/26/2008] [Accepted: 12/03/2008] [Indexed: 12/27/2022] Open
Abstract
Lung cancer is the leading cause of cancer death in the United States and five-year survival remains low. Numerous studies have shown that chronic inflammation may lead to progression of carcinogenesis. As a result of inflammatory stimulation, arachidonic acid (AA) metabolism produces proliferation mediators through complex and dynamic interactions of the products of the LOX/COX enzymes. One important mediator in the activation of the AA pathways is the nuclear protein PPARgamma. Targeting LOX/COX enzymes and inducing activation of PPARgamma have resulted in significant reduction of cell growth in lung cancer cell lines. However, specific COX-inhibitors have been correlated with an increased cardiovascular risk. Clinical applications are still being explored with a novel generation of dual LOX/COX inhibitors. PPARgamma activation through synthetic ligands (TZDs) has revealed a great mechanistic complexity since effects are produced through PPARgamma-dependent and -independent mechanisms. Furthermore, PPARgamma could also be involved in regulation of COX-2. Overexpression of PPARgamma has reported to play a role in control of invasion and differentiation. Exploring the function of PPARgamma, in this new context, may provide a better mechanistic model of its role in cancer and give an opportunity to design a more efficient therapeutic approach in combination with LOX/COX inhibitors.
Collapse
|
|
9
|
Tenenbaum M, Azab AN, Kaplanski J. Effects of estrogen against LPS-induced inflammation and toxicity in primary rat glial and neuronal cultures. ACTA ACUST UNITED AC 2007; 13:158-66. [PMID: 17621558 DOI: 10.1177/0968051907080428] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Several lines of evidence link inflammation with neurodegenerative diseases, which are aggravated by the age-related decline in estrogen levels in postmenopausal women. Lipopolysaccharide (LPS) is used widely to stimulate glial cells to produce pro-inflammatory mediators such as NO, PGE(2), and TNF-alpha, and was found to be toxic in high doses. We examined the effects of a physiological dose of 17beta-estradiol (E2) against LPS-induced inflammation and toxicity (cell death) in rat primary glial and neuronal cultures. Cultures were treated with 0.1 nM E2 for 24 h and then exposed to LPS 0.5-200 microg/ml for another 24 h. Levels of NO, PGE(2), and TNF-alpha in the culture medium were determined by the Griess reaction assay, radio-immunoassay, and enzyme-linked immunoassay, respectively. Cell death was quantified by measuring the leakage of lactate dehydrogenase (LDH) into the medium from dead or dying cells using the non-radioactive cytotoxicity assay. E2 significantly reduced the LPS-induced increase in NO and TNF-alpha (but not PGE(2)) production in glial cells. PGE(2) and TNF-alpha were undetectable in neuronal cultures, while only basal levels of NO were detected, even after stimulation with LPS. Moreover, pretreatment with E2 significantly reduced LPS-induced cell death, as measured by the release of LDH, in both glial and neuronal cultures. These results suggest that the neuroprotective effects attributed to E2 are derived, at least in part, from its anti-inflammatory and cytoprotective effects in both glial and neuronal cells.
Collapse
Affiliation(s)
- Meytal Tenenbaum
- Department of Clinical Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | | | | |
Collapse
|
|
10
|
Bhattacharya S, Banerjee D, Bauri AK, Chattopadhyay S, Bandyopadhyay SK. Healing property of the Piper betel phenol, allylpyrocatechol against indomethacin-induced stomach ulceration and mechanism of action. World J Gastroenterol 2007; 13:3705-13. [PMID: 17659730 PMCID: PMC4250642 DOI: 10.3748/wjg.v13.i27.3705] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the protective activity of allylpyrocatechol (APC), the major antioxidant constituent of Piper betel, against the indomethacin-induced stomach ulceration in the rat model and correlates with its antioxidative and mucin protecting properties.
METHODS: Male Sprague-Dawley rats were divided into five groups. Normal control rats (group I) were given the vehicle oral dose of gum acacia in distilled water (1 mL per rat); ulcerated control and treated rats (groups II-V) were given a single dose of indomethacin (30 mg/kg body wt.); group II rats were sacrificed 4 h after indomethacin administration; groups III-V rats were given the vehicle (1 mL per rat) or APC (2 mg/kg body wt.) or misoprostol (1.43 μg/kg body wt.) once daily by oral intubation for 7 d starting from 4 h after the indomethacin administration. After 7 d, the stomach tissues were excised for histological examination and biochemical analysis.
RESULTS: Treatment with APC (2 mg/kg body wt per day) and misoprostol (1.43 μg/kg body wt per day) for 7 d could effectively heal the stomach ulceration as revealed from the ulcer index and histopathological studies. Compared to the zero day ulcerated group, treatment with APC and misoprostol reduced the ulcer index by 93.4% and 85.4% respectively (P < 0.05). Both APC and misoprostol accelerated ulcer healing observed in natural recovery (P < 0.05), their respective healing capacities not being significantly different. The healing capacities of APC and misoprostol could be attributed to their antioxidant activity as well as the ability to enhance the mucin content of the gastric tissues. Compared to the ulcerated untreated rats, those treated with APC and misoprostol showed near normal MDA levels, while the protein levels were 86% and 78% of the normal value respectively (P < 0.05). Likewise, both APC and misoprostol increased the SOD, catalase, and mucin levels significantly (P < 0.05), the effect of APC being better.
CONCLUSION: APC can protect indomethacin-induced gastric ulceration due to its antioxidative and mucin protecting properties.
Collapse
Affiliation(s)
- S Bhattacharya
- Department of Biochemistry, Dr. B.C. Roy Post Graduate Institute of Basic Medical Sciences and IPGMERR, 244B, Acharya Jagadish Chandra Bose Road, Kolkata 700020, India
| | | | | | | | | |
Collapse
|
|
11
|
Banekovich C, Ott I, Koch T, Matuszczak B, Gust R. Synthesis and biological activities of novel dexibuprofen tetraacetylriboflavin conjugates. Bioorg Med Chem Lett 2006; 17:683-7. [PMID: 17110105 DOI: 10.1016/j.bmcl.2006.10.087] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2006] [Revised: 10/30/2006] [Accepted: 10/30/2006] [Indexed: 12/22/2022]
Abstract
A series of novel dexibuprofen derivatives covalently linked via alkylene spacers of variable length to tetraacetylated riboflavin have been developed. The target compounds became accessible by reaction of the chloromethyl ester of dexibuprofen with tetraacetylriboflavin (compound 7) or by synthesis of the appropriate N3-(omega-iodoalkyl)-2',3',4',5'-Tetraacetylriboflavin followed by treatment with dexibuprofen (derivatives 8-11), respectively. Biological screening revealed that the target compounds exhibit antiproliferative effects on MCF-7 breast cancer and HT-29 colon carcinoma cells with IC50 values in the range of 8-15 microM. Enzymatic studies on human platelets indicated significant COX-1 inhibitory activities of the target compounds.
Collapse
Affiliation(s)
- Christian Banekovich
- Institute of Pharmacy, Leopold-Franzens University of Innsbruck, Innrain 52a, 6020 Innsbruck, Austria
| | | | | | | | | |
Collapse
|
|
12
|
Abstract
The neuropathology of Alzheimer's disease (AD) is characterized by deposits of amyloid beta (Abeta) peptides and neurofibrillary tangles, but also, among other aspects, by signs of a chronic inflammatory process. Epidemiological studies have shown that long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) reduces the risk of developing AD and delays its onset. The classic target of NSAIDs is the prevention of cyclooxygenase (COX) activation. The main mechanism of action of COXs is the synthesis of prostaglandins, some of which have potent inflammatory activity. The discovery of two isoforms of this enzyme, COX-1 and COX-2, and that the latter is inducible by inflammatory cytokines supported the hypothesis that its inhibition would result in a potent antiinflammatory effect and led to the rapid development of selective COX-2 inhibitors, collectively called coxibs. Based on this rationale, some coxibs have been used in clinical trials for AD patients, but all the results obtained so far have been negative. Here, we review our knowledge in terms of COX-2 in the central nervous system, COX-2 and Abeta formation, and finally COX-2 and AD pathogenesis to understand the reasons why these drugs have failed and whether there is any scientific support to keep them as therapeutic tools for this chronic disease.
Collapse
Affiliation(s)
- Omidreza Firuzi
- Department of Pharmacology, University of Pennsylvania, School of Medicine. Philadelphia, PA 19014, USA
| | | |
Collapse
|