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Takada S, Nodera R, Yoshioka K. Effects of Diclofenac Etalhyaluronate (SI-613/ONO-5704) on Cartilage Degeneration in Arthritic Rats and Inflammatory Cytokine-Stimulated Human Chondrocytes. Cartilage 2024:19476035231224050. [PMID: 38317317 PMCID: PMC11569655 DOI: 10.1177/19476035231224050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/08/2023] [Accepted: 12/15/2023] [Indexed: 02/07/2024] Open
Abstract
OBJECTIVE Cartilage degeneration is a key feature of osteoarthritis (OA) and rheumatoid arthritis and is thought to negatively impact patients' quality of life. Diclofenac etalhyaluronate (DEH, SI-613/ONO-5704) is a hyaluronic acid (HA) derivative chemically bound to diclofenac (DF) that has been reported to improve OA symptoms; however, its effect on cartilage degeneration remains unknown. In the present study, we investigated the chondroprotective effect of DEH in rats with collagen-induced arthritis and interleukin-1β-stimulated human chondrocytes. DESIGN Rats with collagen-induced arthritis were administered DEH and HA intra-articularly, and DF orally. Knee joint swelling, histological scores of articular cartilage, and inflammatory (Il1b) and catabolic (Mmp3 and Mmp13) gene expression in the synovial tissue and cartilage were evaluated. In vitro direct effects of DEH on matrix metalloproteinase (MMP)-3 and MMP-13 expression were examined in interleukin-1β-stimulated human chondrocytes. RESULTS In a rat model of collagen-induced arthritis, a single intra-articular dose of DEH inhibited knee joint inflammation and cartilage degeneration. Daily oral administration of DF had similar effects. Conversely, HA administered as a single intra-articular dose had no effect. Only DEH inhibited Mmp3 gene expression in the cartilage, whereas DEH and DF inhibited Mmp3 and Mmp13 mRNA expression in the synovial tissue. In interleukin-1β-stimulated human chondrocytes, DEH and HA inhibited MMP-3 and MMP-13 production, whereas DF had no effect. CONCLUSIONS In this study, we demonstrated the chondroprotective effect of DEH in rats with collagen-induced arthritis and in interleukin-1β-stimulated human chondrocytes. Thus, DEH may suppress cartilage degeneration in patients with musculoskeletal diseases, such as OA.
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Affiliation(s)
- Shuhei Takada
- Central Research Laboratory, Research & Development Division, Seikagaku Corporation, Tokyo, Japan
| | - Risa Nodera
- Central Research Laboratory, Research & Development Division, Seikagaku Corporation, Tokyo, Japan
| | - Keiji Yoshioka
- Central Research Laboratory, Research & Development Division, Seikagaku Corporation, Tokyo, Japan
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Yamaguchi C, Yamamoto D, Fujimaru Y, Asano T, Takaoka A. Acetaminophen Exerts an Analgesic Effect on Muscular Hyperalgesia in Repeated Cold-Stressed Rats through the Enhancement of the Descending Pain Inhibitory System Involving Spinal 5-HT 3 and Noradrenergic α 2 Receptors. Biol Pharm Bull 2021; 44:1067-1074. [PMID: 34135207 DOI: 10.1248/bpb.b21-00178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Musculoskeletal and psychological complaints have increased with the widespread use of visual display terminals, and musculoskeletal pain is known to be closely related to stress. One method of experimentally inducing persistent muscle pain is repeated cold stress (RCS), and animals exposed to such stress exhibit a dysfunction in the descending pain inhibitory system. Acetaminophen (N-acetyl-p-aminophenol; APAP) is widely used to relieve several types of pain, including musculoskeletal pain, and is available as an OTC drug. However, the mechanism underlying its analgesic action has not yet been fully elucidated. In this study, we compared the analgesic effect of APAP on RCS-induced muscular hyperalgesia with those of other analgesics to identify its mechanism of action. The daily oral administration of APAP significantly suppressed the decrease in the mechanical withdrawal threshold caused by RCS, similar to the results for neurotropin but not for the cyclooxygenase inhibitor ibuprofen (IBP). Moreover, the intrathecal administration of antagonists of the 5-hydroxytryptamine (5-HT)3 receptor or α2-adrenoceptor significantly abolished the analgesic effect of APAP but not of IBP. These results suggest that the analgesic effect of APAP on RCS-induced muscular pain might be exerted due to the activation of the descending pathways involving the spinal 5-HT3 receptor or α2-adrenoceptor.
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Affiliation(s)
| | - Daisuke Yamamoto
- Self-Medication R&D Laboratories, Taisho Pharmaceutical Co., Ltd
| | - Yukiko Fujimaru
- Self-Medication R&D Laboratories, Taisho Pharmaceutical Co., Ltd
| | - Toshiki Asano
- Self-Medication R&D Laboratories, Taisho Pharmaceutical Co., Ltd
| | - Akiko Takaoka
- Self-Medication R&D Laboratories, Taisho Pharmaceutical Co., Ltd
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Khayyal MT, Wadie W, Abd El-Haleim EA, Ahmed KA, Kelber O, Ammar RM, Abdel-Aziz H. STW 5 is effective against nonsteroidal anti-inflammatory drugs induced gastro-duodenal lesions in rats. World J Gastroenterol 2019; 25:5926-5935. [PMID: 31660030 PMCID: PMC6815791 DOI: 10.3748/wjg.v25.i39.5926] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 08/16/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Proton pump inhibitors are often used to prevent gastro-intestinal lesions induced by nonsteroidal anti-inflammatory drugs. However, they are not always effective against both gastric and duodenal lesions and their use is not devoid of side effects. AIM To explore the mechanisms mediating the clinical efficacy of STW 5 in gastro-duodenal lesions induced by nonsteroidal anti-inflammatory drugs (NSAIDs), exemplified here by diclofenac, in a comparison to omeprazole. METHODS Gastro-duodenal lesions were induced in rats by oral administration of diclofenac (5 mg/kg) for 6 successive days. One group was given concurrently STW 5 (5 mL/kg) while another was given omeprazole (20 mg/kg). A day later, animals were sacrificed, stomach and duodenum excised and divided into 2 segments: One for histological examination and one for measuring inflammatory mediators (tumor necrosis factor α, interleukins-1β and 10), oxidative stress enzyme (heme oxygenase-1) and apoptosis regulator (B-cell lymphoma 2). RESULTS Diclofenac caused overt histological damage in both tissues, associated with parallel changes in all parameters measured. STW 5 and omeprazole effectively prevented these changes, but STW 5 superseded omeprazole in protecting against histological damage, particularly in the duodenum. CONCLUSION The findings support the therapeutic usefulness of STW 5 and its superiority over omeprazole as adjuvant therapy to NSAIDs to protect against their possible gastro-duodenal side effects.
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Affiliation(s)
- Mohamed T Khayyal
- Department of Pharmacology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Walaa Wadie
- Department of Pharmacology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Enas A Abd El-Haleim
- Department of Pharmacology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Kawkab A Ahmed
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Cairo 12211, Egypt
| | - Olaf Kelber
- Steigerwald Arzneimittelwerk GmbH, Bayer Consumer Health, Darmstadt 64295, Germany
| | - Ramy M Ammar
- Steigerwald Arzneimittelwerk GmbH, Bayer Consumer Health, Darmstadt 64295, Germany
- Department of Pharmacology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33511, Egypt
| | - Heba Abdel-Aziz
- Steigerwald Arzneimittelwerk GmbH, Bayer Consumer Health, Darmstadt 64295, Germany
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Das R, Deshmukh J, Asif K, Sindhura H, Devarathanamma MV, Jyothi L. Comparative evaluation of analgesic and anti-inflammatory efficacy of ibuprofen and traumeel after periodontal flap surgery: A randomized triple-blind clinical trial. J Indian Soc Periodontol 2019; 23:549-553. [PMID: 31849401 PMCID: PMC6906911 DOI: 10.4103/jisp.jisp_85_19] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Background: Pain management after performing flap surgery is of paramount importance. Taking into consideration the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs), and the advantages of homeopathic medication, the analgesic and anti-inflammatory properties of ibuprofen (NSAID) and traumeel (homeopathic AID) following flap surgery were evaluated. Materials and Methods: A randomized, triple-blinded, split-mouth clinical trial, with a sample size of 20 (age range of 20–60 years) was planned. Subjects included patients diagnosed with moderate chronic generalized periodontitis. Two quadrants for each subject were operated on, with an interval of 3 weeks. Random assignment of the operated quadrants to the following medication protocols was carried out by a third person: Ibuprofen, 600 mg and traumeel, 600 mg (up to three tablets) every 8 h for first 24 h and SOS (Si Opus Sit/if needed) thereafter for a period of 1 week as pain medication, respectively. After 1 week, sutures were removed. Primary outcomes were mean postoperative pain (modified visual analog scale) and number of tablets consumed in 1 week. The secondary outcome was postoperative tissue response. Any adverse effects were recorded. Results: Number of tablets consumed and pain perception was lower in traumeel compared to ibuprofen Group (P < 0.001). A better tissue response was shown by the group treated with traumeel as compared to the ibuprofen receiving group (P < 0.05). Three patients reported adverse drug reactions after consumption of ibuprofen. Conclusion: The present study suggested that while managing pain following flap surgery, traumeel was superior as compared to ibuprofen, with minimal or no side effects.
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Affiliation(s)
- Revu Das
- Department of Periodontology, Navodaya Dental College and Hospital, Raichur, Karnataka, India
| | - Jeevanand Deshmukh
- Department of Periodontology, Navodaya Dental College and Hospital, Raichur, Karnataka, India
| | - Kardkal Asif
- Department of Periodontology, Navodaya Dental College and Hospital, Raichur, Karnataka, India
| | - Harsha Sindhura
- Department of Periodontology, Navodaya Dental College and Hospital, Raichur, Karnataka, India
| | | | - Lakshminarayana Jyothi
- Department of Periodontology, Navodaya Dental College and Hospital, Raichur, Karnataka, India
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Kshirsagar AD, Panchal PV, Harle UN, Nanda RK, Shaikh HM. Anti-inflammatory and antiarthritic activity of anthraquinone derivatives in rodents. Int J Inflam 2014; 2014:690596. [PMID: 25610704 PMCID: PMC4290027 DOI: 10.1155/2014/690596] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2014] [Revised: 11/06/2014] [Accepted: 11/06/2014] [Indexed: 01/24/2023] Open
Abstract
Aloe emodin is isolated compound of aloe vera which is used traditionally as an anti-inflammatory agent. In vitro pharmacokinetic data suggest that glucuronosyl or sulfated forms of aloe emodin may provide some limitations in its absorption capacity. Aloe emodin was reported to have in vitro anti-inflammatory activity due to inhibition of inducible nitric oxide (iNO) and prostaglandin E2, via its action on murine macrophages. However, present work evidenced that molecular docking of aloe emodin modulates the anti-inflammatory activity, as well as expression of COX-2 (cyclooxygenase-2) in rodent. The AEC (4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2 carboxylic acid) was synthesized using aloe emodin as starting material. The study was planned for evaluation of possible anti-inflammatory and antiarthritic activity in carrageenan rat induced paw oedema and complete Freund's adjuvant induced arthritis in rats. The AE (aloe emodin) and AEC significantly (P < 0.001) reduced carrageenan induced paw edema at 50 and 75 mg/kg. Complete Freund's adjuvant induced arthritis model showed significant (P < 0.001) decrease in injected and noninjected paw volume, arthritic score. AE and AEC showed significant effect on various biochemical, antioxidant, and hematological parameters. Diclofenac sodium 10 mg/kg showed significant (P < 0.001) inhibition in inflammation and arthritis.
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Affiliation(s)
- Ajay D. Kshirsagar
- School of Pharmacy, Swami Ramanand Teerth Marathwada University, Vishnupuri, Nanded, Maharashtra 431606, India
| | - Prashant V. Panchal
- Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, Maharashtra 411018, India
| | - Uday N. Harle
- Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, Maharashtra 411018, India
| | - Rabindra K. Nanda
- Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, Maharashtra 411018, India
| | - Haidarali M. Shaikh
- Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, Maharashtra 411018, India
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Auda SH. Nimesulide/methyl β-cyclodextrin inclusion complexes: physicochemical characterization, solubility, dissolution, and biological studies. Drug Dev Res 2013; 75:68-75. [PMID: 24648149 DOI: 10.1002/ddr.21156] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 09/24/2013] [Indexed: 11/11/2022]
Abstract
Nimesulide (NIM) is an insoluble nonsteroidal anti-inflammatory drug (NSAID). Complexation of drug with methyl β-cyclodextrin was evaluated to improve solubility and dissolution rate of NIM. Complexation was achieved via a coevaporation technique to obtain different drug to polymer molar ratios (1:1, 1:2, and 1:3). The physicochemical characterization of the systems using powder X-ray diffraction and infrared spectroscopy was carried out to understand the influence of this technological process on the physical status of single components and complex systems and to detect possible interactions between drug and carrier. Moreover, quantitative solubility and in vitro dissolution studies of NIM alone and NIM inclusion complexes were studied in the dissolution media of phosphate buffer pH 5.5 and 7.4. The analysis provided existence of a molecular interaction between drug and carrier together in the complex state. The study showed that the inclusion systems enhanced of drug solubility, dissolution rate, and anti-inflammatory activity.
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Affiliation(s)
- Sayed H Auda
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
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Cyclooxygenase inhibitors protect D-galactosamine/lipopolysaccharide induced acute hepatic injury in experimental mice model. Food Chem Toxicol 2011; 50:861-6. [PMID: 22107987 DOI: 10.1016/j.fct.2011.11.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Revised: 11/01/2011] [Accepted: 11/03/2011] [Indexed: 10/15/2022]
Abstract
We investigated the protective effects of two non-steroid anti-inflammatory drugs, indomethacin (COX-1 and COX-2 inhibitors) and nimesulide (specific COX-2 inhibitor) on the hepatic injury induced by lipopolysaccharide in d-galactosamine sensitized (Gal/LPS) mice. ICR male mice were injected with a single dose of Gal/LPS with or without pre-treatment of 3mg/kg indomethacin or 30 mg/kg nimesulide (single i.p. injection). Sixteen hours later, blood and liver tissues of mice were collected for histological, molecular, and biochemical analyses. Our results showed marked reduction of hepatic necrosis, serum ALT, and tissue TBARS levels in both indomethacin- and nimesulide-pre-treated mice when compared with Gal/LPS-treated mice. Western blot and RT-PCR analysis showed decreased levels of iNOS mRNA, iNOS protein, and nitrotyrosine formation in both COX inhibitor pre-treated groups when compared with Gal/LPS-treated group. There was an inverse relationship between COX-1 and COX-2 expressions, as well as between COX-2 and C/EBP-α expressions in COX inhibitors groups, Gal/LPS and control groups. COX inhibitors reduced the expression of TNF-α mRNA and the activity of NF-κB which were elevated by Gal/LPS treatment. We conclude that COX inhibitors protected the liver from Gal/LPS-induced hepatotoxicity. COX inhibitors could be considered as potential agents in the prevention of acute liver failure and sepsis.
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Ahmed M, Upadhyaya P, Seth V. Comparison of analgesic effects of nimesulide, paracetamol, and their combination in animal models. Indian J Pharmacol 2011; 42:354-7. [PMID: 21189904 PMCID: PMC2991691 DOI: 10.4103/0253-7613.71913] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2010] [Revised: 04/15/2010] [Accepted: 08/05/2010] [Indexed: 11/12/2022] Open
Abstract
Objectives: To compare the analgesic activity of nimesulide and paracetamol alone and their combination in animal models for the degree of analgesia and the time course of action. Materials and Methods: Analgesia was studied in albino rats using formalin test and in albino mice using writhing test and the radiant heat method. For each test, four groups of six animals each were orally fed with a single dose of nimesulide, paracetamol, and combination of nimesulide + paracetamol and gum acacia as control, respectively. Results: In all the three test models, all three drug treatments showed significant analgesia (P < 0.001) as compared to control, but there was no significant difference in the analgesia produced by either drugs alone or in combination. The radiant heat method demonstrated a quicker onset and longer duration of action with nimesulide, whereas writhing test showed a quicker onset of action with paracetamol. In formalin test, greater degree of analgesia was seen with individual drugs than that of the combination, though this difference was not statistically significant. Conclusions: Nimesulide and paracetamol combination offers no advantage over nimesulide alone or paracetamol alone, either in terms of degree of analgesia or onset of action. Therefore, our study supports the reports claiming irrationality of the fixed dose combination of nimesulide and paracetamol.
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Affiliation(s)
- Mushtaq Ahmed
- Department of Pharmacology, Mahatma Gandhi Medical College, Sitapura, Jaipur 302 022, India
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von Trotha KT, Binnebösel M, Truong S, Behrendt FF, Wasmuth HE, Neumann UP, Jansen M. Severe gastric variceal haemorrhage due to splenic artery thrombosis and consecutive arterial bypass. BMC Surg 2011; 11:14. [PMID: 21711534 PMCID: PMC3142481 DOI: 10.1186/1471-2482-11-14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2010] [Accepted: 06/28/2011] [Indexed: 01/16/2023] Open
Abstract
Background Upper gastrointestinal haemorrhage is mainly caused by ulcers. Gastric varicosis due to portal hypertension can also be held responsible for upper gastrointestinal bleeding. Portal hypertension causes the development of a collateral circulation from the portal to the caval venous system resulting in development of oesophageal and gastric fundus varices. Those may also be held responsible for upper gastrointestinal haemorrhage. Case presentation In this study, we describe the case of a 69-year-old male with recurrent severe upper gastrointestinal bleeding caused by arterial submucosal collaterals due to idiopathic splenic artery thrombosis. The diagnosis was secured using endoscopic duplex ultrasound and angiography. The patient was successfully treated with a laparoscopic splenectomy and complete dissection of the short gastric arteries, resulting in the collapse of the submucosal arteries in the gastric wall. Follow-up gastroscopy was performed on the 12th postoperative week and showed no signs of bleeding and a significant reduction in the arterial blood flow within the gastric wall. Subsequent follow-up after 6 months also showed no further gastrointestinal bleeding as well as subjective good quality of life for the patient. Conclusion Submucosal arterial collaterals must be excluded by endosonography via endoscopy in case of recurrent upper gastrointestinal bleeding. Laparoscopic splenectomy provides adequate treatment in preventing any recurrent bleeding, if gastric arterial collaterals are caused by splenic artery thrombosis.
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Tripathi M, Singh BK, Raisuddin S, Kakkar P. Abrogation of nimesulide induced oxidative stress and mitochondria mediated apoptosis by Fumaria parviflora Lam. extract. JOURNAL OF ETHNOPHARMACOLOGY 2011; 136:94-102. [PMID: 21515351 DOI: 10.1016/j.jep.2011.04.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Revised: 03/03/2011] [Accepted: 04/06/2011] [Indexed: 05/30/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE [corrected] Fumaria parviflora Lam. is used for treating aches and pains, diarrhea, fever, influenza and other complications. The herb mixed with honey is taken to prevent vomiting as per Ayurvedic text. AIM OF THE STUDY In vivo studies were conducted to explore the hepatoprotective potential of Fumaria parviflora Lam. Fp extract against nimesulide induced oxidative stress and regulation of critical events in mitochondria mediated apoptosis. MATERIALS AND METHODS Group of Wistar rats were fed with nimesulide for 5 days (80 mg/kg/day, po), another group was pre-treated with Fp extract/silymarin (200mg/kg/day, po) for 5 days followed by nimesulide exposure. Liver serum biomarkers and histopathology were done to assess hepatotoxicity caused by nimesulide. Antioxidant enzymes (SOD, LPO, GPx, GR) were assessed using biochemical assays as well as gene expression by RT-PCR. GSH content and ROS generation was also evaluated using flow cytometry. Key apoptotic markers like phosphatidyl serine externalization, Bax, Bcl-2 translocation, mitochondrial membrane potential, cytochrome c release, caspases (9/3) activation and DNA damage were also observed in all the groups to confirm involvement of mitochondrial pathway. RESULTS Pre-treatment with Fp extract for 5 days significantly reduced the impact of nimesulide induced toxicity as evident from the serum biomarkers of liver damage and histopathology. It also modulated antioxidant enzymes mRNA expression as well as activity (SOD, glutathione peroxidase, glutathione reductase) and reduced lipid peroxidation during nimesulide toxicity. Nimesulide exposure decreased GSH content (92.9%) and increased reactive oxygen species (9.29 fold) which was attenuated in Fp treated rats. Fp pre-treatment significantly altered key apoptotic events like Bcl2 and Bax translocation, inhibited mitochondrial depolarization, prevented cytochrome c release, caspase-9/caspase-3 activation and DNA damage. CONCLUSION Our in vivo findings regarding protection accorded by Fp extract against nimesulide toxicity suggest that Fp not only reduced hepatotoxicity but attenuated critical control points of apoptotic cell death.
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Affiliation(s)
- Madhulika Tripathi
- Herbal Research Section, Indian Institute of Toxicology Research (CSIR), P.O. Box-80, M.G. Marg, Lucknow 226001, Uttar Pradesh, India. madhulika
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