Investigation of the effect of dipyrone on cells isolated from intervertebral disc tissue (original) (raw)
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Electrophysiological evidence for a spinal antinociceptive action of dipyrone
Agents and Actions, 1994
Electrophysiological experiments in anesthetized cats and rats were performed in order to study the effects of dipyrone on single afferent fibers from the knee joint and on spinal cord neurons with knee joint input. The neurons were activated and/or rendered hyperexcitable by an acute inflammation in the knee joint. In the joint nerve in cats, intravenous dipyrone (25-100 mg/kg) reduced ongoing activity in 10/12 thinly myelinated afterents but only in 1/10 unmyelinated afferents; the responses to movements of the inflamed knee were reduced in 8/10 thinly myelinated but only in 3/10 unmyelinated units. The reduction of activity was significant 20-30 min after application and was maximal at 60-180 min. In the spinal cord of spinalized cats, intravenous dipyrone (25-100 mg/kg) reduced ongoing activity and/or responses to pressure onto the inflamed knee in 14/16 neurons and in non-spinalized rats similar effects were seen in 10/11 neurons. Effects on spinal cord neurons started 5-10 rain after application and were maximal after 20-40 min. These data show pronounced suppression of inflammationinduced nociception by dipyrone and they suggest that the spinal cord is a major site of action of this compound.
Analgesic and antiinflammatory effects of dipyrone in rat adjuvant arthritis model
Inflammation, 1994
Dipyrone, a pirazolone derivative, is a known analgesic drug with minor toxic effects associated with its administration. The aim of the present study was to determine the analgesic and antiinflammatory effects of dipyrone in a model of chronic inflammation (adjuvant-induced arthritis in rats). Hind-paw hyperalgesia was detected in arthritic rats from the 10th to the 16th day of observation. Edema development was maximum (twofold increase) at the 14th day of observation compared to control animals and reduced at the 16th day of observation. Dipyrone (1-50 mg/kg) dosedependently reduced both hind-paw hyperalgesia and edema from arthritic rats. However, it was shown to be more potent as analgesic than antiinflammatory in the present model. In contrast, indomethacin (2 mg/kg) and dexamethasone (0.4 mg/kg) completely inhibited hind-paw hyperalgesia and edema development. Our results indicate that dipyrone reduced the hyperalgesia and edema in arthritic rats by a mechanism not involving release of prostaglandin-like substances. The possibility of dipyrone inducing analgesia in arthritic rats through a peripheral action supports the use of dipyrone as an alternative choice dmg for the treatment of pain associated with arthritislike diseases in selected cases.
Evaluation of the effect of daptomycin, a glycopeptide agent, on intact intervertebral disc tissue
Turkish Neurosurgery
AIM: To evaluate the effects of pre-and intra-operatively administered daptomycin (DAP) on the intact human primary intervertebral disc tissue cells. MATERIAL and METHODS: Primary cell cultures were established using tissues obtained through decompressive laminectomy, traumatic intervertebral disc herniation excision, and posterior transpedicular stabilization. Non-drug-administered samples were used as a control group. The samples treated with DAP formed the study group. Molecular assays for proliferation and gene expression were performed. The obtained data were evaluated statistically, and results with a value of p<0.05 were accepted as significant. RESULTS: While no reduction was observed in the proliferation, the gene expression of intact intervertebral disc tissue cells was time-dependently decreased compared to the control group, and these results were reported to be statistically significant. CONCLUSION: This study observed the effect that a pharmaceutical preparation, which was used on intervertebral disc tissue before and after the operation, had on normal, healthy, and intact tissue. It concludes that alterations in the expression of genes involved in the anabolic and/or catabolic process, even in adjacent healthy tissue, may slow down the healing process of the damaged tissue or cause undesired cell differentiation.
Bupivacaine—the deadly friend of intervertebral disc cells
Spine Journal, 2011
BACKGROUND CONTEXT: Bupivacaine is commonly used as an adjunct during provocative discography and is administered intradiscally in patients with discogenic back pain. Recent studies demonstrated that bupivacaine is cytotoxic for articular chondrocytes in vitro at clinically used concentrations (0.25%-0.5%). PURPOSE: To analyze a concentration-dependent effect of bupivacaine on cell viability and gene expression of human intervertebral disc (IVD) cells in an in vitro model. STUDY DESIGN: In vitro cell culture study. PATIENT SAMPLE: Disc cells were isolated from human disc biopsies from 11 patients undergoing surgery because of degenerative disc disease or disc herniation. OUTCOME MEASURES: Cell viability and gene expression after exposure to bupivacaine. METHODS: Human IVD cells were treated with different concentrations of bupivacaine for 2 (n55) or 18 hours (n55) and analyzed for cell viability and proliferation (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay). Additionally, cells were prestimulated with interleukin-1 beta (IL-1b) (5 ng/mL) to increase the levels of proinflammatory cytokines and matrix-degrading enzymes and thereafter treated with 0.75 mmol bupivacaine (as determined in the cell viability test) for 2 (n55) or 18 hours (n55). Prestimulated cells with or without bupivacaine treatment were analyzed for gene expression of IL-1b, IL-6, IL-8, tumor necrosis factor-a (TNF-a), cyclooxygenase-2 (COX-2), matrix metalloproteinase-3 (MMP3), MMP9, MMP13, and a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) using real-time reverse transcription-polymerase chain reaction. Statistical analysis was performed by using the Mann-Whitney U test with a significance level of p!.05. RESULTS: After 18 hours, bupivacaine exhibited either a cytotoxic or a proliferative effect on human IVD cells, depending on the concentration. Similar but lower effects could be observed already after 2 hours. With a concentration of 0.75 mmol (proliferative effect), bupivacaine significantly decreased messenger RNA levels of TNF-a, COX-2, MMP13, and ADAMTS4 after 18 hours. In contrast, expression of IL-6, IL-8, and MMP9 did not differ; expression of IL-1b and MMP3 was stimulated with 0.75 mmol. After 2 hours, we observed a reduction in the expression of COX-2, MMP3, MMP13, and ADAMTS4, without any effect regarding IL-1b. CONCLUSIONS: Application of bupivacaine in clinically relevant concentrations was toxic for IVD cells in vitro. A low concentration stimulated cell proliferation and reduced gene expression of certain matrix-degrading enzymes and proinflammatory cytokines. If these results can be corroborated in tissue explant models or animal studies, caution regarding provocative discography with bupivacaine is prompted. Ó
Evaluation of the effect of apixaban on the primary intact intervertebral disc cell cultures
Annals of Medical Research, 2019
Apixaban is a frequently preferred pharmacological agent in clinics to prevent deep vein thrombosis and pulmonary embolism. Such new oral anticoagulants may cause hemorrhage's in tissues and/or organs or may cause gastrointestinal symptoms without bleeding. It is also reported in the literature that it may lead to mental disorders, unwanted disorders in the urinary tract and skeletalmuscle system. However, when the literature is examined, there are no studies, which are of high-evidential value, evaluating the efficacy of apixaban on healthy, intact intervertebral disc tissue, and matrix-like structures. In this pharmaco-molecular study, it was aimed to investigate the effects of a new oral anticoagulant agent containing the active ingredient apixaban on the intact intervertebral disc tissue cells, extracellular matrix (ECM) structure and to evaluate its positive and / or negative effects on gene expressions of cartilage oligo matrix protein (COMP), chondroadherin (CHAD), and Matrix Metalloproteinase (MMP)s. Material and Methods: The primary cell cultures were prepared from the intact tissues of the patients with the traumatic intervertebral disc herniation. Apixaban was administered to the cultures and molecular analyses were performed for 21 days. The data obtained from the apixaban-administered and non-apixaban-administered samples were evaluated statistically and the significance value was accepted as P <0.05. Results: The changes were observed in the cell proliferation and the expressions of the mentioned genes in the apixabanadministered group. The suppression of COMP value and the increase in MMP-13 value may be indicative of the development of matrix degeneration in the apixaban-administered group, compared to the non-drug-administered control group. Conclusion: The selectivity is one of the most important features of the drugs. However, it should not be forgotten that no drug will only produce the desired effect.
Experimental and Therapeutic Medicine
The aim of the present study was to investigate the effects of etanercept (ETA), a tumor necrosis factor (TNF) inhibitor, on human cell cultures prepared from intact intervertebral disc tissue. ETA is used as a treatment for cases of rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis and ankylosing spondylitis accompanied by moderate or severe joint pain. ETA was applied to primary cell cultures [annulus fibrosus and nucleus pulposus (NP) from intact intervertebral disc tissue]. Cell cultures without ETA treatment served as the control group. Morphological and quantitative molecular analyses of the two groups were performed. The number of viable cells and cell proliferation decreased in the ETA-treated cultures as compared with those in the control group. Furthermore, in the treatment group, the chondroadherin gene, an NP-specific marker, was not expressed after 24 h. By contrast, the cartilage oligo matrix protein was expressed 24, 48 and 72 h post-ETA treatment, while its expression was significantly lower than that in the control group. In addition, the expression of interleukin-1β, as well as matrix metallopeptidase-7 and-19, was markedly decreased. Overall, the cell proliferation and gene expression in the ETA-treated cells were significantly different from those in the control group (P<0.05). These results suggest that the treatment duration and dosage of TNF inhibitors, which are used to suppress active inflammation, should be considered in the clinical setting. These biological agents may delay the healing of intervertebral disc tissue damage by slowing cell proliferation and altering gene expression via anabolic and catabolic pathways.
European Journal of Pharmacology, 1998
Dipyrone injected intraperitoneally i.p. or subplantarly into the mouse paw caused dose-related antinociception against the early and the late phases of formalin-induced licking, with mean ID values of 154.5 and 263.7 mmolrkg, and 2.6 and 1.2 mmolrpaw, 50 Ž . Ž . respectively. Given either by intracerebroventricular i.c.v. or by intrathecal i.t. routes, dipyrone produced a similar inhibition of both phases of the formalin-induced licking, with mean ID values of 0.4 and 1.3 mmolrsite, and 0.4 and 0.9 mmolrsite against the early and 50 the late phase of the formalin response, respectively. Dipyrone, given by i.p., subplantar, i.t. or i.c.v. routes, caused dose-related antinociception of capsaicin-induced licking. The mean ID values were: 207.6 mmolrkg, 2.2 mmolrpaw, 0.4 mmolrsite and 0.14 50 mmolrsite, respectively. In addition, dipyrone given i.p. caused a significant increase of the latency both in the hot-plate and the tail-flick assays. Dipyrone, given i.p., i.t. or i.c.v., reversed significantly the hyperalgesia caused by i.t. injection of glutamate, with mean ID 50 values of 9 mmolrkg, 29 nmolrsite and 94 nmolrsite, respectively. The antinociception caused by dipyrone was not influenced by naloxone, L-arginine, phaclofen, glibenclamide, p-chlorophenylalanine methyl ester, pertussis toxin or by adrenal gland hormones, when assessed against the formalin assay. Dipyrone analgesic action was not secondary to its anti-inflammatory effect, nor was it associated with non-specific effects such as muscle relaxation or sedation actions of animals. Dipyrone at a higher concentration caused significant w 3 x Ž . inhibition of H glutamate binding 37% in cerebral cortical membranes from both mice and rats. However, dipyrone had no significant effect on brain constitutive neuronal nitric oxide synthase activity. It is concluded that dipyrone produces peripheral, spinal and supraspinal antinociception when assessed on formalin and capsaicin-induced pain as well as in glutamate-induced hyperalgesia in mice. Dipyrone antinociception seems unlikely to involve an interaction with the L-arginine-nitric oxide pathway, serotonin system, activation of G protein sensitive to pertussis toxin, interaction of ATP-sensitive K q channels, GABA receptors, or the release of endogenous i B glucocorticoids. However, a modulatory effect on glutamate-induced hyperalgesia and, to a lesser extent, an interaction with glutamate binding sites, seems to account for its analgesic action. q 1998 Elsevier Science B.V.