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PubMed2001

Receptor activator of nuclear factor-kappaB ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases.

BACKGROUND: The current review summarizes the roles of the ligand, receptor activator of nuclear factor-kappaB ligand (RANKL), its receptor, receptor activator of nuclear factor-kappaB (RANK), and its decoy receptor, osteoprotegerin (OPG), on osteoclast biology and bone resorption. Furthermore, it highlights the impact of these compounds on the pathogenesis of malignant bone diseases, including tumor metastasis, humoral hypercalcemia of malignancy, and multiple myeloma. Finally, the authors discuss the therapeutic potential of OPG in the management of malignancies involving the skeleton. METHODS: After its discovery and cloning, the biologic effects of RANKL, RANK, and OPG have been characterized by in vitro experiments and in vivo studies. The generation of knock-out mice and transgenic mice has produced animal models with absent or excessive production of these cytokine components that display opposite abnormal skeletal phenotypes (osteoporosis or osteopetrosis). The potential effect of RANKL and OPG has been assessed by evaluating these compounds in various animal models of metabolic and malignant bone disease and by administering OPG to humans. RESULTS: Abnormal bone resorption due to local or systemic stimulation of osteoclast differentiation and activation is a hallmark of various benign and malignant bone diseases. RANKL, RANK, and OPG form an essential cytokine system that is capable of regulating all aspects of osteoclast functions, including proliferation, differentiation, fusion, activation, and apoptosis. The balance of bone resorption depends on the local RANKL-to-OPG ratio, which is enhanced in bone metastases and humoral hypercalcemia of malignancy. The exogenous administration of OPG to tumor-bearing animals corrects the increased RANKL-to-OPG ratio, and reverses the skeletal complications of malignancies. CONCLUSIONS: Abnormalities of the RANKL/OPG system have been implicated in the pathogenesis of various primary and secondary bone malignancies. The systemic administration of OPG appears to be a potent novel therapeutic agent for treatment of these disorders.

Antineoplastic Agents↗

PubMed1989

Behavior disorders in mentally retarded persons, the dually diagnosed: factors of pathogenesis.

The present report considers organic factors of pathogenesis, in addition to environmental factors, as causal processes in cases of dual disability of mental retardation and behavior disorders. Relevant to organic pathogenesis, in cases of dual diagnosis, basic biological processes are presented, mechanisms concerned with gestational and birth complications that led to fetal-neonatal hypoxic cerebral cortical damage. In such cases, dual diagnosis manifestations of mental retardation and behavior disorders, together with other chronic cerebral disabilities, may be attributed to residues of fetal-neonatal cerebral damage.

Asphyxia Neonatorum↗

PubMed2000

Contribution of OX40/OX40 ligand interaction to the pathogenesis of rheumatoid arthritis.

OX40 ligand (OX40L) and OX40 (CD134) are a pair of cell surface molecules belonging to the TNF/TNF receptor family. Interaction of OX40L with its receptor OX40 is thought to be important in T cell activation through T cell/antigen-presenting cell interaction. However, involvement of these molecules in the pathogenesis of rheumatoid arthritis (RA) remains unclear. To explore the contribution of OX40/OX40L interaction to the pathogenesis of RA in vivo, we evaluated the effect of a neutralizing anti-OX40L monoclonal antibody (mAb) on the development of collagen-induced arthritis (CIA) in DBA/1 mice as an animal model for RA. Administration of anti-OX40L mAb into type II collagen (CII) -immunized DBA/1 mice dramatically ameliorated the disease severity. In vivo treatment with anti-OX40L mAb did not inhibit the expansion of CII-reactive T cells, but suppressed IFN-gamma and anti-CII IgG2a production. Therefore, OX40/OX40L interaction appears to play a critical role in the development of CIA by enhancing Th1-type autoimmune response. In addition, T lymphocytes in synovial fluid and synovial tissue from RA patients expressed OX40, while OX40L was expressed on sublining cells in synovial tissue. These results indicate that OX40/OX40L interaction may play a critical role in the development of RA.

Animals↗

PubMed2000

Lack of evidence for an involvement of Epstein-Barr virus infection of synovial membranes in the pathogenesis of rheumatoid arthritis.

OBJECTIVE: To test the hypothesis that Epstein-Barr virus (EBV) infection of cells within the synovial membrane contributes to the pathogenesis of rheumatoid arthritis (RA). METHODS: Biopsy samples of synovial membrane from 37 patients with RA and from 51 patients with other joint diseases were studied for evidence of EBV infection using in situ hybridization specific for the EBV-encoded RNAs (EBERs). Latent membrane protein 1 (LMP1) and the lytic-cycle BZLF1 protein were detected by immunohistochemistry. RESULTS: Rare EBER-positive B lymphocytes were detected in 7 RA biopsy samples. EBV was not detectable in any other cells. Expression of the LMP1 and BZLF1 proteins of EBV was not observed in any of the samples. No EBV infection was detected in synovial membranes from patients with other joint diseases. CONCLUSION: Our data indicate that EBV infection is not directly involved in the pathogenesis of RA. Any contribution of EBV to the pathogenic process leading to RA is likely to be indirect.

Adult↗

PubMed1992

Aluminium and the pathogenesis of Alzheimer's disease: a summary of evidence.

Known risk factors for Alzheimer's disease (AD) are few and insufficient knowledge is available to recommend steps to reduce AD in our ageing populations. Although not 'the cause', considerable evidence implicates human ingestion of aluminium as a possible risk factor for the expression of dementia of the Alzheimer type. A recent epidemiological study in Ontario relating the incidence of AD to aluminium in drinking water strongly supports this conclusion. To test further the hypothesis that aluminium may play a role in the pathogenesis of AD we conducted a clinical trial employing the trivalent metal ion binding compound, desferrioxamine. The design was a two-year randomized trial with behavioural assessments blinded to study assignment. Sixty-three patients with probable AD were selected who were living at home and were under 74 years. Forty-eight signed an informed consent and completed all initial testing. The main outcome measure was a video-recorded home-behavioural assessment of measures of skills of daily living. The principal outcome was that the mean slope for performance of the skills of daily living for the group without treatment was -1.72% maximum score/month, compared to -0.87% maximum score/month for the group treated with desferrioxamine (P = 0.038). Considerable evidence supports the hypothesis that aluminium has an active role in the pathogenesis of AD.

Aluminum↗

PubMed1987

Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature.

The Noonan syndrome (NS) is a true multiple congenital anomalies (MCA) syndrome with numerous manifestations. An association with lymphedema has been noted, but its pathogenesis is not fully understood. Nine new cases and a review of the literature explore the role of lymphedema in NS, including its pathogenesis, presentations, and phenotypic effects. Consideration is given to developmental stage at time of onset, chronicity, resolution, and anatomic site. It appears likely that lymphedema is a much more frequent concomitant in NS than previously realized. The major source of lymphedema in NS appears to be a presently undefined dysplasia of lymphatic vessels of unknown cause. Further study of lymphedema may provide an understanding of its role in shaping the NS phenotype. Comparison with other MCA syndromes and animal models is made in this regard. Relevance to prenatal diagnosis and treatment is discussed.

Adult↗

PubMed1990

Pathogenesis of mental deficiency in trisomy 21.

In trisomy 21, pathogenesis of mental retardation is still poorly understood although the knowledge of the genic content of chromosome 21 is steadily increasing. Short of discovering how to silence selectively one of the 3 chromosomes 21, no rational medication can be envisaged before pathogenesis has been unraveled, at least partially. A biochemical scheme of impairment of mental efficiency is presented. Secondarily, the possible deleterious effects of a given gene overdose are discussed. Cu/Zn SOD, cystathionine beta synthase, S 100 beta protein, phosphofructokinase, purine synthesis and adenosine pharmacology, thyroid disturbance, and elevated TSH with low rT3 as well as biopterine metabolism interferences are reviewed. It is observed that the metabolic paths controlled by these genes, although unrelated at first glance, are in fact tightly related by their effects, just as if synteny was in some way related to biochemical cooperation or mutually controlled regulation. Experiments in vitro have demonstrated a peculiar sensitivity of trisomic 21 lymphocytes to methotrexate. From this starting point, systematic research of special sensitivities has begun. Clinical observations and relevant statistical methods allow study of the speed of mental development under various medications. The interest of regulating thyroid metabolism, when needed, is exemplified. Reequilibration of monocarbon metabolism is discussed and the seemingly favourable effect of folinic acid medication in pseudo-Alzheimer complication is presented.

Adolescent↗

PubMed2005

Speculations on the pathogenesis of CHARGE syndrome.

To be seriously considered, a theory about the pathogenesis of a multiple congenital anomaly syndrome should meet three criteria: (1) it should explain all of the anomalies associated with the syndrome; (2) it should explain why certain anomalies are not associated with the syndrome; and (3) it should predict anomalies that could be associated with the syndrome, but have not yet been described. The theory must eventually pass the ultimate test, that is, molecular confirmation of the proposed mechanism. Several theories about the pathogenesis of CHARGE syndrome have been proposed, but none of these meet the three criteria stated above. In this study, the author proposes that CHARGE syndrome is due to a disruption of mesenchymal-epithelial interaction (epithelial includes ectoderm and endoderm). The theory is tested against the major, minor, and occasional anomalies that are used to make the clinical diagnosis of CHARGE syndrome. Review of the known embryology of the organs and tissues involved in CHARGE syndrome confirms that mesenchymal-epithelial interactions are necessary for proper formation of these organs and tissues. The presence of limb anomalies in approximately one-third of CHARGE syndrome patients fulfills criteria #3 above, in that limb anomalies were not felt to be a part of CHARGE syndrome until relatively recently. It is known that some patients with chromosomal abnormalities have a phenotype that overlaps with CHARGE syndrome. Given that critical developmental pathways must be robust and redundant in order to minimize errors, it may be that disruption of more than one gene is necessary to generate the CHARGE phenotype, as has been proposed for the holoprosencephaly sequence. Mutations and deletions of CHD7 have recently been identified as causing CHARGE syndrome in more than 50% of tested patients. Given this gene classes' putative role as a general controller of developmental gene expression as well as mesodermal patterning, it would fit the hypothesized mechanisms discussed in the study.

Abnormalities, Multiple↗

PubMed1990

The role of interferon-gamma in the pathogenesis of experimental autoimmune disease of the peripheral nervous system.

The role of interferon-gamma in the pathogenesis of experimental autoimmune disease of the peripheral nervous system was investigated. Administration of rat recombinant interferon-gamma markedly augmented both myelin-induced and T-cell line-mediated experimental autoimmune neuritis. Conversely, in vivo application of a monoclonal antibody to interferon-gamma suppressed the disease. Clinical and electrophysiological findings were corroborated by semiquantitative morphometric analysis. Mechanisms responsible for the enhancing effects of interferon-gamma include upregulation of major histocompatibility complex class II antigen expression in the nerve lesion, increased cellular influx of T cells and macrophages, and heightened macrophage activity with enhanced release of toxic oxygen species. These observations establish a pivotal role of the cytokine interferon-gamma in the pathogenesis of experimental autoimmune disease of the peripheral nervous system.

Animals↗

PubMed1998

Mitochondria in the etiology and pathogenesis of Parkinson's disease.

Mitochondria play a critical role in cellular energy metabolism. The identification of a respiratory chain defect in Parkinson's disease (PD) provides not only a direct link with toxin models of parkinsonism but also insight into the mechanisms involved in etiology and pathogenesis. The presence of the complex I deficiency in PD substantia nigra and platelets suggests the involvement of a systemic cause. Genomic transplantation studies have been undertaken that involve the transfer to a novel nuclear background of mitochondrial DNA (mtDNA) from PD patients with a complex I defect, followed by both mixed and clonal expansion of the resulting cybrids. The mixed cybrids with the PD mtDNA expressed the complex I defect present in the original PD donor platelets. Clonal expansion of one such mixed cybrid culture produced a spectrum of clones with complex I and complex IV activities, ranging from severe deficiency to normal range, a pattern typical of a heteroplasmic mtDNA mutation. Histochemical, immunohistochemical, and functional assessments of delta psi(m) all showed a pattern in the PD clones typical of that produced by a mtDNA mutation. Patients with focal dystonia and a platelet complex I defect were used as disease controls for the cybrid studies. The mitochondrial abnormality was eradicated by transfer of dystonia mtDNA to a control nuclear background in both mixed and clonal cybrids, with no evidence of clonal heterogeneity. These results help to validate our findings in the PD patients and suggest that the complex I deficiency in dystonia is not due to an abnormality of mtDNA. We hypothesize that the mtDNA defect alone may be the cause of PD in a proportion of patients and may contribute to pathogenesis in others. Identification of the mtDNA genotype responsible for PD may allow the testing of neuroprotective strategies in appropriate patients.

DNA, Mitochondrial↗

PubMed1994

Perspectives: a biomechanical model of the pathogenesis of arthroses.

This model views the common, initiating cause of arthroses as excessive articular cartilage microdamage. If so, understanding it would become a central problem for understanding the pathogenesis of arthroses. The model proposes the microdamage can stem from: (1) Excessive total loads on normal joints; (2) underadaptations in a joint's size or shape that leave its momentarily loaded area too small for normal loads; (3) impaired microdamage repair in subchondral bone or articular cartilage; (4) abnormal composition or structure that makes a tissue develop excessive microdamage under normal loads. (5) (2)-(4) above could stem from changed set points or "lead times" for a joint's adaptations and maintenance, which in turn could stem from (6) genetic influences, some drugs, toxins, diseases, and "X," and (7) from combinations of the above. In the pathogenesis of arthroses this model assigns special importance to the stiffness of joint tissues (as distinguished from their strength), to the typical largest unit loads they carry as a result of a subject's usual physical activities, and to microdamage in those tissues.

Arthritis↗

PubMed2003

High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine.

OBJECTIVE: High mobility group box chromosomal protein 1 (HMGB-1), a nuclear DNA binding protein, was recently rediscovered as a new proinflammatory cytokine. The purpose of this study was to demonstrate HMGB-1 expression in vivo and to identify the role of HMGB-1 in the pathogenesis of rheumatoid arthritis (RA). METHODS: HMGB-1 concentrations in synovial fluid (SF) and serum from RA and osteoarthritis (OA) patients were measured by immunoblot analysis. The protein's specific receptor, receptor for advanced glycation end products (RAGE), was examined in SF macrophages (SFMs). We measured levels of proinflammatory cytokines released by SFMs treated with HMGB-1 via enzyme-linked immunosorbent assay and used soluble RAGE (sRAGE) to block the release of tumor necrosis factor alpha (TNFalpha). Immunohistochemical analysis and immunofluorescence assay were employed to examine localization of HMGB-1 in RA synovium and its translocation in SFMs after TNFalpha stimulation. RESULTS: HMGB-1 concentrations were significantly higher in SF of RA patients than in that of OA patients. SFMs expressed RAGE and released TNFalpha, interleukin-1beta (IL-1beta), and IL-6 upon stimulation with HMGB-1. HMGB-1 was found in CD68-positive cells of RA synovium, and TNFalpha stimulation translocated HMGB-1 from the nucleus to the cytosol in SFMs. Blockade by sRAGE inhibited the release of TNFalpha from SFMs. CONCLUSION: HMGB-1 was more strongly expressed in SF of RA patients than in that of OA patients, inducing the release of proinflammatory cytokines from SFMs. HMGB-1 plays a pivotal role in the pathogenesis of RA and may be an original target of therapy as a novel cytokine.

Aged↗

PubMed2004

TRAIL induces apoptosis of chondrocytes and influences the pathogenesis of experimentally induced rat osteoarthritis.

OBJECTIVE: To investigate whether TRAIL influences the pathogenesis of osteoarthritis (OA). METHODS: A recombinant adenoviral vector system (Ad-TRAIL) was used. Expression of TRAIL in a rat chondrocyte cell line (RCJ3.1C.18) and alterations in the expression of death and decoy receptors after Ad-TRAIL infection were measured by Western blot assay. To explore the underlying mechanism, Western blot assays (to detect caspase 8, poly[ADP-ribose] polymerase [PARP], and caspase 3 activation), mitochondrial membrane potential (DeltaPsim) measurement, Hoechst staining, and DNA electrophoresis were conducted. Next, expression of TRAIL and death and decoy receptors was examined by immunochemistry in primary cultured chondrocytes and on cartilage obtained from rats with experimentally induced OA. RESULTS: Ad-TRAIL infection induced expression of TRAIL in RCJ3.1C.18 cells, increased expression of death receptor 4 (DR4), and decreased expression of DR5 and decoy receptor 1 (DcR1). Ad-TRAIL, at doses of 10 and 100 multiplicities of infection, decreased the viability of chondrocytes 4 days after infection. Reduction of DeltaPsim, cytochrome c release, nuclear condensation, activation of caspase 3 and PARP, and DNA fragmentation proved the induction of apoptosis. Activation of caspase 8 was also observed. Ad-TRAIL also induced apoptosis in primary cultured chondrocytes, in which alterations in expression of TRAIL and death receptors were similar to those observed in RCJ3.1C.18 cells. Cartilage obtained from rats with experimentally induced OA showed increased expression of TRAIL and DR4 and decreased expression of DR5 and DcR1 compared with control cartilage. CONCLUSION: TRAIL induces chondrocyte apoptosis, and TRAIL-induced chondrocyte apoptosis may play a role in the pathogenesis of OA.

Animals↗

PubMed2004

Midkine, a heparin-binding growth factor, is fundamentally involved in the pathogenesis of rheumatoid arthritis.

OBJECTIVE: Midkine (MK), a heparin-binding growth factor, promotes growth, survival, and migration of various cells. The essential role of MK in migration of inflammatory cells has been shown using mice deficient in the MK gene (Mdk(-/-) mice). We undertook this study to investigate the role of MK in the pathogenesis of rheumatoid arthritis (RA). METHODS: MK levels in specimens from patients were determined by enzyme-linked immunosorbent assay, and localization of MK was revealed by immunohistochemical analysis. Susceptibility to antibody-induced arthritis was compared between Mdk(-/-) and wild-type (WT) mice. Osteoclast differentiation was monitored using macrophage-like cells isolated from human synovial tissue and macrophages from mouse bone marrow. RESULTS: MK levels in sera and synovial fluid were increased in most RA patients, indicating a strong correlation between MK expression and RA. MK was expressed in macrophage-like cells and fibroblast-like cells in synovial membranes from the patients. In antibody-induced arthritis, Mdk(-/-) mice seldom developed the disease, while most of the WT mice did. Administration of MK to the Mdk(-/-) mice increased the frequency of antibody-induced arthritis. Migration of inflammatory leukocytes to the synovial membranes in the disease model was suppressed in the Mdk(-/-) mice. Furthermore, MK was found to promote the differentiation of osteoclasts from macrophages. CONCLUSION: MK participates in each of the two distinct phases of RA development, namely, migration of inflammatory leukocytes and osteoclast differentiation, and is a key molecule in the pathogenesis of RA.

Adolescent↗

PubMed2004

Genetic association of cutaneous neonatal lupus with HLA class II and tumor necrosis factor alpha: implications for pathogenesis.

OBJECTIVE: Cutaneous neonatal lupus resembles subacute cutaneous lupus erythematosus (SCLE), and photosensitivity is a common symptom. Tumor necrosis factor alpha (TNFalpha) release by ultraviolet light-exposed keratinocytes may be exaggerated in SCLE patients who have the haplotype TNFalpha -308A;DRB1*03. Accordingly, this study was undertaken to seek genetic and histologic evidence for a role of TNFalpha in the pathogenesis of cutaneous neonatal lupus. METHODS: DNA was isolated from 83 children (22 with rash, 35 with congenital heart block [CHB], 26 unaffected siblings) and 58 mothers from the Research Registry for Neonatal Lupus. RESULTS: The -308A allele (associated with higher TNFalpha production), HLA-DRQB1*02, and HLA-DRB1*03 were each present in the majority of children with rash (64%, 68%, and 64%, respectively). The frequency of all 3 6p alleles occurring together in 1 individual was greater in children with rash than in children who had either CHB or no manifestation of neonatal lupus (59% versus 30%; P = 0.02). This association with neonatal lupus rash was equivalent to published findings in a cohort of patients with SCLE, but significantly greater than the association in patients with discoid lupus erythematosus. Prominent TNFalpha staining in the epidermis was observed in lesional skin from 3 children with rash, but not in skin from a healthy neonate. CONCLUSION: Taken together, the finding of a genetic predisposition to generate increased levels of TNFalpha following tissue injury and the histologic demonstration of TNFalpha in the target organ support the notion that this inflammatory cytokine plays a role in the pathogenesis of cutaneous neonatal lupus. Furthermore, the results of these studies provide evidence of a biologic link between neonatal lupus and the rash of SCLE.

Epidermis↗

PubMed2005

The involvement of V(alpha)14 natural killer T cells in the pathogenesis of arthritis in murine models.

OBJECTIVE: To examine the physiologic role of natural killer T (NKT) cells bearing V(alpha)14 T cell receptor (TCR) in the pathogenesis of collagen-induced arthritis (CIA) and antibody-induced arthritis in mice. METHODS: NKT cells were stained with alpha-galactosylceramide-loaded CD1 dimer, and then assessed using flow cytometry. CIA was induced in mice by immunization on days 0 and 21 with type II collagen (CII) emulsified with an equal volume of Freund's complete adjuvant. Anti-CII antibodies were measured by enzyme-linked immunosorbent assay. For antibody-induced arthritis, mice were injected with anti-CII monoclonal antibodies (mAb) followed by lipopolysaccharide, or with serum from KRN TCR-transgenic mice crossed with nonobese diabetic mice (K/BxN). The severity of arthritis was monitored with a macroscopic scoring system. RESULTS: The number of NKT cells increased in the liver at the peak of the clinical course of CIA. Administration of anti-CD1 mAb inhibited development of CIA. The severity of CIA in NKT cell-deficient mice was reduced compared with that in wild-type mice. The IgG1:IgG2a ratio of anti-CII was elevated and production of interleukin-10 from draining lymph node cells was increased in NKT cell-deficient mice. NKT cell-deficient mice were significantly less susceptible to antibody-induced arthritis. CONCLUSION: NKT cells contribute to the pathogenesis of arthritis by enhancing autoantibody-mediated inflammation. NKT cells also contribute to the disease process in a deleterious way, due, at least in part, to the alteration of the Th1/Th2 balance in T cell response to CII.

Animals↗

PubMed2007

HLA-B27 up-regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats: Implications for the pathogenesis of spondylarthritis-like disease.

OBJECTIVE: HLA-B27 is implicated in the pathogenesis of spondylarthritis (SpA), yet the molecular mechanisms are incompletely defined. HLA-B27 misfolding has been associated with endoplasmic reticulum stress and activation of the unfolded protein response (UPR) in macrophages from HLA-B27/human beta(2)-microglobulin-transgenic (B27-transgenic) rats. This study was performed to assess the mechanisms that drive activation of the HLA-B27-induced UPR and to determine whether splenocytes respond in a similar manner. METHODS: Splenocytes were isolated and bone marrow macrophages were derived from B27-transgenic and wild-type rats. Cells were treated for up to 24 hours with cytokines that induce class I major histocompatibility complex expression. HLA-B27 expression and misfolding were assessed by real-time reverse transcription-polymerase chain reaction, flow cytometry, and immunoblotting. Activation of the UPR was measured by quantifying UPR target gene expression and X-box binding protein 1 messenger RNA (mRNA) splicing. RESULTS: HLA-B27 mRNA up-regulation was accompanied by a dramatic increase in the accumulation of misfolded heavy chains and preceded robust activation of the UPR in macrophages. When macrophages were treated with various cytokines, the magnitude of the UPR correlated strongly with the degree of HLA-B27 up-regulation. In contrast, B27-transgenic splenocytes exhibited only low-level differences in the expression of UPR target genes after exposure to interferon-gamma or concanavalin A, which resulted in minimal HLA-B27 up-regulation. CONCLUSION: These results suggest that HLA-B27-associated activation of the UPR in macrophages is attributable to the accumulation of misfolded heavy chains, and that certain cell types may be more susceptible to the effects of HLA-B27 misfolding. Strategies that eliminate HLA-B27 up-regulation and/or the accumulation of misfolded heavy chains may be useful in evaluating the role of these events in the pathogenesis of SpA.

Animals↗

PubMedDate not supplied

In vivo evidence suggesting a role for purine-catabolizing enzymes in the pathogenesis of cisplatin-induced nephrotoxicity in rats and effect of erdosteine against this toxicity.

The aim of this experimental study was to investigate the possible role of adenosine deaminase (AD) and xanthine oxidase (XO) in the pathogenesis of cisplatin-induced nephrotoxicity and the effect of erdosteine in decreasing the toxicity. The intraperitoneal injection of cisplatin (7 mg kg(-1) body weight) induced a significant increase in plasma creatinine level and blood urea nitrogen (BUN), and plasma and damaged renal tissue activities of AD and XO in rats. Co-treatment with erdosteine (10 mg kg(-1)day(-1)) attenuated the increase in the plasma creatinine and BUN levels, and significantly prevented the increase in tissue and plasma AD and XO activities (P<0.05). The results of this study revealed that XO and AD may play an important role in the pathogenesis of cisplatin-induced nephrotoxicity. The potent free radical scavenger erdosteine may have protective potential in this process and it will become a promising drug in the prevention of this undesired side-effect of cisplatin, but further studies are needed to illuminate the exact protection mechanism of erdosteine against cisplatin-induced nephrotoxicity.

Acute Kidney Injury↗